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Sample records for sublingual monomeric allergoid

  1. Early cytokine modulation after the rapid induction phase of sublingual immunotherapy with mite monomeric allergoids.

    Science.gov (United States)

    Di Gioacchino, M; Perrone, A; Petrarca, C; Di Claudio, F; Mistrello, G; Falagiani, P; Dadorante, V; Verna, N; Braga, M; Ballone, E; Cavallucci, E

    2008-01-01

    The influence of different treatment schedules of sublingual immunotherapy (SLIT) in activating IL-10-producing T-cells, crucial in inducing allergen-specific tolerance, is not completely understood. The present work was designed to evaluate allergen driven interleukin release by mononuclear cells in the early phase of SLIT, after application of different induction schemes. Twenty mite-allergic patients were enrolled, 10 (group A) treated with a traditional 98 day induction scheme and 10 (group B) with a 16 day scheme with monomeric allergoid vaccine. At the end of the induction phase, the cumulative doses taken by group A and group B patients were equivalent to 50.5 and 50.3 microg of mite group 1 allergens, respectively. The release of Th1-, Th2- and Treg-related interleukins was assessed in culture supernatants of 5 microg/ml Der-p1-stimulated mononuclear cells, isolated before and after the induction phases. No relevant treatment-related side effects were observed. Interleukin release was similar in the two groups at the enrolment. Non-stimulated and Der p 1 stimulated release of studied cytokines was similar in the two groups at enrolment. Der p 1 stimulation significantly increased IL-10 release (pallergoids are utilized.

  2. A 12-week DBPC dose-finding study with sublingual monomeric allergoid tablets in house dust mite-allergic patients.

    Science.gov (United States)

    Hüser, C; Dieterich, P; Singh, J; Shah-Hosseini, K; Allekotte, S; Lehmacher, W; Compalati, E; Mösges, R

    2017-01-01

    In sublingual immunotherapy, optimal doses are a key factor for therapeutic outcomes. The aim of this study with tablets containing carbamylated monomeric house dust mite allergoids was to determine the most effective and safe dose. In this double-blind, placebo-controlled dose-finding study, 131 patients with house dust mite-induced allergic rhinoconjunctivitis were randomized to 12-week treatments with 300 UA/day, 1000 UA/day, 2000 UA/day, 3000 UA/day or placebo. Conjunctival provocation tests (CPT) were performed before, during and after treatment. The change in mean allergic severity (primary endpoint), calculated from the severity of the CPT reaction, and the proportion of patients with an improved CPT threshold (secondary endpoint) determined the treatment effect. The mean allergic severity decreased in all groups, including the placebo group. It was lower in all active treatment groups (300 UA/day: 0.14, 1000 UA/day: 0.15, 2000 UA/day: 0.10, 3000 UA/day: 0.15) than in the placebo group (0.30). However, this difference was not statistically significant (P allergoid sublingual tablets is well tolerated and reduces the CPT reaction in house dust mite-allergic patients. © 2016 The Authors. Allergy Published by John Wiley & Sons Ltd.

  3. Carbamylated monomeric allergoids as a therapeutic option for sublingual immunotherapy of dust mite- and grass pollen-induced allergic rhinoconjunctivitis: a systematic review of published trials with a meta-analysis of treatment using Lais® tablets.

    Science.gov (United States)

    Mösges, R; Ritter, B; Kayoko, G; Allekotte, S

    2010-10-01

    Lais® allergoid tablets contain allergens that are modified by carbamylation. Due to their modified chemical structure, they are suitable for sublingual immunotherapy (SLIT) (13, 16, 17, 24). Based on their small molecule size of 12 to 40 kDa, they can be easily absorbed via the oral mucosa (1). In this review, we studied the efficacy of SLIT with carbamylated monomeric allergoid tablets in the treatment of grass pollen- and dust mite-induced allergic rhinoconjunctivitis on the basis of symptom and medication score improvements. Following a selective internet and databank search, six trials-some placebo-controlled-regarding the treatment of grass pollen- (n = 266) and dust mite-induced (n = 241) allergic rhinoconjunctivitis were used to draw conclusions regarding the clinical efficacy of allergoid tablets. The primary endpoints in these trials were decreases in the need for allergy medications and/or reductions in the occurrence of rhinoconjunctivitis symptoms. Data was recorded from patient diaries regarding their symptoms and medications used and conclusions were then drawn about the effectiveness and tolerabieity of Lais® tablets. The average improvement in symptom score in three trials of grass pollen allergy treatment was 34% in comparison to the placebo group. The treatment of dust mite-induced rhinoconjunctivitis produced an average symptom score improvement of 22% compared to the placebo or control groups. The intake of symptomatic rescue medication during allergoid tablet therapy declined. Treatment of grass pollen allergies and dust mite-induced rhinoconjunctivitis showed an average medication score improvement of 49% and 24%, respectively. Few side effects were documented in the trials and predominantly local effects were observed. Severe systemic side effects did not occur. On the basis of the trial results summarized in this review, we suggest that SLIT using Lais® sublingual tablets is an effective and well-tolerated form of treatment.

  4. 11 Efficacy and Tolerability of HDM Injective Immunotherapy With Monomeric Allergoid

    Science.gov (United States)

    Compalati, Enrico; Atzeni, Isabella; Cabras, Sergio; Fancello, Paolo; Gaspardini, Giulio; Longo, Rocco; Patella, Vincenzo; Tore, Giorgio

    2012-01-01

    Background Subcutaneous immunotherapy (SCIT) is an effective treatment of respiratory allergy and carbamylated monomeric allergoids (monoids), by virtue of their reduced IgE-binding activity, resulted clinically safe by sublingual administration. Purpose of this study was to investigate the efficacy and tolerability of immunotherapy with house dust mites (HDM) monoid administered by injective route in patients with allergic rhinoconjunctivitis (AR). Methods A preparation of 0.70 mL of 10 BU/mL containing modified extract with 50% Dermatophagoides pteronyssinus and 50% Dermatophagoides farinae (amount of major allergen: 4 μg of group 1 per milliliter) was delivered monthly for 12 months, following a 5-week build-up induction phase (0.10–0.20–0.30–0.50–0.70 mL), to 58 patients (60% males, mean age 25.1 ± 12.7) suffering from AR due to mites for at least 2 years, whereas 60 patients with similar baseline characteristics were observed as controls. All patients were allowed to assume traditional drug therapy for their condition. At the end of the study changes from baseline in symptoms scores, in number of days with drug assumption, in severity of AR (according to ARIA classification) were compared between the 2 groups; moreover an overall assessment of clinical efficacy and tolerability was based on patients' and physicians' judgements (unsatisfactory, mild, good, optimal). Results In respect to baseline both groups showed, after 1 year, an improvement in symptoms score (P allergoid was associated with a significant clinical benefit observed through objective and subjective outcomes; the traditional safety of monomeric allergoids was confirmed by the subjective judgements of tolerability.

  5. Monoid sublingual immunotherapy.

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    Palma-Carlos, A G; Santos, A S; Branco-Ferreira, M; Pregal, A L; Palma-Carlos, M L

    2006-03-01

    Sublingual monoid immunotherapy with monomeric allergoids has been largely used in Europe in the last few years. An open trial of allergoid in tablets has been done in rhinitic patients allergic to house dust mites, grass pollens and Parietaria with clear improvement in clinics and drug consumption scores. In a second phase a double blind placebo controlled trial of grass pollens allergoids have been done in hay fever patients with significant decrease on the scores of rhinorrea, sneezing and conjunctivitis nasal steroid consumption and clinical score after serial nasal challenges. Monomeric allergoids are an efficace and safe immunotherapy in allergic rhinitis.

  6. Dose-finding study of carbamylated monomeric allergoid tablets in grass-allergic rhinoconjunctivitis patients.

    Science.gov (United States)

    Mösges, Ralph; Rohdenburg, Christina; Eichel, Andrea; Zadoyan, Gregor; Kasche, Elena-Manja; Shah-Hosseini, Kija; Lehmacher, Walter; Schmalz, Petra; Compalati, Enrico

    2017-11-01

    To determine the optimal effective and safe dose of sublingual immunotherapy tablets containing carbamylated monomeric allergoids in patients with grass pollen-induced allergic rhinoconjunctivitis. In this prospective, randomized, double-blind, active-controlled, multicenter, Phase II study, four different daily doses were applied preseasonally for 12 weeks. Of 158 randomized adults, 155 subjects (safety population) received 300 units of allergy (UA)/day (n = 36), 600 UA/day (n = 43), 1000 UA/day (n = 39), or 2000 UA/day (n = 37). After treatment, 54.3, 47.6, 59.0 and 51.4% of patients, respectively, ceased to react to the highest allergen concentration in a conjunctival provocation test. Furthermore, the response threshold improved in 70.4, 62.9, 76.7 and 66.7% of patients, respectively. No serious adverse events occurred. This study found 1000 UA/day to be the optimal effective and safe dose.

  7. Oral myeloid cells uptake allergoids coupled to mannan driving Th1/Treg responses upon sublingual delivery in mice.

    Science.gov (United States)

    Soria, I; López-Relaño, J; Viñuela, M; Tudela, J-I; Angelina, A; Benito-Villalvilla, C; Díez-Rivero, C M; Cases, B; Manzano, A I; Fernández-Caldas, E; Casanovas, M; Palomares, O; Subiza, J L

    2018-04-01

    Polymerized allergoids coupled to nonoxidized mannan (PM-allergoids) may represent novel vaccines targeting dendritic cells (DCs). PM-allergoids are better captured by DCs than native allergens and favor Th1/Treg cell responses upon subcutaneous injection. Herein we have studied in mice the in vivo immunogenicity of PM-allergoids administered sublingually in comparison with native allergens. Three immunization protocols (4-8 weeks long) were used in Balb/c mice. Serum antibody levels were tested by ELISA. Cell responses (proliferation, cytokines, and Tregs) were assayed by flow cytometry in spleen and lymph nodes (LNs). Allergen uptake was measured by flow cytometry in myeloid sublingual cells. A quick antibody response and higher IgG2a/IgE ratio were observed with PM-allergoids. Moreover, stronger specific proliferative responses were seen in both submandibular LNs and spleen cells assayed in vitro. This was accompanied by a higher IFNγ/IL-4 ratio with a quick IL-10 production by submandibular LN cells. An increase in CD4 + CD25 high FOXP3 + Treg cells was detected in LNs and spleen of mice treated with PM-allergoids. These allergoids were better captured than native allergens by antigen-presenting (CD45 + MHC-II + ) cells obtained from the sublingual mucosa, including DCs (CD11b + ) and macrophages (CD64 + ). Importantly, all the differential effects induced by PM-allergoids were abolished when using oxidized instead of nonoxidized PM-allergoids. Our results demonstrate for the first time that PM-allergoids administered through the sublingual route promote the generation of Th1 and FOXP3 + Treg cells in a greater extent than native allergens by mechanisms that might well involve their better uptake by oral antigen-presenting cells. © 2018 The Authors. Allergy Published by John Wiley & Sons Ltd.

  8. Allergen-Specific Immunotherapy with Monomeric Allergoid in a Mouse Model of Atopic Dermatitis

    Science.gov (United States)

    Babakhin, Alexander; Andreev, Sergey; Nikonova, Alexandra; Shilovsky, Igor; Buzuk, Andrey; Elisyutina, Olga; Fedenko, Elena; Khaitov, Musa

    2015-01-01

    Atopic dermatitis (AD) is a widespread and difficult to treat allergic skin disease and is a tough challenge for healthcare. In this study, we investigated whether allergen-specific immunotherapy (ASIT) with a monomeric allergoid obtained by succinylation of ovalbumin (sOVA) is effective in a mouse model of atopic dermatitis. An experimental model of AD was reproduced by epicutaneous sensitization with ovalbumin (OVA). ASIT was performed with subcutaneous (SC) administration of increasing doses of OVA or sOVA. The levels of anti-OVA antibodies, as well as cytokines, were detected by ELISA. Skin samples from patch areas were taken for histologic examination. ASIT with either OVA or sOVA resulted in a reduction of both the anti-OVA IgE level and the IgG1/IgG2a ratio. Moreover, ASIT with sOVA increased the IFN-γ level in supernatants after splenocyte stimulation with OVA. Histologic analysis of skin samples from the sites of allergen application showed that ASIT improved the histologic picture by decreasing allergic inflammation in comparison with untreated mice. These data suggest that ASIT with a succinylated allergen represents promising approach for the treatment of AD. PMID:26275152

  9. A review of allergoid immunotherapy: is cat allergy a suitable target?

    Science.gov (United States)

    Nguyen, Nhung T; Raskopf, Esther; Shah-Hosseini, Kija; Zadoyan, Gregor; Mösges, Ralph

    2016-01-01

    To modify the course of allergy, different types of specific allergen immunotherapy have been developed such as sublingual immunotherapy and subcutaneous immunotherapy with native allergens or subcutaneous immunotherapy with polymerized allergoids. However, the optimal specific immunotherapy, especially for cat allergy, remains undetermined. Few studies investigating immunotherapy in cat allergy have been published, and the risk of serious adverse reactions and systemic reactions has often been an important issue. Monomeric allergoids have lower allergenic potential while their immunogenicity remains constant, resulting in excellent safety with notable efficacy. Specific immunotherapy with monomeric allergoids could, therefore, be of high value, especially in cat allergy as well as other types of allergy, and bring relief to a great community of patients.

  10. Allergoids for allergy treatment.

    Science.gov (United States)

    Carnes, Jeronimo; Gallego, Maria T; Moya, Raquel; Iraola, Victor

    2018-02-21

    Background Chemically modified allergen extracts, known as allergoids, are commonly used for treating allergic patients. In general terms, the concept of allergoids implies allergen extracts with a reduction of their allergenicity maintaining their immunogenicity. Different methods to obtain allergoids have been developed in the past years, opening attractive lines of research. Objective To review the different approaches to allergoid development as well as their characterization, mechanism of action and efficacy and safety issues. Methods A revision and analysis of the different types of allergoids has been performed, with special attention to patents submitted and granted in the last years. Additionally, updated information about the mechanism of action and clinical evidence and safety of allergoids has been discussed. Results Principally, allergoids are obtained by the polymerization of native allergen extracts with aldehydes, including formaldehyde or glutaraldehyde. However, recent patents and publications about different chemical modifications have been presented, as well as about the use of new adjuvants with allergoids. Regarding the characterization, allergoids require more sophisticated analytical methods than native extracts, as a consequence of their properties and characteristics. Conclusion In the last years, the partial understanding of the mechanism of action and the generation of clinical evidence of different types of allergoids, linked to their excellent safety profile and their convenience for a quick build up phase, have made of allergoids an excellent product for allergy treatment. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  11. Effect of two doses of carbamylated allergoid extract of dust mite on nasal reactivity.

    Science.gov (United States)

    Scalone, G; Compalati, E; Bruno, M E; Mistrello, G

    2013-11-01

    Background and Objective. Single SLIT studies with native allergen extracts support a dose-response effect for clinical and immunological outcomes. Conversely for carbamylated allergoids this dose-response effects is less evident, likely because the threshold for efficacy is more easily reached through the enhanced bioavailability of the extract consequent to the selective chemical modification. Thus this pilot study investigates the dose-response effect on nasal specific reactivity and safety of two unusual doses of carbamylated allergoid in patients mono-sensitized to house dust mites. Methods. A prospective open randomized study involved 6-65 year-old Italian patients with clinically relevant sensitization to house dust mites and positive response to nasal provocation challenge. Monomeric carbamylated allergoid was delivered once daily at the dose of 1000 AU or 2000 AU from June to September 2009, during the lowest level of mites exposure. Primary outcomes were the change of the threshold of allergen concentration for a positive nasal provocation test (NPT) before and after the treatment and the product safety. Secondary outcome was the change  in the mean percentage fall of peak nasal inspiratory flow (PNIF) following nasal challenge. Results. Thirty-four patients were enrolled. Fifteen in group 1 and 14 in group 2 concluded the study. After 12 weeks all patients treated in group 1 and all but one in group 2 showed an increase in the threshold dose provoking a positive NPT. Those with no symptoms onset with the highest dose delivered were 80% in group 1 and 78.6% in group 2 (p=0.92). From first to second challenge, the mean percentage fall of PNIF  was reduced with no statistical difference between groups (p=0.95), and with no difference between the final mean percentage falls (p=0.65). No serious adverse reactions occurred and the frequency of events, all mild, was similar in the two groups. Conclusions. Twelve weeks of carbamylated sublingual allergoid

  12. Characterization of allergoids.

    Science.gov (United States)

    Himly, Martin; Carnés, Jerónimo; Fernández-Caldas, Enrique; Briza, Peter; Ferreira, Fatima

    2009-01-01

    So far it has not been possible to measure the amount of major allergens in the complexes after chemical modification. Furthermore, the presence of minor allergens remained obscure, unless antibodies were successfully generated by animal immunization with allergoids and shown to be reactive with purified natural or recombinant allergens in immunological assays. Thus, we adapted and employed a set of physicochemical methods with the aim of elucidating the molecular size and allergen composition of allergoids. Using online-HPSEC light scattering and DLS, it was shown that two thirds of depigmented allergoid prepared from birch pollen extracts adopted a MW between 1000 and 2000 kDa. The question of reproducibility of the polymerization reaction was addressed by investigating four batches of P. pratense allergoid. Three out of the four batches contained 73 to 77% of polymerized molecules in the above-mentioned range of molecular sizes. One batch showed a significantly higher content of molecules with a MW exceeding 2 MDa. Analysis of allergen composition in B. alba allergoids revealed the presence of all relevant Bet v 1 isoforms and minor allergens except for Bet v 3 and Bet v 4, which was in good agreement with the allergens detected in the native extracts. It should be noted that Bet v 3 has not been detected at the protein level before. Similarly, good agreement in allergen composition between allergoid and native extract was also found for D. pteronyssinus. Presently, the European Directorate for Quality of Medicines and Healthcare (EDQM) is committed to the application of the 3R principles (i. e. replace, reduce, refine the use of animals) for the quality control of medicines wherever possible. This is reflected by the regular review of the monographs of the European Pharmacopoeia and the introduction of alternative tests. For instance, recently it was decided to replace the rabbit pyrogen test by an in vitro test. Furthermore, through the Biological

  13. Sublingual Immunotherapy: Recent Advances

    Directory of Open Access Journals (Sweden)

    Enrico Compalati

    2013-01-01

    Full Text Available The practice of administering sublingual immunotherapy for respiratory allergy is gaining more and more diffusion worldwide as a consequence of the robust demonstration of clinical efficacy and safety provided by recent high-powered and well-designed studies, confirming for individual seasonal allergens the results of previous metanalyses in adult and pediatric populations. Preliminary evidence derives from recent rigorous trials on perennial allergens, like house dust mites, and specifically designed studies addressed the benefits on asthma. Emerging research suggests that SLIT may have a future role in other allergic conditions such as atopic dermatitis, food, latex and venom allergy. Efforts to develop a safer and more effective SLIT for inhalant allergens have led to the development of allergoids, recombinant allergens and formulations with adjuvants and substances targeting antigens to dendritic cells that possess a crucial role in initiating immune responses. The high degree of variation in the evaluation of clinical effects and immunological changes requires further studies to identify the candidate patients to SLIT and biomarkers of short and long term efficacy. Appropriate management strategies are urgently needed to overcome the barriers to SLIT compliance.

  14. [Specific immunotherapy with depigmented allergoids].

    Science.gov (United States)

    Klimek, L; Thorn, C; Pfaar, O

    2010-01-01

    Specific immunotherapy is the only available causative treatment for IgE-mediated allergic conditions. The state of the art is treatment via the subcutaneous route with crude extracts in a water solution, with physically linked (semidepot) extracts or chemically modified semidepot extracts (allergoids). A relatively new purification method combines depigmentation followed by polymerization with glutaraldehyde. This modification results in increased tolerance with a reduction in both local and systemic adverse effects. As controlled clinical trials have shown, the effectiveness is comparable to that of specific immunotherapy with crude allergen extracts. Recent data suggest that the modified polymerized allergoids allow a safe rush titration in a few days or even in 1 day (ultra-rush titration).

  15. [A comparative immunochemical analysis of allergoids and allergens].

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    Fradkin, V A; Tsvetkov, N V; Diakiv, V V; Lavrenchik, E I

    1992-01-01

    In comparison with allergens having protein fragments with a molecular weight not exceeding 110 kD, allergoids have been found to consist of larger fragments with a molecular weight of 10-150 kD. Allergoids have less charged components than initial allergens and less antigenic components. Allergoids retain their capacity for stimulating the production of antibodies, specific to all antigenic components.

  16. Health economic comparison of SLIT allergen and SCIT allergoid immunotherapy in patients with seasonal grass-allergic rhinoconjunctivitis in Germany.

    Science.gov (United States)

    Verheggen, Bram G; Westerhout, Kirsten Y; Schreder, Carl H; Augustin, Matthias

    2015-01-01

    Allergoids are chemically modified allergen extracts administered to reduce allergenicity and to maintain immunogenicity. Oralair® (the 5-grass tablet) is a sublingual native grass allergen tablet for pre- and co-seasonal treatment. Based on a literature review, meta-analysis, and cost-effectiveness analysis the relative effects and costs of the 5-grass tablet versus a mix of subcutaneous allergoid compounds for grass pollen allergic rhinoconjunctivitis were assessed. A Markov model with a time horizon of nine years was used to assess the costs and effects of three-year immunotherapy treatment. Relative efficacy expressed as standardized mean differences was estimated using an indirect comparison on symptom scores extracted from available clinical trials. The Rhinitis Symptom Utility Index (RSUI) was applied as a proxy to estimate utility values for symptom scores. Drug acquisition and other medical costs were derived from published sources as well as estimates for resource use, immunotherapy persistence, and occurrence of asthma. The analysis was executed from the German payer's perspective, which includes payments of the Statutory Health Insurance (SHI) and additional payments by insurants. Comprehensive deterministic and probabilistic sensitivity analyses and different scenarios were performed to test the uncertainty concerning the incremental model outcomes. The applied model predicted a cost-utility ratio of the 5-grass tablet versus a market mix of injectable allergoid products of € 12,593 per QALY in the base case analysis. Predicted incremental costs and QALYs were € 458 (95% confidence interval, CI: € 220; € 739) and 0.036 (95% CI: 0.002; 0.078), respectively. Compared to the allergoid mix the probability of the 5-grass tablet being the most cost-effective treatment option was predicted to be 76% at a willingness-to-pay threshold of € 20,000. The results were most sensitive to changes in efficacy estimates, duration of the pollen season, and

  17. Frequency of booster injections of allergoids.

    Science.gov (United States)

    Norman, P S; Creticos, P S; Marsh, D G

    1990-01-01

    In 1982, 43 ragweed-sensitive patients receiving maintenance injections of full doses of ragweed allergoid were selected for a study of the immunologic and clinical efficacy of booster injections only four times a year. These patients had participated for 2 to 7 years as part of a trial of mixes of up to four allergoids to common pollens in the mid-Atlantic area tailored to each patient's skin test sensitivity. They were divided into a group (21 patients) to receive injections every 3 months and a group (22 patients) to receive injections about every 6 weeks (eight injections per year). Patients were rerandomized after 1 year so that half of each original group switched to the alternate treatment, and this program was continued until after the ragweed season of 1985. Thirty-four patients were still under study the last year. Doses, per injection, were 100 allergoid units (1 allergoid unit equals 100 PNU) of each allergen in the mixture. Symptom scores during the 8 weeks of each of the four ragweed seasons were not significantly higher in the 3-month treated group. IgG antibody levels to Amb a I (antigen E) were followed until early 1984 and were not significantly different in the two groups, even though the 6-week treated patients received a two times higher cumulative dose per year. Rates of local and systemic reactions (percent of injections eliciting reactions) were not different in the groups, which means that the 3-month treated group had about half as many reactions by virtue of taking half as many injections.(ABSTRACT TRUNCATED AT 250 WORDS)

  18. Characterization of allergoids from ovalbumin in vitro and in vivo.

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    Salgado, J; Casadevall, G; Puigneró, V; Queralt, J

    1996-01-01

    Several in vivo and in vitro methods for monitoring immunological properties of two allergoids obtained by formaldehyde treatment of ovalbumin (OA) were developed. The calculated molecular weight of allergoids was 80 kD (OA-F1) and 165 kD (OA-F2), respectively. The allergenic activity in vitro of allergoids in mast-cell histamine release assay was 1000 times lower than of OA. Both allergoids showed reduced ability to induce passive cutaneous anaphylaxis in the Sprague-Dawley rats or systemic anaphylaxis in Dunkin-Harley guinea-pigs. The ability of OA and allergoids to bind to the OA-specific IgE antibodies was measured in vivo by the inhibition of passive cutaneous anaphylaxis (PCA-inhibition). Allergoid binding to IgE was 51-66% lower than the native allergen. Moreover, the avidity of OA-specific IgG antibodies, measured by ELISA-inhibition, for allergoids and allergen was of the same order. Allergoids induced a different pattern of humoral immune response from that, induced by the native allergen. Thus, after immunization of BALB/c mouse, both allergoids induced a higher production of IgG and a lower production of IgE than OA, only OA-F2 induced a lower production of IgG1. The differences in the IgA response to the immunogens was not significant. Delayed hypersensitivity studies in the BALB/c mouse showed that allergoids were 5- to 12-times less effective in inducing a cell-mediated immune response than OA. The present study provides a battery of immunological methods for preclinical testing of modified allergens.

  19. Sublingual allergen immunotherapy

    DEFF Research Database (Denmark)

    Calderón, M A; Simons, F E R; Malling, Hans-Jørgen

    2012-01-01

    To cite this article: Calderón MA, Simons FER, Malling H-J, Lockey RF, Moingeon P, Demoly P. Sublingual allergen immunotherapy: mode of action and its relationship with the safety profile. Allergy 2012; 67: 302-311. ABSTRACT: Allergen immunotherapy reorients inappropriate immune responses......-presenting cells (mostly Langerhans and myeloid dendritic cells) exhibit a tolerogenic phenotype, despite constant exposure to danger signals from food and microbes. This reduces the induction of pro-inflammatory immune responses leading to systemic allergic reactions. Oral tissues contain relatively few mast...... cells and eosinophils (mostly located in submucosal areas) and, in comparison with subcutaneous tissue, are less likely to give rise to anaphylactic reactions. SLIT-associated immune responses include the induction of circulating, allergen-specific Th1 and regulatory CD4+ T cells, leading to clinical...

  20. Dose-response relationship of a new Timothy grass pollen allergoid in comparison with a 6-grass pollen allergoid.

    Science.gov (United States)

    Pfaar, O; Hohlfeld, J M; Al-Kadah, B; Hauswald, B; Homey, B; Hunzelmann, N; Schliemann, S; Velling, P; Worm, M; Klimek, L

    2017-11-01

    Subcutaneous allergen immunotherapy with grass pollen allergoids has been proven to be effective and safe in the treatment of patients with allergic rhinoconjunctivitis. Based on the extensive cross-reactivity among Pooideae species, it has been suggested that grass pollen extracts could be prepared from a single species, rather than from a multiple species mixture. To find the optimal dose of a Phleum pratense (P. pratense) allergoid preparation and compare its efficacy and safety to a 6-grass pollen allergoid preparation. In this double-blind, placebo-controlled study (EudraCT: 2011-000674-58), three doses of P. pratense allergoid (1800 therapeutic units (TU), standard-dose 6000 TU and 18 000 TU) were compared with placebo and the marketed 6-grass pollen allergoid (6000 TU). In a pre-seasonal dosing regimen, 102 patients were randomized to five treatment groups and received nine subcutaneous injections. The primary efficacy endpoint was the change in weal size (late-phase reaction [LPR]) in response to the intracutaneous testing (ICT) before and after treatment, comparing the active allergoids to placebo. Secondary outcomes were the change in Total Nasal Symptom Score (TNSS) assessed in the allergen exposure chamber (AEC), the changes in P. pratense-serum-specific IgG 4 and the incidence of adverse events (AEs). All three doses of the P. pratense and the 6-grass pollen allergoid preparations were significantly superior to placebo for the primary outcome, whereas there were no significant differences in the change in TNSS. Compared to the standard-dose, the high-dose of P. pratense did not produce any additional significant benefit, but showed a slight increase in AEs. Yet this increase in AEs was lower than for the 6-grass pollen preparation. The standard-dose of the new P. pratense allergoid was comparable to the marketed 6-grass pollen preparation at equal dose for the parameters measured. © 2017 The Authors. Clinical & Experimental Allergy Published by John

  1. Tumors of the sublingual gland

    DEFF Research Database (Denmark)

    Andreasen, Simon; Bjørndal, K; Agander, T K

    2016-01-01

    Tumors of the salivary glands are a heterogeneous group of diseases most often originating in the major salivary glands. Only a minor proportion of mainly malignant tumors arise in the sublingual gland. Due to the rarity of sublingual gland tumors (SGTs), little is known about the clinicopathologic...... are malignant, most frequently ACC with a high rate of metastatic spread. The diagnostic value of FNAC in SGTs seems inferior to what is found for other major salivary glands. DSS is determined by stage and T-stage and not by histopathological parameters. International collaboration is warranted to confirm...

  2. Buccal and sublingual vaccine delivery.

    Science.gov (United States)

    Kraan, Heleen; Vrieling, Hilde; Czerkinsky, Cecil; Jiskoot, Wim; Kersten, Gideon; Amorij, Jean-Pierre

    2014-09-28

    Because of their large surface area and immunological competence, mucosal tissues are attractive administration and target sites for vaccination. An important characteristic of mucosal vaccination is its ability to elicit local immune responses, which act against infection at the site of pathogen entry. However, mucosal surfaces are endowed with potent and sophisticated tolerance mechanisms to prevent the immune system from overreacting to the many environmental antigens. Hence, mucosal vaccination may suppress the immune system instead of induce a protective immune response. Therefore, mucosal adjuvants and/or special antigen delivery systems as well as appropriate dosage forms are required in order to develop potent mucosal vaccines. Whereas oral, nasal and pulmonary vaccine delivery strategies have been described extensively, the sublingual and buccal routes have received considerably less attention. In this review, the characteristics of and approaches for sublingual and buccal vaccine delivery are described and compared with other mucosal vaccine delivery sites. We discuss recent progress and highlight promising developments in the search for vaccine formulations, including adjuvants and suitable dosage forms, which are likely critical for designing a successful sublingual or buccal vaccine. Finally, we outline the challenges, hurdles to overcome and formulation issues relevant for sublingual or buccal vaccine delivery. Copyright © 2014. Published by Elsevier B.V.

  3. Studies on `allergoids' prepared from naturally occurring allergens

    Science.gov (United States)

    Marsh, D. G.; Lichtenstein, L. M.; Campbell, D. H.

    1970-01-01

    The highly purified major allergenic component of rye grass pollen (Group I) was used to investigate the possibility of destroying selectively the allergenic properties of an antigen, while largely retaining its original immunizing capacities. The allergen was treated under mild conditions with formalin alone or formalin plus a reactive low molecular weight additive. Certain derivatives (allergoids) showed well over 99 per cent reduction in allergenicity, determined by the histamine released from allergic human leucocytes in vitro, but were still able to combine with rabbit antibody against native antigen. Furthermore, the allergoids stimulated production (in guinea-pigs) of appreciable amounts of antibody able to inhibit native allergen-mediated human allergic histamine release in vitro and to cross-react with native antigen by PCA tests in normal guinea-pigs. Residual allergenicity and cross-immunogenicity (by the inhibition assay) of the different formalinized derivatives varied appreciably according to the additive used in formalinization, but the cross-reactivities of the different preparations in quantitative precipitin analysis against rabbit anti-native antigen serum were similar. The residual allergenicities of individual derivatives varied by up to 1000-fold in different cell preparations, suggesting a heterogeneity of allergenic determinants. Allergoid derivatives showed no hapten-like activity in that they were unable to inhibit allergen-mediated histamine release from leucocytes. The theoretical and practical application of allergoids is discussed, including their potential usefulness in improving the immunotheraphy of atopic humans. ImagesFIG. 2 PMID:4192674

  4. Artemisia vulgaris pollen allergoids digestibility in the simulated conditions of the gastrointestinal tract

    OpenAIRE

    RATKO M. JANKOV; NATALIJA DJ. POLOVIC; MARIJA DJ. GAVROVIC-JANKULOVIC; LIDIJA BURAZER; DANICA DJERGOVIC-PETROVIC; OLGA VUCKOVIC; OLIKA DROBNJAK; ZORICA SPORCIC; MARINA ATANASKOVIC-MARKOVIC; RATKO M. JANKOV

    2006-01-01

    Chemically modified allergens (allergoids) have found use in both traditional and novel forms of immunotherapy of allergic disorders. Novel forms of immunotherapy include local allergen delivery, via the gastrointestinal tract. This study conveys the gastrointestinal stability of three types ofmugwort pollen allergoids under simulated conditions of the gut. Allergoids of the pollen extract of Artemisia vulgaris were obtained by means of potassium cyanate, succinic and maleic anhydride. Gastro...

  5. Structural studies of novel glycoconjugates from polymerized allergens (allergoids) and mannans as allergy vaccines

    OpenAIRE

    Manzano, Ana I.; Cañada, F. Javier; Cases, Bárbara; Sirvent, Sofia; Soria-Castro, Irene; Palomares, O; Fernández-Caldas, E.; Casanovas, Miguel; Jiménez-Barbero, Jesús; Subiza, José L.

    2015-01-01

    Immunotherapy for treating IgE-mediated allergies requires high doses of the corresponding allergen. This may result in undesired side effects and, to avoid them, hypoallergenic allergens (allergoids) polymerized with glutaraldehyde are commonly used. Targeting allergoids to dendritic cells to enhance cell uptake may result in a more effective immunotherapy. Allergoids coupled to yeast mannan, as source of polymannoses, would be suitable for this purpose, since mannose-binding receptors are e...

  6. 98 Specific IGE and IGG Binding to Allergoids of Phleum pratense

    OpenAIRE

    Cases, Barbara; Fernandez-Caldas, Enrique; Tudela, Jose Ignacio; Fernandez, Eva Abel; Sanchez-Garcia, Silvia; Ibañez, M. Dolores; Escudero, Carmelo; Casanovas, Miguel

    2012-01-01

    Background Allergoids were first used in the decades of the 60s and 70s of the last century as an effective treatment of allergic respiratory diseases. Allergoids can be modified with formaldehyde or glutaraldehyde. Modified allergens, or allergoids, decrease the risk of adverse reactions while administering higher allergen doses. The objective of this study was to analyse specific IgE and IgG binding to glutaraldehyde modified and non-modified allergen extracts of Phleum pratense. Methods Th...

  7. Sublingual piroxicam in migraine without aura.

    Science.gov (United States)

    Ravishankar, K; Tayade, Himanshu; Mandlik, Rahul

    2011-08-01

    The aim of the present study was to compare the analgesic efficacy of a single dose of sublingual piroxicam to that of a placebo during acute attacks of migraine without aura. The drug (N = 30) or a placebo (N = 30) was administered, on randomisation and double-blind basis, to 60 patients between 18 and 50 years of age suffering from migraine without aura. The patients were instructed to take a single tablet sublingually [corresponding to piroxicam 40 mg or placebo] and the severity of the painful symptomatology and associated symptoms were evaluated by this study. The patients treated with sublingual piroxicam showed a significant (P piroxicam administration. In 83.3%, the drug resulted in excellent to good response as compared to only 10% in the placebo group. No local and systemic side effects were reported with sublingual piroxicam. The present study has demonstrated that for the acute management of migraine without aura sublingual piroxicam showed significant analgesic effect with excellent tolerability.

  8. Fractionation and immunological characterization of allergens and allergoids of Prosopis juliflora pollen.

    Science.gov (United States)

    Thakur, I S; Kamal; Mishra, S

    1991-06-01

    Allergoids of Prosopis juliflora pollen were prepared by formalinization of crude allergen and glycoprotein. Fractionation of crude allergen and allergoids on Sephadex G-100 resulted in separation of proteins of varying molecular size and a glycoprotein of 81 to 13 KD. Allergoids prepared from the glycoprotein fractionated into two proteins of approximately 200 KD and more than 200 KD. Crossed immunoelectrophoresis indicated 12 and gel diffusion test 3 precipitating antigens incrude allergen extract; by these tests allergoids depicted 8 and 3 precipitin bands, respectively. The precipitin analysis showed heterogeneity of allergenic determinants and also variation in cross-immunogenicity of the formalinized derivatives. The skin prick and radioallergosorbent tests depicted greater activity of fractionated crude allergens than the allergoids. The above tests suggest altered and concealed antigenic determinants as result of formalinization of P. juliflora pollen which, however, showed reduced allergenic activity relative to the native allergen.

  9. Structural studies of novel glycoconjugates from polymerized allergens (allergoids) and mannans as allergy vaccines.

    Science.gov (United States)

    Manzano, Ana I; Javier Cañada, F; Cases, Bárbara; Sirvent, Sofia; Soria, Irene; Palomares, Oscar; Fernández-Caldas, Enrique; Casanovas, Miguel; Jiménez-Barbero, Jesús; Subiza, José L

    2016-02-01

    Immunotherapy for treating IgE-mediated allergies requires high doses of the corresponding allergen. This may result in undesired side effects and, to avoid them, hypoallergenic allergens (allergoids) polymerized with glutaraldehyde are commonly used. Targeting allergoids to dendritic cells to enhance cell uptake may result in a more effective immunotherapy. Allergoids coupled to yeast mannan, as source of polymannoses, would be suitable for this purpose, since mannose-binding receptors are expressed on these cells. Conventional conjugation procedures of mannan to proteins use oxidized mannan to release reactive aldehydes able to bind to free amino groups in the protein; yet, allergoids lack these latter because their previous treatment with glutaraldehyde. The aim of this study was to obtain allergoids conjugated to mannan by an alternative approach based on just glutaraldehyde treatment, taking advantage of the mannoprotein bound to the polymannose backbone. Allergoid-mannan glycoconjugates were produced in a single step by treating with glutaraldehyde a defined mixture of allergens derived from Phleum pratense grass pollen and native mannan (non-oxidized) from Saccharomyces cerevisae. Analytical and structural studies, including 2D-DOSY and (1)H-(13)C HSQC nuclear magnetic resonance spectra, demonstrated the feasibility of such an approach. The glycoconjugates obtained were polymers of high molecular weight showing a higher stability than the native allergen or the conventional allergoid without mannan. The allergoid-mannan glycoconjugates were hypoallergenic as detected by the IgE reactivity with sera from grass allergic patients, even with lower reactivity than conventional allergoid without mannan. Thus, stable hypoallergenic allergoids conjugated to mannan suitable for using in immunotherapy can be achieved using glutaraldehyde. In contrast to mannan oxidation, the glutaraldehyde approach allows to preserve mannoses with their native geometry, which may be

  10. Comparison of allergenicity and immunogenicity of an intact allergen vaccine and commercially available allergoid products for birch pollen immunotherapy.

    Science.gov (United States)

    Lund, L; Henmar, H; Würtzen, P A; Lund, G; Hjortskov, N; Larsen, J N

    2007-04-01

    Specific immunotherapy with intact allergen vaccine is a well-documented treatment for allergic diseases. Different vaccine formulations are currently commercially available, the active ingredient either being intact allergens or chemically modified allergoids. The rationale behind allergoids is to decrease allergenicity while maintaining immunogenicity. However, data from the German health authorities based on reporting of adverse events over a 10-year period did not indicate increased safety of allergoids over intact allergens. The objective of this study was to investigate the effect of chemical modification on allergenicity and immunogenicity comparing four commercial allergoid products for birch pollen immunotherapy with an intact allergen vaccine. Solid-phase IgE inhibition and histamine release assays were selected as model systems for allergenicity, and a combination of human T cell proliferation and IgG titres following mouse immunizations were used to address the immunogenicity of the intact allergen vaccine and the four allergoids. In all assays, the products were normalized with respect to the manufacturer's recommended maintenance dose. IgE inhibition experiments showed a change in epitope composition comparing intact allergen vaccine with allergoid. One allergoid product induced enhanced histamine release compared to the intact allergens, while the other three allergoids showed reduced release. Standard T cell stimulation assays using lines from allergic patients showed a reduced response for all allergoids compared with the intact allergen vaccine regardless of the cell type used for antigen presentation. All allergoids showed reduced capacity to induce allergen-specific IgG responses in mice. While some allergoids were associated with reduced allergenicity, a clear reduction in immunogenicity was observed for all allergoid products compared with the intact allergen vaccine, and the commercial allergoids tested therefore do not fulfil the allergoid

  11. Detection of allergen composition and in vivo immunogenicity of depigmented allergoids of Betula alba.

    Science.gov (United States)

    Carnés, J; Himly, M; Gallego, M; Iraola, V; Robinson, D S; Fernández-Caldas, E; Briza, P

    2009-03-01

    Chemical modification of allergen vaccines to reduce IgE binding improves safety while maintaining clinical efficacy. However, this also complicates the characterization of allergoids using techniques as for native allergen extracts. The objective of this study was to analyse the molecular size of Betula alba depigmented allergoids, conservation of major allergens in the allergoids and in vivo antibody response to immunization. The molecular size of depigmented allergoids was evaluated by high performance-size exclusion chromatography and light scattering techniques. Protein composition was compared with native extracts by capillary liquid chromatography-tandem mass spectrometry based peptide mapping. Rabbits were immunized with depigmented allergoid of Betula pollen adsorbed onto aluminium hydroxide (Depigoid). IgG antibodies against individual allergens were determined by ELISA and immunoblot. Depigmented allergoids contained a range of high molecular weight particles, approximately 60% of which had a molecular weight of 1-3 MDa. Peptide sequencing confirmed the preservation of five isoforms of Bet v 1, as well as Bet v 2, Bet v 6 and Bet v 7. Sera from immunized rabbits showed high levels of specific IgG to rBet v 1.0101 and rBet v 2. The mean protein content was 544+/-106 microg per mg of freeze-dried material for depigmented allergoids and 434+/-71 for native extracts. They retain the capacity to induce specific IgG antibodies against individual allergens present in the native extract. These findings confirm the immunogenicity of depigmented allergoids and may explain why patients treated with these vaccines are protected against the native allergens. Analysis of molecular size and allergen content may be useful techniques for characterization and standardization of allergoid products.

  12. Tinnitus after administration of sublingual immunotherapy

    DEFF Research Database (Denmark)

    Juel, Jacob

    2017-01-01

    , for example, itching, swelling, irritation, ulceration of the oropharynx and nausea, abdominal pain, diarrhoea, and vomiting. More severe side effects are dominated by systemic and respiratory tract manifestations. RESULTS: In this clinical case, the author reports a right-sided transient tinnitus lasting...... for 48 h after administration of sublingual immunotherapy for house dust mite in allergic rhinitis. CONCLUSIONS: This case provide important insights for clinical practice, as tinnitus has not been previously reported as a side effect of sublingual immunotherapy with house dust mite allergens....

  13. Studies on allergoids from naturally occurring allergens. III. Preparation of ragweed pollen allergoids by aldehyde modification in two steps.

    Science.gov (United States)

    Marsh, D G; Norman, P S; Roebber, M; Lichtenstein, L M

    1981-12-01

    We have devised a new process for modifying heat-labile allergens, which employs a sequential "two-step" incubation at temperatures of 10 degree C and 30 degree to 32 degree C. This process was found to produce effective ragweed "allergoids" with low allergenicity and good immunogenicity, which makes them useful for the therapy of allergic humans. Modification with formaldehyde produced derivatives ("formallergoids") that were about 10-fold less allergenic in allergic humans (as measured by leukocyte histamine-release assay), and similarly or more immunogenic in guinea pigs, than glutaraldehyde-modified allergens ("glutarallergoids"). Further analysis by RAST inhibition showed that a ragweed formallergoid was sixfold less reactive than a glutarallergoid with a pool of human IgE antibodies. However, the formallergoid had retained the ability to induce a wide array of antibodies against native ragweed antigens, since rabbit anti-formallergoid serum was able to recognize at least 12 different ragweed antigens, including AgE. Gel-filtration experiments showed that both the formallergoid and glutarallergoid materials contained polymers having apparent molecular weights distributed around 260,000 and 230,000 daltons, respectively (approximate range 30,000 to 900,000 daltons). Our studies provide the immunochemical basis for the use of these allergoids in the therapy of allergic humans.

  14. 98 Specific IGE and IGG Binding to Allergoids of Phleum pratense

    Science.gov (United States)

    Cases, Barbara; Fernandez-Caldas, Enrique; Tudela, Jose Ignacio; Fernandez, Eva Abel; Sanchez-Garcia, Silvia; Ibañez, M. Dolores; Escudero, Carmelo; Casanovas, Miguel

    2012-01-01

    Background Allergoids were first used in the decades of the 60s and 70s of the last century as an effective treatment of allergic respiratory diseases. Allergoids can be modified with formaldehyde or glutaraldehyde. Modified allergens, or allergoids, decrease the risk of adverse reactions while administering higher allergen doses. The objective of this study was to analyse specific IgE and IgG binding to glutaraldehyde modified and non-modified allergen extracts of Phleum pratense. Methods The sera of 69 patients sensitized to P. pratense were tested. All these patients had signs and symptoms of rhinoconjunctivitis with, or without, asthma in May and June of 2011. All these patients had positive skin prick tests to a standardized extract of P. pratense, and other grass species. Most patients were also sensitized to olive pollen. Specific IgE and IgG binding were analysed by direct ELISA against P. pratense native (non-modified) and allergoid extracts. Relative potencies were evaluated through ELISA inhibition assays, and the protein composition of non-modified and allergoid samples was determined by Mass Spectrometry (MS/MS). Results Mean Specific IgE levels against the native extract was 16.68 ± 11.65 Units (U) and against the allergoid: 7.26 ± 8.24 U (P allergoid (P = 0.16; Mann-Whitney). Linear regression coefficients obtained between immunoglobulin reactivity against both extracts were: r2 = 0.51 for specific IgE and r2 = 0.83 for specific IgG. An important decrease in the allergenic activity, measured by inhibition ELISA, was clearly observed. The MS/MS assay revealed the presence of the mayor allergen, and some isoforms, in non-modified and allergoid extracts. Conclusions Results obtained demonstrate that the glutaraldehyde polymerization process induces an important decrease in specific IgE binding to allergoids of P. pratense while there are no significant differences in specific IgG binding. The allergenic composition of the P. pratense allergoid was

  15. T cell reactivity with allergoids: influence of the type of APC.

    Science.gov (United States)

    Kahlert, H; Grage-Griebenow, E; Stüwe, H T; Cromwell, O; Fiebig, H

    2000-08-15

    The use of allergoids for allergen-specific immunotherapy has been established for many years. The characteristic features of these chemically modified allergens are their strongly reduced IgE binding activity compared with the native form and the retained immunogenicity. T cell reactivity of chemically modified allergens is documented in animals, but in humans indirect evidence of reactivity has been concluded from the induction of allergen-specific IgG during immunotherapy. Direct evidence of T cell reactivity was obtained recently using isolated human T cells. To obtain further insight into the mechanism of action of allergoids, we compared the Ag-presenting capacity of different APC types, including DC and macrophages, generated from CD14+ precursor cells from the blood of grass pollen allergic subjects, autologous PBMC, and B cells. These APC were used in experiments together with Phl p 5-specific T cell clones under stimulation with grass pollen allergen extract, rPhl p 5b, and the respective allergoids. Using DC and macrophages, allergoids exhibited a pronounced and reproducible T cell-stimulating capacity. Responses were superior to those with PBMC, and isolated B cells failed to present allergoids. Considerable IL-12 production was observed only when using the DC for Ag presentation of both allergens and allergoids. The amount of IL-10 in supernatants was dependent on the phenotype of the respective T cell clone. High IL-10 production was associated with suppressed IL-12 production from the DC in most cases. In conclusion, the reactivity of Th cells with allergoids is dependent on the type of the APC.

  16. Adjuvant effects of aluminium hydroxide-adsorbed allergens and allergoids - differences in vivo and in vitro.

    Science.gov (United States)

    Heydenreich, B; Bellinghausen, I; Lund, L; Henmar, H; Lund, G; Adler Würtzen, P; Saloga, J

    2014-06-01

    Allergen-specific immunotherapy (SIT) is a clinically effective therapy for immunoglobulin (Ig)E-mediated allergic diseases. To reduce the risk of IgE-mediated side effects, chemically modified allergoids have been introduced. Furthermore, adsorbance of allergens to aluminium hydroxide (alum) is widely used to enhance the immune response. The mechanisms behind the adjuvant effect of alum are still not completely understood. In the present study we analysed the effects of alum-adsorbed allergens and allergoids on their immunogenicity in vitro and in vivo and their ability to activate basophils of allergic donors. Human monocyte derived dendritic cells (DC) were incubated with native Phleum pratense or Betula verrucosa allergen extract or formaldehyde- or glutaraldehyde-modified allergoids, adsorbed or unadsorbed to alum. After maturation, DC were co-cultivated with autologous CD4(+) T cells. Allergenicity was tested by leukotriene and histamine release of human basophils. Finally, in-vivo immunogenicity was analysed by IgG production of immunized mice. T cell proliferation as well as interleukin (IL)-4, IL-13, IL-10 and interferon (IFN)-γ production were strongly decreased using glutaraldehyde-modified allergoids, but did not differ between alum-adsorbed allergens or allergoids and the corresponding unadsorbed preparations. Glutaraldehyde modification also led to a decreased leukotriene and histamine release compared to native allergens, being further decreased by adsorption to alum. In vivo, immunogenicity was reduced for allergoids which could be partly restored by adsorption to alum. Our results suggest that adsorption of native allergens or modified allergoids to alum had no consistent adjuvant effect but led to a reduced allergenicity in vitro, while we observed an adjuvant effect regarding IgG production in vivo. © 2014 British Society for Immunology.

  17. [A comparative evaluation of the biological action of allergens and allergoids prepared from plant pollen by the double radial immunodiffusion method].

    Science.gov (United States)

    Lavrenchik, E I; Korytina, O L

    1989-09-01

    Antisera to allergens and allergoids prepared from timothy, orchard grass, birch and wormwood pollen have been obtained and used in the double radial immunodiffusion test. The preparations of the allergoid row have been found capable of inducing immune response in laboratory animals (rabbits). Both forms of pollen preparations, allergens and allergoids, have been shown to possess common antigenic determinants reacting with antibodies present in antisera to allergens and allergoids. The absence of identity in the ratio of manifestations of gel precipitation reactions for allergoid with respect to the initial forms of allergens of individual pollen preparation has been noted.

  18. High resolution sonography of sublingual space

    International Nuclear Information System (INIS)

    Jain, P.

    2008-01-01

    Full text: Ultrasound examination of the sublingual region is a non-invasive, safe, inexpensive and widely available procedure, unaffected by the amalgam in teeth which is a source of considerable artefact on CT and MRI images. With a little practice and good understanding of the anatomy, ultrasound can be a very helpful primary examination. If the lesion is clearly seen, no further imaging may be required.

  19. [The use of Russian allergoids for the specific immunotherapy of pollinosis].

    Science.gov (United States)

    Fradkin, V A; Roshal', N I; Goriachkina, L A; Nikonorova, M V; Astaf'eva, N G; Luss, L V; Raĭkis, V N

    1993-01-01

    For three years 128 pollinosis patients received specific immunotherapy with cereals, weed and tree pollen allergens manufactured by the Scientific and Industrial Amalgamation "Allergen" (Stavropol). For comparison, a group of 42 patients was treated with the corresponding allergens according to the commonly used treatment scheme. Patients who had earlier undergone treatment with water-saline extracts of allergens, that proved to be ineffective, formed a special group. In sensitive patients reaction to the skin test with allergoids was by half less pronounced than reaction to the skin test with allergens. In allergometric titration on the nasal mucosa, reaction to the introduction of allergoids could be registered when they were used at a 10- to 100-fold higher concentration than allergens. The course of specific immunotherapy with allergoids was found to lead to a decrease in the level of allergen-specific IgE antibodies (p > 0.05) and total IgE (p allergoids was more effective than that with water-saline extracts of allergens. The use of allergoids made it possible to prescribe specific immunotherapy to a wider circle of patients.

  20. Responses of human birch pollen allergen-reactive T cells to chemically modified allergens (allergoids).

    Science.gov (United States)

    Dormann, D; Ebner, C; Jarman, E R; Montermann, E; Kraft, D; Reske-Kunz, A B

    1998-11-01

    Allergoids are widely used in specific immunotherapy for the treatment of IgE-mediated allergic diseases. The aim of this study was to analyse whether a modification of birch pollen allergens with formaldehyde affects the availability of T-cell epitopes. Efficient modification of the allergens was verified by determining IgE and IgG binding activity using ELISA inhibition tests. T-cell responses to birch pollen allergoids were analysed in polyclonal systems, using peripheral blood mononuclear cells (PBMC) of five birch pollen-allergic individuals, as well as birch pollen extract-reactive T-cell lines (TCL), established from the peripheral blood of 14 birch pollen-allergic donors. To determine whether the modification of natural (n)Bet v 1 with formaldehyde or maleic anhydride results in epitope-specific changes in T-cell reactivities, 22 Bet v 1-specific T-cell clones (TCC), established from nine additional birch pollen-allergic individuals, were tested for their reactivity with these products. The majority of PBMC and TCL showed a reduced response to the birch pollen extract allergoid. Bet v 1-specific TCC could be divided into allergoid-reactive and -non-reactive TCC. No simple correlation between possible modification sites of formaldehyde in the respective T-cell epitopes and the stimulatory potential of the allergoid was observed. Mechanisms of suppression or of anergy induction were excluded as an explanation for the non-reactivity of representative TCC. All TCC could be stimulated by maleylated and unmodified nBet v 1 to a similar extent. These results demonstrate differences in the availability of T-cell epitopes between allergoids and unmodified allergens, which are most likely due to structural changes within the allergen molecule.

  1. Physicochemical and immunologic characterization of low-molecular-weight allergoids of Dactylis glomerata pollen proteins.

    Science.gov (United States)

    Cirković, T D; Bukilica, M N; Gavrović, M D; Vujcić, Z M; Petrović, S; Jankov, R M

    1999-02-01

    Orchard grass (Dactylis glomerata) pollen proteins were chemically modified by means of acid anhydrides (maleic and succinic anhydride) to obtain low-molecular-weight allergoids. Chemical modification in both cases led to the replacement of one positive charge (epsilon amino group of Lys) by one negative charge, yielding proteins with changed physicochemical properties in comparison to the native orchard grass-pollen proteins. Physicochemical characterization of derivatives was done by gel chromatography, SDS-PAGE, and isoelectric focusing. To examine the IgE-binding properties of these derivatives, we carried out immunoblotting. To examine the ability of derivatives to induce IgG production, we immunized rabbits. Skin prick testing with the allergoids was performed on 15 individuals allergic to orchard grass pollens and on two healthy subjects. It was shown that the modified proteins retain their original molecular weights, but change pI to more acidic values. In the case of allergoids, a strong reduction in IgE binding was found. Immunization of rabbits with allergoids showed that the derivatives retain the ability to induce IgG production, and that the antisera obtained in such a way react to native (unmodified) extract. The ability of derivatives to induce allergic reaction was significantly reduced. The patients (86.6%) included in our study exhibited less than 50% of native extract response. Among them, 53.3% had no response to one or both allergoids. These modification procedures yield allergoids with a reduced allergenic activity and preserved immunogenic potential suitable for use in immunotherapy.

  2. Allergenicity, immunogenicity and dose-relationship of three intact allergen vaccines and four allergoid vaccines for subcutaneous grass pollen immunotherapy.

    Science.gov (United States)

    Henmar, H; Lund, G; Lund, L; Petersen, A; Würtzen, P A

    2008-09-01

    Different vaccines containing intact allergens or chemically modified allergoids as active ingredients are commercially available for specific immunotherapy. Allergoids are claimed to have decreased allergenicity without loss of immunogenicity and this is stated to allow administration of high allergoid doses. We compared the allergenicity and immunogenicity of four commercially available chemically modified grass pollen allergoid products with three commercially available intact grass pollen allergen vaccines. The allergenicity was investigated with immunoglobulin (Ig)E-inhibition and basophil activation assays. Human T cell proliferation and specific IgG-titres following mouse immunizations were used to address immunogenicity. Furthermore, intact allergen vaccines with different contents of active ingredients were selected to study the influence of the allergen dose. In general, a lower allergenicity for allergen vaccines was clearly linked to a reduced immunogenicity. Compared with the vaccine with the highest amount of intact allergen, the allergoids caused reduced basophil activation as well as diminished immunogenicity demonstrated by reduced T cell activation and/or reduced induction of murine grass-specific IgG antibodies. Interestingly, intact allergen vaccines with lower content of active ingredient exhibited similarly reduced allergenicity, while immunogenicity was still higher or equal to that of allergoids. The low allergenicity observed for some allergoids was inherently linked to a significantly lower immunogenic response questioning the rationale behind the chemical modification into allergoids. In addition, the linkage between allergenicity, immunogenicity and dose found for intact allergen vaccines and the immunogen as well as allergenic immune responses observed for allergoids suggest that the modified allergen vaccines do not contain high doses of immunologically active ingredients.

  3. Quality requirements for allergen extracts and allergoids for allergen immunotherapy.

    Science.gov (United States)

    Zimmer, J; Bonertz, A; Vieths, S

    2017-12-01

    All allergen products for allergen immunotherapy currently marketed in the European Union are pharmaceutical preparations derived from allergen-containing source materials like pollens, mites and moulds. Especially this natural origin results in particular demands for the regulatory requirements governing allergen products. Furthermore, the development of regulatory requirements is complicated by the so far missing universal link between certain quality parameters, in particular biological potency, on the one hand and clinical efficacy on the other hand. As a consequence, each allergen product for specific immunotherapy has to be assessed individually for its quality, safety and efficacy. At the same time, biological potency of allergen products is most commonly determined using IgE inhibition assays based on human sera relative to product-specific in house references, ruling out full comparability of products from different manufacturers. This review article aims to summarize the current quality requirements for allergen products including the special requirements implemented for control of chemically modified allergen extracts (allergoids). Copyright © 2017 SEICAP. Published by Elsevier España, S.L.U. All rights reserved.

  4. Local immunological mechanisms of sublingual immunotherapy.

    Science.gov (United States)

    Allam, Jean-Pierre; Novak, Natalija

    2011-12-01

    To summarize novel insights into the immunological mechanisms of sublingual immunotherapy (SLIT). Within the recent decades, several alternative noninvasive allergen application strategies have been investigated in allergen-specific immunotherapy (AIT), of which intra-oral allergen application to sublingual mucosa has been proven to be well tolerated and effective. To date, SLIT is widely accepted by most allergists as an alternative option to conventional subcutaneous immunotherapy (SCIT). Although detailed immunological mechanisms remain to be elucidated, much scientific effort has been made to shed some light on local and systemic immunological responses to SLIT in mice as well as humans. Only a few studies focused on the detailed mechanisms following allergen application to the oral mucosa as part of the sophisticated mucosal immunological network. Within this network, the pro-tolerogenic properties of local antigen-presenting cells (APCs) such as dendritic cells - which are able to enforce tolerogenic mechanisms and to induce T-cell immune responses - play a central role. Further on, basic research focused not only on the immune response in nasal and bronchial mucosa but also on the systemic T-cell immune response. Thus, much exiting data have been published providing a better understanding of immunological features of SLIT but far more investigations are necessary to uncover further exciting details on the key mechanisms of SLIT.

  5. Double-blind, placebo-controlled immunotherapy with mixed grass-pollen allergoids. I. Rush immunotherapy with allergoids and standardized orchard grass-pollen extract.

    Science.gov (United States)

    Bousquet, J; Hejjaoui, A; Skassa-Brociek, W; Guérin, B; Maasch, H J; Dhivert, H; Michel, F B

    1987-10-01

    Forty-five grass pollen-allergic patients were randomly assigned to three groups according to their skin test and RAST sensitivities and the severity of seasonal rhinitis. Eleven patients were treated with placebo (group 1), 19 patients (group 2) were treated with a six-mixed grass-pollen allergoid prepared by mild formalinization with a two-step procedure, and 15 other patients were treated with a standardized orchard grass-pollen extract (group 3). Because of a different immunotherapy schedule, only patients placed in groups 1 and 2 received the extracts in a double-blind fashion. Rush immunotherapy was performed in 3 to 6 days, and the maintenance dose was subsequently administered weekly for 4 weeks and every 2 weeks until the end of the grass-pollen season. During the season, a coseasonal treatment was administered. Systemic reactions occurred during the rush protocol in 36.8% of patients treated with allergoid and 20% of patients who received the standardized extract. Only patients treated with allergoid had systemic reactions during maintenance dose. The reactions observed with the standardized extract were more severe. Total doses of allergoid ranged from 2350 to 13,500 protein nitrogen units. Symptoms and medication scores during the peak of the season were analyzed. Patients treated with the standardized allergen had a significant reduction of the number of days of symptoms during the month of June (9.5 +/- 6.7 days; p less than 0.005) and of medication scores (1.3 +/- 1.4; p less than 0.01) compared to patients receiving placebo (19.4 +/- 8.1 days; medication score, 2.8 +/- 2.1).(ABSTRACT TRUNCATED AT 250 WORDS)

  6. Analysis of the CD4(+) T cell responses to house dust mite allergoid

    NARCIS (Netherlands)

    Kalinski, P.; Lebre, M. C.; Kramer, D.; de Jong, E. C.; van Schijndel, J. W. P. M.; Kapsenberg, M. L.

    2003-01-01

    Background: Modified allergen extracts (allergoids) with reduced IgE-binding capacity are successfully used in immunotherapy of atopic allergy. Their reduced T-cell stimulatory capacity is less well studied and is a subject of the present study. Methods: We compared the ability of native house dust

  7. Immunogenicity of Phleum pratense depigmented allergoid vaccines: experimental study in rabbits.

    Science.gov (United States)

    Iraola, V; Gallego, M T; López-Matas, M A; Morales, M; Bel, I; García, N; Carnés, J

    2012-01-01

    Immunogenicity studies are based on accurate preclinical and clinical assessment of pharmaceutical products. The immunogenicity of modified allergen vaccines has not been fully elucidated, and the mechanisms involved are not well understood. Animal and human models have recently shown that depigmented allergoids induce specific immunoglobulin (Ig) G against individual allergens, thus supporting the clinical efficacy of these vaccines. The aim of this study was to investigate the production of specific IgG against individual antigens and their isoforms in rabbits injected with depigmented allergoid extracts of Phleum pratense pollen. Two New Zealand rabbits were immunized with depigmented-polymerized extracts adsorbed onto aluminum hydroxide (Depigoid) of P pratense. Rabbits were injected 3 times (35 microg Phl p 5). Specific IgG titers against native, depigmented, and depigmented-polymerized extracts and individual allergens (rPhl p 1 and rPhl p 5a) were analyzed by direct enzyme-linked immunosorbent assay. The capacity of these synthesized antibodies to recognize individual native and depigmented allergens and different isoforms was evaluated by immunoblot and 2-D analysis. All rabbits produced high titers of specific IgG against the 3 extracts. Rabbits injected with depigmented allergoids produced similar specific antibody titers against native, depigmented, and depigmented-polymerized extracts. Serum samples recognized individual allergens and their isoforms in the nonmodified extracts. Vaccines containing depigmented allergoid extracts of P pratense induce immunogenicity in vivo. The antibodies produced after injection of these extracts clearly recognized allergens and different isoforms in their native configuration.

  8. Molecular fingerprinting of complex grass allergoids: size assessments reveal new insights in epitope repertoires and functional capacities.

    Science.gov (United States)

    Starchenka, S; Bell, A J; Mwange, J; Skinner, M A; Heath, M D

    2017-01-01

    Subcutaneous allergen immunotherapy (SCIT) is a well-documented treatment for allergic disease which involves injections of native allergen or modified (allergoid) extracts. The use of allergoid vaccines is a growing sector of the allergy immunotherapy market, associated with shorter-course therapy. The aim of this study was the structural and immunological characterisation of group 1 (Lol p 1) IgG-binding epitopes within a complex mix grass allergoid formulation containing rye grass. HP-SEC was used to resolve a mix grass allergoid preparation of high molecular weight into several distinct fractions with defined molecular weight and elution profiles. Allergen verification of the HP-SEC allergoid fractions was confirmed by mass spectrometry analysis. IgE and IgG immunoreactivity of the allergoid preparations was explored and Lol p 1 specific IgG-binding epitopes mapped by SPOT synthesis technology (PepSpot™) with structural analysis based on a Lol p 1 homology model. Grass specific IgE reactivity of the mix grass modified extract (allergoid) was diminished in comparison with the mix grass native extract. A difference in IgG profiles was observed between an intact mix grass allergoid preparation and HP-SEC allergoid fractions, which indicated enhancement of accessible reactive IgG epitopes across size distribution profiles of the mix grass allergoid formulation. Detailed analysis of the epitope specificity showed retention of six Lol p 1 IgG-binding epitopes in the mix grass modified extract. The structural and immunological changes which take place following the grass allergen modification process was further unravelled revealing distinct IgG immunological profiles. All epitopes were mapped on the solvent exposed area of Lol p 1 homology model accessible for IgG binding. One of the epitopes was identified as an 'immunodominant' Lol p 1 IgG-binding epitope (62-IFKDGRGCGSCFEIK-76) and classified as a novel epitope. The results from this study support the concept

  9. CT features of invasion of sublingual space by malignant oropharyngeal tumors

    International Nuclear Information System (INIS)

    Wei Yi; Xiao Jiahe; Zhou Xiangping; Deng Kaihong

    2003-01-01

    Objective: To investigate the CT features of the invasion of sublingual space by malignant oropharyngeal tumors in order to provide more accurate information for clinical treatment. Methods: Fifty-eight cases of pathologically proven malignant oropharyngeal tumors were collected and retrospectively analyzed. Results: Among all the cases, invasion of sublingual space by malignant oropharyngeal tumors could be seen in 14 cases, of which, 7 cases got access to sublingual space through tongue base, 3 cases through parapharyngeal space, 2 cases through pterygomandibular raphe, 2 cases through uncertain routes. Invasion of sublingual space manifested on CT scan as obliteration of fat plane in sublingual space and involvement of the sublingual vessels in the space. Conclusion: Malignant oropharyngeal tumors can invade the adjacent sublingual space via tongue base, pterygomandibular raphe, and parapharyngeal space. The invasion of sublingual space by malignant oropharyngeal tumors manifests in CT as effacement of sublingual fat plane and envelopment of hyoid artery

  10. [Treatment of small and sublingual salivary glands cysts by laser].

    Science.gov (United States)

    Bogatov, V V; Vybornov, V V; Malinovskiĭ, I Iu

    2011-01-01

    The differents variants of treatment of retention cysts of mucous membrane of oral cavity and sublingual salivary gland cysts were presented and analysed. Results of doppler examination as a method of research blood microcirculation in postoperation time were presented.

  11. Development of nanoparticle based delivery systems for sublingual immunotherapy

    DEFF Research Database (Denmark)

    Alija, Hava; Rask, Carola; Brimnes, Jens

    The prevalence of IgE mediated allergic diseases is increasing dramatically in industrialized countries. Sublingual immunotherapy (SLIT) has been demonstrated to be a safe and efficacious treatment for IgE mediated allergic diseases, but requires protracted treatment duration. Even though SLIT...... (OVA)-induced allergic airway inflammation model for their ability to improve immune tolerance induction of ovalbumin (protein and peptide) when delivered sublingually. In the liposome study, mice were treated sublingually during two weeks with free or liposome encapsulated OVA (OVA-liposomes) followed...... by intraperitoneal injections and intranasal challenge. Mice treated sublingually with OVA-liposomes showed a significant reduction of airway eosinophilia, OVA-specific IgE antibodies and splenocyte proliferation in comparison to free OVA. In addition, reduced levels of IFN-ɣ and IL-5 were observed in spleen cell...

  12. Sublingual immunotherapy: World Allergy Organization position paper 2013 update

    Science.gov (United States)

    2014-01-01

    We have prepared this document, “Sublingual Immunotherapy: World Allergy Organization Position Paper 2013 Update”, according to the evidence-based criteria, revising and updating chapters of the originally published paper, “Sublingual Immunotherapy: World Allergy Organization Position Paper 2009”, available at http://www.waojournal.org. Namely, these comprise: “Mechanisms of sublingual immunotherapy;” “Clinical efficacy of sublingual immunotherapy” – reporting all the data of all controlled trials published after 2009; “Safety of sublingual immunotherapy” – with the recently published Grading System for adverse reactions; “Impact of sublingual immunotherapy on the natural history of respiratory allergy” – with the relevant evidences published since 2009; “Efficacy of SLIT in children” – with detailed analysis of all the studies; “Definition of SLIT patient selection” – reporting the criteria for eligibility to sublingual immunotherapy; “The future of immunotherapy in the community care setting”; “Methodology of clinical trials according to the current scientific and regulatory standards”; and “Guideline development: from evidence-based medicine to patients' views” – including the evolution of the methods to make clinical recommendations. Additionally, we have added new chapters to cover a few emerging crucial topics: “Practical aspects of schedules and dosages and counseling for adherence” – which is crucial in clinical practice for all treatments; “Perspectives and new approaches” – including recombinant allergens, adjuvants, modified allergens, and the concept of validity of the single products. Furthermore, “Raising public awareness about sublingual immunotherapy”, as a need for our patients, and strategies to increase awareness of allergen immunotherapy (AIT) among patients, the medical community, all healthcare stakeholders, and public opinion, are also reported in detail. PMID:24679069

  13. Enhanced efficacy of sublingual immunotherapy by liposome-mediated delivery of allergen

    DEFF Research Database (Denmark)

    Aliu, Have; Rask, Carola; Brimnes, Jens

    2017-01-01

    Immunotherapy by sublingual administration of allergens provides high patient compliance and has emerged as an alternative to subcutaneous immunotherapy for the - treatment of IgE-associated allergic diseases. However, sublingual immunotherapy (SLIT) can cause adverse events. Development...

  14. Adjuvant effects of aluminium hydroxide-adsorbed allergens and allergoids – differences in vivo and in vitro

    Science.gov (United States)

    Heydenreich, B; Bellinghausen, I; Lund, L; Henmar, H; Lund, G; Adler Würtzen, P; Saloga, J

    2014-01-01

    Allergen-specific immunotherapy (SIT) is a clinically effective therapy for immunoglobulin (Ig)E-mediated allergic diseases. To reduce the risk of IgE-mediated side effects, chemically modified allergoids have been introduced. Furthermore, adsorbance of allergens to aluminium hydroxide (alum) is widely used to enhance the immune response. The mechanisms behind the adjuvant effect of alum are still not completely understood. In the present study we analysed the effects of alum-adsorbed allergens and allergoids on their immunogenicity in vitro and in vivo and their ability to activate basophils of allergic donors. Human monocyte derived dendritic cells (DC) were incubated with native Phleum pratense or Betula verrucosa allergen extract or formaldehyde-or glutaraldehyde-modified allergoids, adsorbed or unadsorbed to alum. After maturation, DC were co-cultivated with autologous CD4+ T cells. Allergenicity was tested by leukotriene and histamine release of human basophils. Finally, in-vivo immunogenicity was analysed by IgG production of immunized mice. T cell proliferation as well as interleukin (IL)-4, IL-13, IL-10 and interferon (IFN)-γ production were strongly decreased using glutaraldehyde-modified allergoids, but did not differ between alum-adsorbed allergens or allergoids and the corresponding unadsorbed preparations. Glutaraldehyde modification also led to a decreased leukotriene and histamine release compared to native allergens, being further decreased by adsorption to alum. In vivo, immunogenicity was reduced for allergoids which could be partly restored by adsorption to alum. Our results suggest that adsorption of native allergens or modified allergoids to alum had no consistent adjuvant effect but led to a reduced allergenicity in vitro, while we observed an adjuvant effect regarding IgG production in vivo. PMID:24528247

  15. Specific immunotherapy with allergoids in atopic subjects, hyporeactive to other vaccines.

    Science.gov (United States)

    Vargiu, G; Valcurone, G; Agostoni, A; Sacchi, G; Tassi, G C

    1986-01-01

    Allergoids comply with the therapeutic requirement to reach high doses of the injected allergen, since the modifications of the allergens cause a loss of allergenicity, though the immunogenicity is being retained. Considering that it is possible to use a starting dose 40 times higher in comparison with retard vaccines, we thought it very expedient to treat with allergoids 18 patients allergic to parietaria, and 12 patients allergic to grass pollen, who had shown no clinical improvement after immunotherapy, lasting for at least three years with retard vaccines. The therapeutic results obtained are the following: improvement in 66% of the parietaria allergic patients after the first year, and of the 72% in the second year, of the 75% of the grass pollen allergic patients after the first year and of the 83% in the second year. They can be interpreted as due to the fact that such patients are always poorly reactive to the doses of allergens commonly present in retard vaccines. On the contrary, they do react to allergoids, both due to the high amount of allergen administered, and to the fact that polymerization brings about a stronger epitopic expression matched by a higher immunogenic activity. Moreover, the data are also indicative for a good relationship between the antibody titer of antigen-specific blocking IgG and the clinical effectiveness valued by means of symptom and medication scores.

  16. Tolerance induction after specific immunotherapy with pollen allergoids adjuvanted by monophosphoryl lipid A in children.

    Science.gov (United States)

    Rosewich, M; Schulze, J; Eickmeier, O; Telles, T; Rose, M A; Schubert, R; Zielen, S

    2010-06-01

    Specific immunotherapy (SIT) is a well-established and clinically effective treatment for allergic diseases. A pollen allergoid formulated with the T helper type 1 (Th1)-inducing adjuvant monophosphoryl lipid A (MPL) facilitates short-term SIT. Little is known about mechanisms of tolerance induction in this setting. In a prospective study, 34 patients allergic to grass pollen (25 male, nine female, median age 10.2 years) received a total of 44 SIT courses (20 in the first, 24 in the second) with MPL-adjuvanted pollen allergoids. Immunogenicity was measured by levels of specific immunoglobulin G (IgG(grass)) and IgG4(grass) by antibody blocking properties on basophil activation, and by induction of CD4(+), CD25(+) and forkhead box P3 (FoxP3(+)) regulatory T cells (T(reg)). Specific IgG and IgG4 levels increased only slightly in the first year of SIT. In the second year these changes reached significance (P allergoids formulated with the Th1-inducing adjuvant MPL needs at least two courses to establish tolerance.

  17. Single-course specific immunotherapy with mixed pollen allergoids: results of a multi-centre study.

    Science.gov (United States)

    Drachenberg, K J; Pröll, S; Urban, E; Woroniecki, S R

    2003-01-01

    A short-term immunotherapy vaccine for the treatment of pollen allergy has been developed utilising L-tyrosine adsorbed allergoids. The reduced number of injections could provide advantages over long-term therapy schedules. This would improve compliance and support application of specific immunotherapy (SIT) to a greater extent. We report a multicenter study to evaluate the efficacy and safety of this treatment in a clinical practice setting. Patients (n = 1808) with a diagnosis of sensitivities to various pollens and symptoms of allergic asthma and/or allergic rhinitis and/or allergic conjunctivitis were selected. The vaccine formulation was made up according to individual sensitivities and contained L-tyrosine adsorbed allergoids. The patients were treated with a 3-injection initial course followed by a 3-injection maintenance course. Efficacy was measured by consumption of symptomatic anti-allergic medication compared with that in the previous season and by physician assessment using a 5-point scale. All adverse events were recorded. Efficacy was demonstrated by a considerable decrease in regular and frequent use of medication compared with that in the previous season (p allergoid/L-tyrosine vaccine in a clinical practice setting provided a high level of efficacy with a low incidence of mainly mild adverse events.

  18. [Characteristics of sublingual vein and expressions of vascular endothelial growth factor and hypoxia-inducible factor 1alpha proteins in sublingual tissues of Beagle dogs with portal hypertension].

    Science.gov (United States)

    Li, Bai-yu; Wang, Li-na; Yue, Xiao-qiang; Li, Bai

    2009-05-01

    To observe sublingual vein characteristics and the expressions of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor 1alpha (HIF-1alpha) proteins in sublingual tissues of Beagle dogs with cirrhotic portal hypertension. Twelve Beagle dogs were randomly divided into normal control group and cirrhotic portal hypertension group. There were 6 dogs in each group. A canine model of cirrhosis portal hypertension was established by injecting dimethylnitrosamine (DMN) into portal vein once a week for 7 weeks. The characteristics of sublingual vein were observed. Portal venous pressure was measured by using bioelectric recording techniques. The expressions of VEGF and HIF-1alpha proteins in sublingual vein were detected by immunohistochemical method. The shape and color of sublingual vein in beagle dogs in the cirrhotic portal hypertension group changed obviously as compared with the normal control group. Immunohistochemical results showed that there were almost no expressions of VEGF and HIF-1alpha proteins in sublingual tissues in the normal control group; however, the expressions of VEGF and HIF-1alpha proteins in sublingual tissues in the cirrhotic portal hypertension group significantly increased. Changes of portal pressure may lead to the formation of the abnormal sublingual vein by increasing the expressions of VEGF and HIF-1alpha proteins in sublingual tissues in Beagle dogs with portal hypertension.

  19. The Impact on Allergy-Related Cells of a Birch Pollen Allergoid, with and without Monophosphoryl Lipid A, in Comparison with the Native Equivalent.

    Science.gov (United States)

    Worm, Margitta; Ernst, Dennis; Kraller, Markus; Babina, Magda

    2017-01-01

    The clinical efficacy and safety of allergoid immunotherapy have been demonstrated in clinical trials. However, simultaneous monitoring of the immunological changes by allergoids versus allergens in the cells of the same individual has not been extensively performed, and the impact of concurrent Toll-like receptor 4 (TLR4) ligation has not been specified. Three types of birch allergen were utilized: glutaraldehyde-treated allergoid (extract A), the same allergoid plus monophosphoryl lipid A (MPL), i.e., TLR4 ligand (extract A*), and native allergen (extract B). Antigen-specific responses after the in vitro stimulation of blood cells with the extracts were assessed by studying costimulatory receptors on the B cell surface by flow cytometry, cytokine responses by ELISA, and CD63 and CD203c upregulation (basophil activation test) in allergic versus nonallergic subjects. HLA-DR selectively increased upon allergen or allergoid treatment in the allergic group only. The extract types elicited similar cytokine responses, with IL-6 and IL-10 production detected only in certain atopic subjects. The allergoids revealed a strong reduction (100- to allergoid employed was sharply reduced when compared to the native allergen, while its immunogenicity was largely retained, especially in the presence of MPL. We also provide further evidence that allergic and nonallergic individuals show preexisting differences in their immune repertoires. © 2017 S. Karger AG, Basel.

  20. Formulation and evaluation of sublingual tablets of losartan potassium

    Directory of Open Access Journals (Sweden)

    Nikunj J. Aghera

    2012-05-01

    Full Text Available Objective: Sublingual tablets of Losartan Potassium were prepared to improve its bioavailability, to avoid pre-systemic metabolism in the gastrointestinal tract and hepatic first pass elimination. Methods: The Sublingual tablets were prepared by direct compression procedure using different concentration of Starch 1500 and microcrystalline cellulose. Compatibility studies of drug and polymer were performed by FTIR spectroscopy and DSC. Preformulation property of API was evaluated. Postcompressional parameters such disintegration time, wetting time, water absorption ratio, in vitro drug release and in vivo bioavailability study of optimized formulation were determined. Results: FTIR spectroscopy and DSC study revealed that there was no possible interaction between drug and polymers. The precompression parameters were in acceptable range of pharmacopoeial specification. The disintegration time of optimized formulation (F3 was upto 48 sec. The in vitro release of Losartan Potassium was upto 15 min. The percentage relative bioavailability of Losartan Potassium from optimized sublingual tablets was found to be 144.7 %. Conclusions: Sublingual tablets of Losartan Potassium were successfully prepared with improved bioavailability.

  1. Time Evolution of Sublingual Microcirculatory Changes in Recreational Marathon Runners

    Science.gov (United States)

    Arstikyte, Justina; Vaitkaitiene, Egle; Vaitkaitis, Dinas

    2017-01-01

    We aimed to evaluate changes in sublingual microcirculation induced by a marathon race. Thirteen healthy male controls and 13 male marathon runners volunteered for the study. We performed sublingual microcirculation, using a Cytocam-IDF device (Braedius Medical, Huizen, Netherlands), and systemic hemodynamic measurements four times: 24 hours prior to their participation in the Kaunas Marathon (distance: 41.2 km), directly after finishing the marathon, 24 hours after the marathon, and one week after the marathon. The marathon runners exhibited a higher functional capillary density (FCD) and total vascular density of small vessels at the first visit compared with the controls. Overall, we did not find any changes in sublingual microcirculation of the marathon runners at any of the other visits. However, in a subgroup of marathon runners with a decreased FCD compared to the subgroup with increased FCD, the subgroup with decreased FCD had shorter running time (190.37 ± 30.2 versus 221.80 ± 23.4 min, p = 0.045), ingested less fluids (907 ± 615 versus 1950 ± 488 mL, p = 0.007) during the race, and lost much more weight (−2.4 ± 1.3 versus −1.0 ± 0.8 kg, p = 0.041). Recreational marathon running is not associated with an alteration of sublingual microcirculation. However, faster running and dehydration may be crucial for further impairing microcirculation. PMID:28828386

  2. Time Evolution of Sublingual Microcirculatory Changes in Recreational Marathon Runners.

    Science.gov (United States)

    Pranskunas, Andrius; Arstikyte, Justina; Pranskuniene, Zivile; Bernatoniene, Jurga; Kiudulaite, Inga; Vaitkaitiene, Egle; Vaitkaitis, Dinas; Brazaitis, Marius

    2017-01-01

    We aimed to evaluate changes in sublingual microcirculation induced by a marathon race. Thirteen healthy male controls and 13 male marathon runners volunteered for the study. We performed sublingual microcirculation, using a Cytocam-IDF device (Braedius Medical, Huizen, Netherlands), and systemic hemodynamic measurements four times: 24 hours prior to their participation in the Kaunas Marathon (distance: 41.2 km), directly after finishing the marathon, 24 hours after the marathon, and one week after the marathon. The marathon runners exhibited a higher functional capillary density (FCD) and total vascular density of small vessels at the first visit compared with the controls. Overall, we did not find any changes in sublingual microcirculation of the marathon runners at any of the other visits. However, in a subgroup of marathon runners with a decreased FCD compared to the subgroup with increased FCD, the subgroup with decreased FCD had shorter running time (190.37 ± 30.2 versus 221.80 ± 23.4 min, p = 0.045), ingested less fluids (907 ± 615 versus 1950 ± 488 mL, p = 0.007) during the race, and lost much more weight (-2.4 ± 1.3 versus -1.0 ± 0.8 kg, p = 0.041). Recreational marathon running is not associated with an alteration of sublingual microcirculation. However, faster running and dehydration may be crucial for further impairing microcirculation.

  3. Time Evolution of Sublingual Microcirculatory Changes in Recreational Marathon Runners

    Directory of Open Access Journals (Sweden)

    Andrius Pranskunas

    2017-01-01

    Full Text Available We aimed to evaluate changes in sublingual microcirculation induced by a marathon race. Thirteen healthy male controls and 13 male marathon runners volunteered for the study. We performed sublingual microcirculation, using a Cytocam-IDF device (Braedius Medical, Huizen, Netherlands, and systemic hemodynamic measurements four times: 24 hours prior to their participation in the Kaunas Marathon (distance: 41.2 km, directly after finishing the marathon, 24 hours after the marathon, and one week after the marathon. The marathon runners exhibited a higher functional capillary density (FCD and total vascular density of small vessels at the first visit compared with the controls. Overall, we did not find any changes in sublingual microcirculation of the marathon runners at any of the other visits. However, in a subgroup of marathon runners with a decreased FCD compared to the subgroup with increased FCD, the subgroup with decreased FCD had shorter running time (190.37±30.2 versus 221.80±23.4 min, p=0.045, ingested less fluids (907±615 versus 1950±488 mL, p=0.007 during the race, and lost much more weight (-2.4±1.3 versus -1.0±0.8 kg, p=0.041. Recreational marathon running is not associated with an alteration of sublingual microcirculation. However, faster running and dehydration may be crucial for further impairing microcirculation.

  4. Artemisia vulgaris pollen allergoids digestibility in the simulated conditions of the gastrointestinal tract

    Directory of Open Access Journals (Sweden)

    RATKO M. JANKOV

    2006-09-01

    Full Text Available Chemically modified allergens (allergoids have found use in both traditional and novel forms of immunotherapy of allergic disorders. Novel forms of immunotherapy include local allergen delivery, via the gastrointestinal tract. This study conveys the gastrointestinal stability of three types ofmugwort pollen allergoids under simulated conditions of the gut. Allergoids of the pollen extract of Artemisia vulgaris were obtained by means of potassium cyanate, succinic and maleic anhydride. Gastrointestinal tract conditions (saliva, and gastric fluid were simulated in accordance with the EU Pharmacopoeia. The biochemical and immunochemical properties of the derivatives following exposure to different conditions were monitored by determining the number of residual amino groups with 2,4,6-trinitrobenzenesulfonic acid, SDS PAGE, immunoblotting and inhibition of mugwort-specific IgE. Exposure to saliva fluid for 2 min did not influence the biochemical and immunochemical properties of the derivatives. In the very acidic conditions of the simulated gastric fluid, the degree of demaleylation and desuccinylation, even after 4 h exposure, was low, ranging from 10 to 30 %. The digestion patterns with pepsin proceeded rapidly in both the unmodified and modified samples. In all four cases, a highly resistant IgE-binding protein theMwof which was about 28 – 35 kD, was present. Within the physiological conditions, no new IgE binding epitopes were revealed, as demonstrated by immunoblot and CAP inhibition of the mugwort specific IgE binding. An important conclusion of this study is the stability of the modified derivatives in the gastrointestinal tract of patients, within physiological conditions. The means that they are suitable for use inmuch higher concentrations in local forms of immunotherapy than unmodified ones.

  5. Depigmented Allergoids Reveal New Epitopes with Capacity to Induce IgG Blocking Antibodies

    OpenAIRE

    L?pez-Matas, M. Angeles; Gallego, Mayte; Iraola, V?ctor; Robinson, Douglas; Carn?s, Jer?nimo

    2013-01-01

    Background. The synthesis of allergen-specific blocking IgGs that interact with IgE after allergen immunotherapy (SIT) has been related to clinical efficacy. The objectives were to investigate the epitope specificity of IgG-antibodies induced by depigmented-polymerized (Dpg-Pol) allergoids and unmodified allergen extracts, and examine IgE-blocking activity of induced IgG-antibodies. Methods. Rabbits were immunized with native and Dpg-Pol extracts of birch pollen, and serum samples were obtain...

  6. Adenoid cystic carcinoma of sublingual glands. Surgery and radiotherapy combination

    International Nuclear Information System (INIS)

    Campagnale, Ramiro; Campagnale, Rodrigo; Varalli, Lucas

    2005-01-01

    The Adenoid Cystic Carcinoma (ACC) or Cilindroma is a strange entity classified by the WHO within the carcinomas of salivary glands. It represents only 1 % of all the wicked tumours of the oral and maxillofacial region although, when making reference to the salivary glands, it constitutes 5% of the parotid, submaxilar and sublingual carcinomas, and about 50% of the smallest ones. The most frequent location is in the palatine glands and its main characteristics are: slow but persistent growth, high rates of local relapse and metastasis at distance originating the death between the first 5 and 10 years in 50-70% of the cases approximately. A case of localization is presented in sublingual gland which was first treated surgically and later with radiotherapy, obtaining good results. (author) [es

  7. Time evolution of sublingual microcirculatory changes in recreational marathon runners

    OpenAIRE

    Pranskūnas, Andrius; Kiudulaitė, Inga; Šimkienė, Jūratė; Damanskytė, Diana; Pranskūnienė, Živilė; Arštikytė, Justina; Vaitkaitis, Dinas; Pilvinis, Vidas; Brazaitis, Marius

    2017-01-01

    Introduction: Marathon race transiently elevates the probability of sudden death. Also during long-distance run may occur various gastrointestinal symptoms with range from mild nausea to hemorrhagic stool. However microcirculatory nature of this disturbances is not clear. Microcirculation of sublingual mucosa is part of interest, because it is easy and noninvasively accessible, changes have relation with mortality and it is part of the upper digestive tract. Here, we evaluate changes in subli...

  8. Stability evaluation of house dust mite vaccines for sublingual immunotherapy

    Directory of Open Access Journals (Sweden)

    MARIJA GAVROVIĆ-JANKULOVIĆ

    2010-01-01

    Full Text Available Allergen-specific immunotherapy with house dust mite (HDM allergen extracts can effectively alleviate the symptoms of allergic rhinitis and asthma. The efficacy of the immunotherapeutic treatment is highly dependent on the quality of house dust mite vaccines. This study was performed to assess the stability of house dust mite allergen vaccines prepared for sublingual immunotherapy. Lyophilized Dermatophagoides pteronyssinus (Dpt mite bodies were the starting material for the production of sublingual vaccines in four therapeutic concentrations. The stability of the extract for vaccine production, which was stored below 4 °C for one month, showed consistence in the protein profile in SDS PAGE. ELISA-inhibition showed that the potencies of Dpt vaccines during a 12 month period were to 65–80 % preserved at all analyzed therapeutic concentrations. This study showed that glycerinated Dpt vaccines stored at 4 °C preserved their IgE-binding potential during a 12 month period, implying their suitability for sublingual immunotherapeutic treatment of HDM allergy.

  9. Formulation and Evaluation of New Glimepiride Sublingual Tablets

    Directory of Open Access Journals (Sweden)

    Wafa Al-Madhagi

    2017-01-01

    Full Text Available Oral mucosal delivery of drugs promotes rapid absorption and high bioavailability, with a subsequent immediate onset of pharmacological effect. However, many oral mucosal deliveries are compromised by the possibility of the patient swallowing the active substance before it has been released and absorbed locally into the systemic circulation. The aim of this research was to introduce a new glimepiride formula for sublingual administration and rapid drug absorption that can be used in an emergency. The new sublingual formulation was prepared after five trials to prepare the suitable formulation. Two accepted formulations of the new sublingual product were prepared, but one of them with disintegration time of 1.45 min and searching for preferred formulation, the binder, is changed with Flulac and starch slurry to prepare formula with disintegration time of 21 seconds that supports the aim of research to be used in an emergency. The five formulations were done, after adjusting to the binder as Flulac and aerosil with disintegration time of 21 seconds and accepted hardness as well as the weight variation. The assay of a new product (subglimepiride is 103% which is a promising result, confirming that the formula succeeded. The new product (subglimepiride is accepted in most quality control tests and it is ready for marketing.

  10. Sublingual epidermoid cyst presenting with distinctive magnetic resonance imaging findings.

    Science.gov (United States)

    Yoshida, Naohiro; Kodama, Kozue; Iino, Yukiko

    2014-06-18

    A case of sublingual epidermoid cyst presenting distinctive magnetic resonance imaging (MRI) findings is described. A 39-year-old man presented to our hospital with a three months progressive left submandibular swelling, difficulty moving his tongue, and snoring. Preoperative evaluation with MRI and fine needle aspiration cytology (FNAC) revealed that the heterogeneous cystic lesion contained the squamous cells, which is compatible with ectodermal tissue. The mass was located above the mylohyoid muscle and spread to the pharyngeal space. By considering the size, infection history, patient age, and location, the cyst was completely resected under general anesthesia via cervical approach without any complication. Histopathologically, the cyst wall was lined by stratified squamous epithelium with no skin appendage, suggesting an epidermoid cyst. Ultrasound (US), MRI and FNAC were very useful of the preoperative diagnosis for oral and sublingual lesion. The postoperative course was uneventful and without recurrence after 24 months. This case showed that epidermoid cysts formed the rarely heterogeneous cystic tumor and it underlined usefulness of preoperative diagnosis, such as US, MRI and FNAC for oral and sublingual tumor.

  11. Quantitative Studies of Sublingual PCO2 as a Resuscitation End-Point in the Diagnosis and Treatment of Hemorrhagic Shock

    National Research Council Canada - National Science Library

    Ivatury, Pao

    2005-01-01

    This clinical study is examining the relationship between sublingual PCO2 (PslCO2) to real-time changes in microcirculatory blood flow of the sublingual mucosa in victims of traumatic and hemorrhagic shock...

  12. Intranasal and sublingual delivery of inactivated polio vaccine.

    Science.gov (United States)

    Kraan, Heleen; Soema, Peter; Amorij, Jean-Pierre; Kersten, Gideon

    2017-05-09

    Polio is on the brink of eradication. Improved inactivated polio vaccines (IPV) are needed towards complete eradication and for the use in the period thereafter. Vaccination via mucosal surfaces has important potential advantages over intramuscular injection using conventional needle and syringe, the currently used delivery method for IPV. One of them is the ability to induce both serum and mucosal immune responses: the latter may provide protection at the port of virus entry. The current study evaluated the possibilities of polio vaccination via mucosal surfaces using IPV based on attenuated Sabin strains. Mice received three immunizations with trivalent sIPV via intramuscular injection, or via the intranasal or sublingual route. The need of an adjuvant for the mucosal routes was investigated as well, by testing sIPV in combination with the mucosal adjuvant cholera toxin. Both intranasal and sublingual sIPV immunization induced systemic polio-specific serum IgG in mice that were functional as measured by poliovirus neutralization. Intranasal administration of sIPV plus adjuvant induced significant higher systemic poliovirus type 3 neutralizing antibody titers than sIPV delivered via the intramuscular route. Moreover, mucosal sIPV delivery elicited polio-specific IgA titers at different mucosal sites (IgA in saliva, fecal extracts and intestinal tissue) and IgA-producing B-cells in the spleen, where conventional intramuscular vaccination was unable to do so. However, it is likely that a mucosal adjuvant is required for sublingual vaccination. Further research on polio vaccination via sublingual mucosal route should include the search for safe and effective adjuvants, and the development of novel oral dosage forms that improve antigen uptake by oral mucosa, thereby increasing vaccine immunogenicity. This study indicates that both the intranasal and sublingual routes might be valuable approaches for use in routine vaccination or outbreak control in the period after

  13. Clinical efficacy of sublingual and subcutaneous birch pollen allergen-specific immunotherapy

    DEFF Research Database (Denmark)

    Khinchi, M S; Poulsen, Lars K.; Carat, F

    2004-01-01

    Both sublingual allergen-specific immunotherapy (SLIT) and subcutaneous immunotherapy (SCIT) have a documented clinical efficacy, but only few comparative studies have been performed.......Both sublingual allergen-specific immunotherapy (SLIT) and subcutaneous immunotherapy (SCIT) have a documented clinical efficacy, but only few comparative studies have been performed....

  14. Double-blind, placebo-controlled immunotherapy with mixed grass-pollen allergoids. IV. Comparison of the safety and efficacy of two dosages of a high-molecular-weight allergoid.

    Science.gov (United States)

    Bousquet, J; Hejjaoui, A; Soussana, M; Michel, F B

    1990-02-01

    Specific immunotherapy is still widely used in grass-pollen allergy, but its side effects may limit its use. We tested the safety and efficacy of a formalinized high-molecular-weight allergoid prepared from a mixed grass-pollen extract with two injection schedules in a double-blind, placebo-controlled study. Eighteen patients received placebo, 19 received the low-dose schedule (maximal dose: 2000 PNU) and 20 received the high-dose schedule (maximal dose: 10,000 PNU). Only one patient presented a systemic reaction of moderate severity for a dose of 1200 PNU. Before the onset of the pollen season, patients had a nasal challenge with orchard grass-pollen grains, a skin test titration, and the titration of serum-specific IgG. Both groups of patients presented a significant reduction in nasal and skin sensitivities and a significant increase in IgG compared to placebo. Symptoms and medications for rhinitis and asthma were studied during the season, and both groups receiving allergoids had a significant reduction of symptom-medication scores for nasal and bronchial symptoms. There was a highly significant correlation between nasal symptom-medication scores during the season and the results of nasal challenges. High-molecular-weight allergoids are safe and effective.

  15. Pharmacokinetics and pharmacodynamics of detomidine following sublingual administration to horses.

    Science.gov (United States)

    Dimaio Knych, Heather K; Stanley, Scott D

    2011-10-01

    To characterize pharmacokinetics and pharmacodynamics of detomidine gel administered sublingually in accordance with label instructions to establish appropriate withdrawal guidelines for horses before competition. 12 adult racehorses. Horses received a single sublingual administration of 0.04 mg of detomidine/kg. Blood samples were collected before and up to 72 hours after drug administration. Urine samples were collected for 5 days after detomidine administration. Plasma and urine samples were analyzed via liquid chromatography-mass spectrometry, and resulting data were analyzed by use of noncompartmental analysis. Chin-to-ground distance, heart rate and rhythm, glucose concentration, PCV, and plasma protein concentration were also assessed following detomidine administration. Mean ± SD terminal elimination half-life of detomidine was 1.5 ± 1 hours. Metabolite concentrations were below the limit of detection (0.02, 0.1, and 0.5 ng/mL for detomidine, carboxydetomidine, and hydroxydetomidine, respectively) in plasma by 24 hours. Concentrations of detomidine and its metabolites were below the limit of detection (0.05 ng/mL for detomidine and 0.10 ng/mL for carboxydetomidine and hydroxydetomidine) in urine by 3 days. All horses had various degrees of sedation after detomidine administration. Time of onset was ≤ 40 minutes, and duration of sedation was approximately 2 hours. Significant decreases, relative to values at time 0, were detected for chin-to-ground distance and heart rate. There was an increased incidence and exacerbation of preexisting atrioventricular blocks after detomidine administration. A 48-hour and 3-day withdrawal period for detection in plasma and urine samples, respectively, should be adopted for sublingual administration of detomidine gel.

  16. Immunological mechanisms of sublingual allergen-specific immunotherapy.

    Science.gov (United States)

    Novak, Natalija; Bieber, T; Allam, J-P

    2011-06-01

    Within the last 100 years of allergen-specific immunotherapy, many clinical and scientific efforts have been made to establish alternative noninvasive allergen application strategies. Thus, intra-oral allergen delivery to the sublingual mucosa has been proven to be safe and effective. As a consequence, to date, sublingual immunotherapy (SLIT) is widely accepted by most allergists as an alternative to conventional subcutaneous immunotherapy. Although immunological mechanisms remain to be elucidated in detail, several studies in mice and humans within recent years provided deeper insights into local as well as systemic immunological features in response to SLIT. First of all, it was shown that the target organ, the oral mucosa, harbours a sophisticated immunological network as an important prerequisite for SLIT, which contains among other cells, local antigen-presenting cells (APC), such as dendritic cells (DCs), with a constitutive disposition to enforce tolerogenic mechanisms. Further on, basic research on local DCs within the oral mucosa gave rise to possible alternative strategies to deliver the allergens to other mucosal regions than sublingual tissue, such as the vestibulum oris. Moreover, characterization of oral DCs led to the identification of target structures for both allergens as well as adjuvants, which could be applied during SLIT. Altogether, SLIT came a long way since its very beginning in the last century and some, but not all questions about SLIT could be answered so far. However, recent research efforts as well as clinical approaches paved the way for another exciting 100 years of SLIT. © 2011 John Wiley & Sons A/S.

  17. Schwannoma of the sublingual gland: report of a case

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Eun Sook; Choi, Soon Chul; Park, Tae Won; You, Dong Soo [Dept. of Oral and Maxillofacial Radiology, College of Dentistry, Seoul National University, Seoul (Korea, Republic of)

    1994-08-15

    Schwannoma, also referred to as neurilemmoma, is a solitary, benign and slow growing tumor of nerve sheath origin. This rare lesion originates from Schwann cell of peripheral, autonomic and cranial nerve. Extracranial neurogenic tumor of the head and neck is uncommon. Schwannoma of the salivary gland is a particularly rare form of an extracranial neurogenic tumor, with most presenting in the parotid gland originating from a peripheral branch of the facial nerve. In this report, an unusual case of schwannoma in the sublingual region is presented and the literature concerning this subject is reviewed.

  18. Development of midazolam sublingual tablets: in vitro study.

    Science.gov (United States)

    Odou, P; Barthelemy, C; Robert, H

    1998-01-01

    Midazolam is a benzodiazepine with short elimination half-life, used as induction or continuous agent for general anesthesia. At present, only injectable solution is available from French hospital pharmacies. The aim of the study is the development of 5 mg midazolam sublingual tablets to realize a short general anesthesia without intravenous or intramuscular injection. Incorporation of citric acid in the tablet formulation leads to an increase of dissolution rates of active drug, but a decrease of diffusion through lipid membranes is observed with 10 mg of citric acid when using the Dibbern's Resomat three phases apparatus. One explanation of this result is that midazolam (pKa = 6.1) in presence of 10 mg of citric acid is ionised. The ionised form, more hydrophilic, cannot cross the artificial lipid membrane and therefore the diffusion decreases. On the other hand, the decrease of diffusion's rate, when pH increases, is explained by the precipitation of midazolam at pH higher than 6. A compromise between dissolution and diffusion results leads us to choose the sublingual formulation containing 5 mg of citric acid per tablet.

  19. Evaluation of sublingual microcirculation in children with dengue shock

    Directory of Open Access Journals (Sweden)

    Daniella Mancino da Luz Caixeta

    2013-07-01

    Full Text Available OBJECTIVE: To report the sublingual microcirculation observed using Sidestream Dark Field imaging in two children with dengue shock. METHOD: Two children, aged 9 and 10 years, were admitted to the pediatric intensive care unit with dengue shock and multiple organ dysfunction. Sublingual microcirculation was assessed in each patient on the first and second days of shock and was assessed a final time when the patients were no longer in shock (on the day prior to extubation using Sidestream Dark Field technology. The De Backer score and microvascular flow index were used for the analyses. RESULTS: Both patients had reduced perfused small vessel density in the first two days and showed predominantly intermittent or no microcirculation flow, as demonstrated by a low microvascular flow index. The blood flow in the large vessels was not affected. Prior to the extubation, the microvascular flow index had increased, although the perfused small vessel density remained diminished, suggesting persistent endothelial dysfunction. CONCLUSIONS: Severe microcirculation changes may be involved in the pathophysiological mechanisms that lead to the final stages of dengue shock, which is frequently irreversible and associated with high mortality rates. Microcirculatory monitoring may help elucidate the physiopathology of dengue shock and prove useful as a prognostic tool or therapeutic target.

  20. Debut of Gastroesophageal Reflux Concomitant with Administration of Sublingual Immunotherapy

    Directory of Open Access Journals (Sweden)

    Jacob Juel

    2017-01-01

    Full Text Available Gastroesophageal reflux disease (GORD is an often debilitating condition characterised by retrograde flow of content from stomach into the oesophagus, where the low pH of the stomach acid irritates the mucosa of the oesophagus. The most dominant symptoms in GORD are pyrosis, regurgitation, and dysphagia. Sublingual immunotherapy (SLIT was first described in 1986. Following this description, the use has greatly increased in the treatment of allergic rhinitis, as an alternative to subcutaneously administered immunotherapy. Side effects are commonly of oropharyngeal and gastrointestinal nature, for example, swelling, itching, irritation, ulceration of the oropharynx and nausea, abdominal pain, vomiting, and diarrhoea. More serious side effects are dominated by respiratory tract and systemic manifestations. A 30-year-old male experienced refractory, relentless, and debilitation GORD subsequent to administration of sublingual immunotherapy for house dust mite in allergic rhinitis. The patient had to stop the SLIT after two weeks of administration due to GORD. The cessation resulted in rapid resolution of symptoms.

  1. Monomeric tartrate resistant acid phosphatase induces insulin sensitive obesity.

    Directory of Open Access Journals (Sweden)

    Pernilla Lång

    2008-03-01

    Full Text Available Obesity is associated with macrophage infiltration of adipose tissue, which may link adipose inflammation to insulin resistance. However, the impact of inflammatory cells in the pathophysiology of obesity remains unclear. Tartrate resistant acid phosphatase (TRAP is an enzyme expressed by subsets of macrophages and osteoclasts that exists either as an enzymatically inactive monomer or as an active, proteolytically processed dimer.Using mice over expressing TRAP, we show that over-expression of monomeric, but not the dimeric form in adipose tissue leads to early onset spontaneous hyperplastic obesity i.e. many small fat cells. In vitro, recombinant monomeric, but not proteolytically processed TRAP induced proliferation and differentiation of mouse and human adipocyte precursor cells. In humans, monomeric TRAP was highly expressed in the adipose tissue of obese individuals. In both the mouse model and in the obese humans the source of TRAP in adipose tissue was macrophages. In addition, the obese TRAP over expressing mice exhibited signs of a low-grade inflammatory reaction in adipose tissue without evidence of abnormal adipocyte lipolysis, lipogenesis or insulin sensitivity.Monomeric TRAP, most likely secreted from adipose tissue macrophages, induces hyperplastic obesity with normal adipocyte lipid metabolism and insulin sensitivity.

  2. Relationship between sublingual and intestinal microcirculatory perfusion in patients with abdominal sepsis

    NARCIS (Netherlands)

    Boerma, E. Christiaan; van der Voort, Peter H. J.; Spronk, Peter E.; Ince, Can

    2007-01-01

    Objective: To evaluate the relation between sublingual and intestinal microcirculatory alterations in patients with abdominal sepsis. Design. Prospective observational study. Setting. A 23-bed mixed intensive care unit of a tertiary teaching hospital. Patients: Twenty-three patients with abdominal

  3. Sublingual Nitroglycerin Administration in Coronary Computed Tomography Angiography : a Systematic Review

    NARCIS (Netherlands)

    Takx, Richard A. P.; Suchá, D.; Park, Jakob; Leiner, Tim; Hoffmann, Udo

    2015-01-01

    To systematically investigate the literature for the influence of sublingual nitroglycerin administration on coronary diameter, the number of evaluable segments, image quality, heart rate and blood pressure, and diagnostic accuracy of coronary computed tomography (CT) angiography. A systematic

  4. Critical appraisal of the clinical utility of sublingual immunotherapy in allergy

    Directory of Open Access Journals (Sweden)

    S. Aissa

    2016-12-01

    We performed a literature review in order to remind the mechanisms of action and to demonstrate efficacy and tolerability of the sublingual immunotherapy in the treatment of allergic rhinoconjunctivitis and asthma and its impact on the quality of life.

  5. Adenoid cystic carcinoma of the sublingual gland: A case report

    Energy Technology Data Exchange (ETDEWEB)

    Song, Ji Young [Dept. of Oral and Maxillofacial Surgery, School of Medicine, Jeju National University, Jeju (Korea, Republic of)

    2016-12-15

    Adenoid cystic carcinoma (ACC) of the sublingual gland is an extremely rare neoplasm. The clinicopathological characteristics of ACC are slow-growing swelling with or without ulceration, perineural spread, local recurrence, and distant metastasis. This report describes a 58-year-old male who had a slowly growing swelling without ulceration on the right side of the mouth floor that had been present for 1 month. In a radiological examination, the mass showed multilocular cystic features and no bony or tongue muscle invasion. No enlarged cervical lymph nodes were detected. Excisional biopsy and histological analysis showed that the lesion was ACC. In addition to reporting a rare case of ACC, this report also discusses the differential diagnosis and treatment of ACC with a review of the relevant literature.

  6. Sublingual immunotherapy for allergic rhinitis: where are we now?

    Science.gov (United States)

    Incorvaia, Cristoforo; Mauro, Marina; Ridolo, Erminia

    2015-01-01

    Sublingual immunotherapy (SLIT) was introduced in the 1980s as a safer option to subcutaneous immunotherapy and in the latest decade achieved significant advances. Its efficacy in allergic rhinitis is supported by a number of meta-analyses. The development of SLIT preparations in tablets to fulfill the requirements of regulatory agencies for quality of allergen extracts made available optimal products for grass-pollen-induced allergic rhinitis. Preparations of other allergens based on the same production methods are currently in progress. A notable outcome of SLIT, that is shared with subcutaneous immunotherapy, is the evident cost-effectiveness, showing significant cost savings as early as 3 months from starting the treatment, that become as high as 80% compared with drug treatment in the ensuing years.

  7. Sublingual fast dissolving niosomal films for enhanced bioavailability and prolonged effect of metoprolol tartrate

    OpenAIRE

    Allam, Ayat; Fetih, Gihan

    2016-01-01

    Ayat Allam, Gihan Fetih Department of Pharmaceutics, Faculty of Pharmacy, Assiut University, Assiut, Egypt Abstract: The aim of the present work was to prepare and evaluate sublingual fast dissolving films containing metoprolol tartrate-loaded niosomes. Niosomes were utilized to allow for prolonged release of the drug, whereas the films were used to increase the drug’s bioavailability via the sublingual route. Niosomes were prepared using span 60 and cholesterol at different drug to...

  8. Histoanatomical study of the Sublingual Salivary Gland in the Camel

    Directory of Open Access Journals (Sweden)

    M.a Ebrahimi

    2008-02-01

    Full Text Available The heads of ten adult camels were used in this study. Following skin removal, the length, width and thickness of the gland was measured by ruler and caliper. Dye injection was used to distinguish the sublingual duct papilla and 1cm sections from the gland were removed and fixed to prepare histologic sections stained with H & E for microscopic studies. The long, ribbon like and lobulated monostomatic part of the gland is situated underneath the tongue alongside the hypoglossus muscle. This part of the gland begins from the mandibular symphysis and is continued caudally to near the root of the tongue. The average length, width and thickness of this part were 15.2±0.02, 2.2±0.03 and 0.5±0.05 cm respectively. The polystomatic part was observed as scattered and lobulated near the submucosa and in front of the monostomatic part with decreasing concentration caudally. The average size of these fragments was approximately 0.5±0.02 cm. The overall appearance of the gland was lobulated with a pink colour. The monostomatic part has a single duct entering the sublingual caruncle. The minute polystomatic ducts open into the depressions alongside the tongue inside the oral cavity. These ducts are numerous. Histologically, the gland is surrounded by a capsule of dense connective tissue. Trabcules from the capsule penetrate the gland and divide it into lobules. Loose connective tissue makes up the framework of the gland and there are tubulo-acinus glands in the spaces of this framework. Approximately 95% of the secretory cells of this gland consist of mucous secreting cells. Myoepithelial cells are seen on the external surface of the secretory cells and also alongside the connecting ducts.

  9. Monitoring Microcirculatory Blood Flow with a New Sublingual Tonometer in a Porcine Model of Hemorrhagic Shock

    Directory of Open Access Journals (Sweden)

    Péter Palágyi

    2015-01-01

    Full Text Available Tissue capnometry may be suitable for the indirect evaluation of regional hypoperfusion. We tested the performance of a new sublingual capillary tonometer in experimental hemorrhage. Thirty-six anesthetized, ventilated mini pigs were divided into sham-operated (n=9 and shock groups (n=27. Hemorrhagic shock was induced by reducing mean arterial pressure (MAP to 40 mmHg for 60 min, after which fluid resuscitation started aiming to increase MAP to 75% of the baseline value (60–180 min. Sublingual carbon-dioxide partial pressure was measured by tonometry, using a specially coiled silicone rubber tube. Mucosal red blood cell velocity (RBCV and capillary perfusion rate (CPR were assessed by orthogonal polarization spectral (OPS imaging. In the 60 min shock phase a significant drop in cardiac index was accompanied by reduction in sublingual RBCV and CPR and significant increase in the sublingual mucosal-to-arterial PCO2 gap (PSLCO2 gap, which significantly improved during the 120 min resuscitation phase. There was significant correlation between PSLCO2 gap and sublingual RBCV (r=-0.65, p<0.0001, CPR (r=-0.64, p<0.0001, central venous oxygen saturation (r=-0.50, p<0.0001, and central venous-to-arterial PCO2 difference (r=0.62, p<0.0001. This new sublingual tonometer may be an appropriate tool for the indirect evaluation of circulatory changes in shock.

  10. Depigmented allergoids reveal new epitopes with capacity to induce IgG blocking antibodies.

    Science.gov (United States)

    López-Matas, M Angeles; Gallego, Mayte; Iraola, Víctor; Robinson, Douglas; Carnés, Jerónimo

    2013-01-01

    The synthesis of allergen-specific blocking IgGs that interact with IgE after allergen immunotherapy (SIT) has been related to clinical efficacy. The objectives were to investigate the epitope specificity of IgG-antibodies induced by depigmented-polymerized (Dpg-Pol) allergoids and unmodified allergen extracts, and examine IgE-blocking activity of induced IgG-antibodies. Rabbits were immunized with native and Dpg-Pol extracts of birch pollen, and serum samples were obtained. Recognition of linear IgG-epitopes of Bet v 1 and Bet v 2 and the capacity of these IgG-antibodies to block binding of human-IgE was determined. Serum from rabbits immunized with native extracts recognised 11 linear epitopes from Bet v 1, while that from Dpg-Pol-immunized animals recognised 8. For Bet v 2, 8 epitopes were recognized by IgG from native immunized animals, and 9 from Dpg-Pol immunized one. Dpg-Pol and native immunized serum did not always recognise the same epitopes, but specific-IgG from both could block human-IgE binding sites for native extract. Depigmented-polymerized birch extract stimulates the synthesis of specific IgG-antibodies which recognize common but also novel epitopes compared with native extracts. IgG-antibodies induced by Dpg-Pol effectively inhibit human-IgE binding to allergens which may be part of the mechanism of action of SIT.

  11. Clinical benefits of treatment with SQ house dust mite sublingual tablet in house dust mite allergic rhinitis.

    Science.gov (United States)

    Demoly, P; Kleine-Tebbe, J; Rehm, D

    2017-10-01

    Treatment with SQ (standardised quality) house dust mite sublingual tablet for 1 year resulted in a decreased probability of having an allergic rhinitis (AR) exacerbation day (from 11% [placebo] to 5% [SQ house dust mite sublingual tablet]) and an increased probability of having a mild AR day (from 16% [placebo] to 34% [SQ house dust mite sublingual tablet]). © 2017 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.

  12. Buccal or sublingual misoprostol for cervical ripening and induction of labour.

    Science.gov (United States)

    Muzonzini, G; Hofmeyr, G J

    2004-10-18

    This is one of a series of reviews of cervical ripening and labour induction using standardised methodology. Misoprostol administered by the oral and sublingual routes have the advantage of rapid onset of action, while the sublingual and vaginal routes have the advantage of prolonged activity and greatest bioavailability. To determine the effectiveness and safety of misoprostol administered buccally or sublingually for third trimester cervical ripening and induction of labour. We searched the Cochrane Pregnancy and Childbirth Group trials register (8 December 2003), the Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 4, 2003), and bibliographies of relevant papers. Randomised controlled trials comparing buccal or sublingual misoprostol used for third trimester cervical ripening or labour induction with placebo/no treatment or other methods listed above it on a predefined list of labour induction methods. A generic strategy was developed to deal with the large volume and complexity of trial data relating to labour induction. Data were extracted onto standardized forms, checked for accuracy, and analysed using RevMan software. Three studies (502 participants) compared buccal/sublingual misoprostol respectively with a vaginal regimen (200 microg versus 50 microg) and with oral administration (50 versus 50 microg and 50 versus 100microg).The buccal route was associated with a trend to fewer caesarean sections than with the vaginal route (18/73 versus 28/79; relative risk (RR) 0.70; 95% confidence interval (CI) 0.42 to 1.15). There were no significant differences in any other outcomes. When the same dosage was used sublingually versus orally, the sublingual route was associated with less failures to achieve vaginal delivery within 24 hours (12/50 versus 19/50; RR 0.63, 95% CI 0.34 to 1.16), reduced oxytocin augmentation (17/50 versus 23/50; RR 0.74, 95% CI 0.45 to 1.21) and reduced caesarean section (8/50 versus 15/50; RR 0.53, 95% CI 0.25 to

  13. IgG binding of mugwort pollen allergens and allergoids exposed to simulated gastrointestinal conditions measured by a self-developed ELISA test

    Directory of Open Access Journals (Sweden)

    RATKO M. JANKOV

    2004-07-01

    Full Text Available This study considers the influence of exposure to simulated gastrointestinal conditions (saliva, gut, intestine and acidic conditions of the gut on IgG binding of unmodified allergens and three types of LMW allergoids of Artemisia vulgaris pollen extract obtained by means of potassium cyanate, succinic and maleic anhydride. It also concerns the optimization of a self-developed ELISA assay for comparison of the specific IgG binding of mugwort pollen extract and modified mugwort pollen derivatives. The ELISA was conducted with a mugwort pollen extract coupled to the plate, using the sera from 12 mugwort-pollen allergic patients. The exposure to saliva fluid for 2 min did not influence the IgG binding properties of allergens and allergoids. Exposure of mugwort pollen allergens and LMW allergoids to the acidic conditions of the gut did not dramatically change their IgG binding properties. By exposing mugwort pollen extract and LMW derivatives to the SGF conditions for 1 h, the percent of IgG binding epitopes was reduced to a half of its starting value in the extract and to about 30 % in all the allergoid samples. After prolonged exposure only the carbamyl derivative showed reduced IgG binding. Changes of the IgG binding potential of all four samples after exposure in SIF followed a similar pattern.

  14. Monomeric Yeast Frataxin is an Iron-Binding Protein

    International Nuclear Information System (INIS)

    Cook, J.; Bencze, K.; Jankovic, A.; Crater, A.; Busch, C.; Bradley, P.; Stemmler, A.; Spaller, M.; Stemmler, T.

    2006-01-01

    Friedreich's ataxia, an autosomal cardio- and neurodegenerative disorder that affects 1 in 50 000 humans, is caused by decreased levels of the protein frataxin. Although frataxin is nuclear-encoded, it is targeted to the mitochondrial matrix and necessary for proper regulation of cellular iron homeostasis. Frataxin is required for the cellular production of both heme and iron-sulfur (Fe-S) clusters. Monomeric frataxin binds with high affinity to ferrochelatase, the enzyme involved in iron insertion into porphyrin during heme production. Monomeric frataxin also binds to Isu, the scaffold protein required for assembly of Fe-S cluster intermediates. These processes (heme and Fe-S cluster assembly) share requirements for iron, suggesting that monomeric frataxin might function as the common iron donor. To provide a molecular basis to better understand frataxin's function, we have characterized the binding properties and metal-site structure of ferrous iron bound to monomeric yeast frataxin. Yeast frataxin is stable as an iron-loaded monomer, and the protein can bind two ferrous iron atoms with micromolar binding affinity. Frataxin amino acids affected by the presence of iron are localized within conserved acidic patches located on the surfaces of both helix-1 and strand-1. Under anaerobic conditions, bound metal is stable in the high-spin ferrous state. The metal-ligand coordination geometry of both metal-binding sites is consistent with a six-coordinate iron-(oxygen/nitrogen) based ligand geometry, surely constructed in part from carboxylate and possibly imidazole side chains coming from residues within these conserved acidic patches on the protein. On the basis of our results, we have developed a model for how we believe yeast frataxin interacts with iron

  15. Allergoid-specific T-cell reaction as a measure of the immunological response to specific immunotherapy (SIT) with a Th1-adjuvanted allergy vaccine.

    Science.gov (United States)

    von Baehr, V; Hermes, A; von Baehr, R; Scherf, H P; Volk, H D; Fischer von Weikersthal-Drachenberg, K J; Woroniecki, S

    2005-01-01

    Specific immunotherapy (SIT) is believed to modulate CD4+ T-helper cells. In order to improve safety, SIT vaccines are often formulated with allergoids (chemically modified allergens). Interaction between T-cells and allergoids is necessary to influence cellular cytokine expression. There have been few reports on identification the early cellular effects of SIT. Patients allergic to grass and/or mugwort pollen (n= 21) were treated with a 4-shot allergy vaccine (Pollinex Quattro) containing appropriate allergoids (grass/rye and/or mugwort) adsorbed to L-tyrosine plus a Th1 adjuvant, monophosphoryl lipid A (MPL). Fourteen grass-allergic patients served as untreated controls. Using the peripheral blood mononuclear cells of these patients, an optimized lymphocyte transformation test (LTT) was employed to monitor the in vitro proliferative response of T-cells to an allergoid challenge (solubilised Pollinex Quattro) before the first and last injection and then 2 and 20 weeks after the final injection. Control challenges utilised preparations of a similar pollen vaccine without the adjuvant MPL and a tree pollen vaccine with and without MPL. The LTT showed increased LTT stimulation indices (SI) in 17/20 SIT patients when the solublised vaccine preparation was used as a challenge before the last injection and 2 weeks after, in comparison to pre-treatment levels. Twenty weeks after therapy, the SI decreased to baseline level. A vaccine challenge without MPL gave lower SI levels. A challenge of a clinically inappropriate tree allergoid vaccine gave no response, and a nontreated group also showed no response. Following a short-course SIT adjuvated with MPL, challenges of allergoids were shown to activate allergen-specific T cells in vitro. There was an additional stimulating effect when the challenge was in combination with MPL. There were no non-specific effects of MPL, shown by the tree allergoid/MPL control. The timing of the response was closely correlated to the

  16. Immunotherapy (oral and sublingual) for food allergy to fruits.

    Science.gov (United States)

    Yepes-Nuñez, Juan Jose; Zhang, Yuan; Roqué i Figuls, Marta; Bartra Tomas, Joan; Reyes, Juan Manuel; Pineda de la Losa, Fernando; Enrique, Ernesto

    2015-11-09

    Food allergy is an abnormal immunological response following exposure (usually ingestion) to a food. Elimination of the allergen is the principle treatment for food allergy, including allergy to fruit. Accidental ingestion of allergenic foods can result in severe anaphylactic reactions. Allergen-specific immunotherapy (SIT) is a specific treatment, when the avoidance of allergenic foods is problematic. Recently, studies have been conducted on different types of immunotherapy for the treatment of food allergy, including oral (OIT) and sublingual immunotherapy (SLIT). To determine the efficacy and safety of oral and sublingual immunotherapy in children and adults with food allergy to fruits, when compared with placebo or an elimination strategy. The Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL, and AMED were searched for published results along with trial registries and the Journal of Negative Results in BioMedicine for grey literature. The date of the most recent search was July 2015. Randomised controlled trials (RCTs) comparing OIT or SLIT with placebo or an elimination diet were included. Participants were children or adults diagnosed with food allergy who presented immediate fruit reactions. We used standard methodological procedures expected by the Cochrane Collaboration. We assessed treatment effect through risk ratios (RRs) for dichotomous outcomes. We identified two RCTs (N=89) eligible for inclusion. These RCTs addressed oral or sublingual immunotherapy, both in adults, with an allergy to apple or peach respectively. Both studies enrolled a small number of participants and used different methods to provide these differing types of immunotherapy. Both studies were judged to be at high risk of bias in at least one domain. Overall, the quality of evidence was judged to be very low due to the small number of studies and participants and possible bias. The studies were clinically heterogeneous and hence we did not pool the

  17. Prehospital high-dose sublingual nitroglycerin rarely causes hypotension.

    Science.gov (United States)

    Clemency, Brian M; Thompson, Jeffrey J; Tundo, Gina N; Lindstrom, Heather A

    2013-10-01

    High-dose intravenous nitroglycerin is a common in-hospital treatment for respiratory distress due to congestive heart failure (CHF) with hypertension. Intravenous (IV) nitroglycerin administration is impractical in the prehospital setting. In 2011, a new regional Emergency Medical Services (EMS) protocol was introduced allowing advanced providers to treat CHF with high-dose oral nitroglycerin. The protocol calls for patients to be treated with two sublingual tabs (0.8 mg) when systolic blood pressure (SBP) was >160 mm Hg, or three sublingual tabs (1.2 mg) when SBP was >200 mm Hg, every five minutes as needed. Hypothesis/Problem To assess the protocol's safety, the incidence of hypotension following prehospital administration of multiple simultaneous nitroglycerin (MSN) tabs by EMS providers was studied. This study was a retrospective cohort study of patients from a single commercial EMS agency over a 6-month period. Records from patients with at least one administration of MSN were reviewed. For each administration, the first documented vital signs pre- and post-administration were compared. Administrations were excluded if pre- or post-administration vital signs were missing. One hundred case-patients had at least one MSN administration by an advanced provider during the study period. Twenty-five case-patients were excluded due to incomplete vital signs. Seventy-five case-patients with 95 individual MSN administrations were included for analysis. There were 65 administrations of two tabs, 29 administrations of three tabs, and one administration of four tabs. The mean change in SBP following MSN was -14.7 mm Hg (SD = 30.7; range, +59 to -132). Three administrations had documented systolic hypotension in the post-administration vital signs (97/71, 78/50 and 66/47). All three patients were over 65 years old, were administered two tabs, had documented improved respiratory status, and had repeat SBP of at least 100. The incidence of hypotension following MSN

  18. Misoprostol sublingual versus vaginal para indução do parto a termo Sublingual versus vaginal misoprostol for labor induction of term pregnancies

    Directory of Open Access Journals (Sweden)

    Olímpio Barbosa de Moraes Filho

    2005-01-01

    Full Text Available OBJETIVO: comparar efetividade e segurança de uso de comprimido sublingual de 25 µg de misoprostol com o comprimido vaginal de 25 µg do misoprostol na indução do parto com idade gestacional e > 37 semanas e colo uterino desfavorável. MÉTODOS: realizou-se ensaio clínico controlado e aleatorizado, não cego, na Maternidade Monteiro de Morais (CISAM-UPE, em Recife, no período de outubro de 2003 a fevereiro de 2004. Participaram do estudo 123 gestantes com idade gestacional e > 37 semanas, índice de Bishop PURPOSE: to compare the effectiveness and safety of sublingual misoprostol (25 µg versus vaginal misoprostol (25 µg (Prostokos® for labor induction with gestational age > 37 weeks and unripe cervices. METHODS: a randomized controlled clinical trial was performed at the Maternidade Monteiro de Morais (CISAM-UPE, in Recife - PE, Brazil, from October 2003 to February 2004. One hundred and twenty-three women with gestational age > 37 weeks, Bishop score <8, not in labor and with medical indication for interruption of pregnancy were included in this study. The women received randomly 25 µg sublingual misoprostol or 25 µg vaginal misoprostol every 6 h, not exceeding eight doses. In order to evaluate the differences between the groups, means, standard deviations, Student's t-test, c² trend and Mann-Whitney test were used. The statistical significance was considered to be 5%. RESULTS: there were no significant differences between the number of women with vaginal delivery in the sublingual group as compared with the vaginal group (65.5 vs 75.8%, p<0.22, or in the interval of time between the induction onset and delivery (24 h and 42 min vs 20 h and 37 min respectively, p=0.11. The two groups, sublingual and vaginal, also did not differ as to the hyperstimulation syndrome (1.7 vs 3.2%, p=0.95, meconium incidence (5.2 vs 4.8%, p=0.74, Apgar score <7 at 5 min (3.4 vs 4.8%, p=0.98 and other adverse effects. CONCLUSION: twenty-five micrograms of

  19. The adsorption of allergoids and 3-O-desacyl-4'-monophosphoryl lipid A (MPL®) to microcrystalline tyrosine (MCT) in formulations for use in allergy immunotherapy.

    Science.gov (United States)

    Bell, A J; Heath, M D; Hewings, S J; Skinner, M A

    2015-11-01

    Infectious disease vaccine potency is affected by antigen adjuvant adsorption. WHO and EMA guidelines recommend limits and experimental monitoring of adsorption in vaccines and allergy immunotherapies. Adsorbed allergoids and MPL® in MATA-MPL allergy immunotherapy formulations effectively treat IgE mitigated allergy. Understanding vaccine antigen adjuvant adsorption allows optimisation of potency and should be seen as good practice; however current understanding is seldom applied to allergy immunotherapies. The allergoid and MPL® adsorption to MCT in MATA-MPL allergy immunotherapy formulations was experimental determination using specific allergen IgE allerginicity and MPL® content methods. Binding forces between MPL® and MCT were investigated by competition binding experiments. MATA-MPL samples with different allergoids gave results within 100-104% of the theoretical 50μg/mL MPL® content. Unmodified drug substance samples showed significant desirable IgE antigenicity, 1040-170 QAU/mL. MATA-MPL supernatant samples with different allergoids gave results of ≤2 μg/mL MPL® and ≤0.1-1.4 QAU/mL IgE antigenicity, demonstrating approximately ≥96 & 99% adsorption respectively. Allergoid and MPL® adsorption in different MATA-MPL allergy immunotherapy formulations is consistent and meets guideline recommendations. MCT formulations treated to disrupt electrostatic, hydrophobic and ligand exchange interactions, gave an MPL® content of ≤2 μg/mL in supernatant samples. MCT formulations treated to disrupt aromatic interactions, gave an MPL® content of 73-92 μg/mL in supernatant samples. MPL® adsorption to l-tyrosine in MCT formulations is based on interactions between the 2-deoxy-2-aminoglucose backbone on MPL® and aromatic ring of l-tyrosine in MCT, such as C-H⋯π interaction. MCT could be an alternative adjuvant depot for some infectious disease antigens. Copyright © 2015. Published by Elsevier Inc.

  20. Depigmented Allergoids Reveal New Epitopes with Capacity to Induce IgG Blocking Antibodies

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    M. Angeles López-Matas

    2013-01-01

    Full Text Available Background. The synthesis of allergen-specific blocking IgGs that interact with IgE after allergen immunotherapy (SIT has been related to clinical efficacy. The objectives were to investigate the epitope specificity of IgG-antibodies induced by depigmented-polymerized (Dpg-Pol allergoids and unmodified allergen extracts, and examine IgE-blocking activity of induced IgG-antibodies. Methods. Rabbits were immunized with native and Dpg-Pol extracts of birch pollen, and serum samples were obtained. Recognition of linear IgG-epitopes of Bet v 1 and Bet v 2 and the capacity of these IgG-antibodies to block binding of human-IgE was determined. Results. Serum from rabbits immunized with native extracts recognised 11 linear epitopes from Bet v 1, while that from Dpg-Pol-immunized animals recognised 8. For Bet v 2, 8 epitopes were recognized by IgG from native immunized animals, and 9 from Dpg-Pol immunized one. Dpg-Pol and native immunized serum did not always recognise the same epitopes, but specific-IgG from both could block human-IgE binding sites for native extract. Conclusions. Depigmented-polymerized birch extract stimulates the synthesis of specific IgG-antibodies which recognize common but also novel epitopes compared with native extracts. IgG-antibodies induced by Dpg-Pol effectively inhibit human-IgE binding to allergens which may be part of the mechanism of action of SIT.

  1. Morphology and morphometry of the human sublingual glands in mouth floor enlargements of edentulous patients

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    Josiane Costa Rodrigues de SA

    2013-12-01

    Full Text Available Asymptomatic mouth floor enlargements may be observed in edentulous patients. These masses, which protrude from the mouth floor, may complicate the fitting of dentures and require surgery. Whether this "entity" may be considered an anatomical variation of the mouth floor or represent specific alterations in the sublingual gland is not known. Objective: The aim of this work is to investigate the morphological and morphometric aspects of the sublingual glands of edentulous patients with mouth floor enlargements and compare the glands of these patients with the sublingual glands of human cadavers. Material and Methods: Microscopic evaluation was performed on human sublingual glands from edentulous patients with mouth floor enlargements (n=20 and edentulous cadavers (n=20. The patients and cadavers were of similar ages. The data were compared using Mann-Whitney U, Fisher's exact and Student's t tests (p0.05. Only the variables "autolysis" and "congested blood vessels" presented statistical difference between groups (p=0.014; p=0.043. The morphometric study revealed that the volume densities of acini, ducts, stroma and adipose tissue were similar between the groups (p>0.05. CONCLUSION: The microscopic characteristics of the sublingual glands in mouth floor enlargements in edentulous patients correspond to characteristics associated with the normal aging process. The glands are not pathological and represent an age-related alteration that occurs with or without the presence of the mouth floor enlargements.

  2. Selection of patients for sublingual versus subcutaneous immunotherapy.

    Science.gov (United States)

    Larenas Linnemann, Désirée E S; Blaiss, Michael S

    2014-01-01

    Allergen immunotherapy is the sole treatment for IgE-mediated allergic diseases directed at the underlying mechanism. The two widely accepted administration routes are sublingual (SLIT) and subcutaneous (SCIT). We reviewed how patients should best be selected for immunotherapy and how the optimal administration route can be defined. Before deciding SCIT or SLIT, appropriate selection of patients for allergen immunotherapy (AIT) is mandatory. To be eligible for AIT, subjects must have a clear medical history of allergic disease, with exacerbation of symptoms on exposure to one or more allergens and a corresponding positive skin or in vitro test. Then the route of administration should be based on: published evidence of clinical and immunologic efficacy (which varies per allergic disease and per allergen); mono- or multi-allergen immunotherapy, for SLIT multi-allergen immunotherapy was not effective; safety: adverse events with SLIT are more frequent, but less severe; and, costs and patient preferences, closely related to adherence issues. All these are discussed in the article.

  3. Local Side Effects of Sublingual and Oral Immunotherapy.

    Science.gov (United States)

    Passalacqua, Giovanni; Nowak-Węgrzyn, Anna; Canonica, Giorgio Walter

    Sublingual immunotherapy (SLIT) is increasingly used worldwide, and several products have been recently registered as drugs for respiratory allergy by the European Medicine Agency and the Food and Drug Administration. Concerning inhalant allergens, the safety of SLIT is overall superior to that of subcutaneous immunotherapy in terms of systemic adverse events. No fatality has been ever reported, and episodes of anaphylaxis were described only exceptionally. Looking at the historical and recent trials, most (>90%) adverse events are "local" and confined to the site of administration. For this reason, a specific grading system has been developed by the World Allergy Organization to classify and describe local adverse events. There is an increasing amount of literature concerning oral desensitization for food allergens, referred to as oral immunotherapy. Also, in this case, local side effects are predominant, although systemic adverse events are more frequent than with inhalant allergens. We review herein the description of local side effects due to SLIT, with a special focus on large trials having a declared sample size calculation. The use of the Medical Dictionary for Regulatory Activities nomenclature for adverse events is mentioned in this context, as recommended by regulatory agencies. It is expected that a uniform classification/grading of local adverse events will improve and harmonize the surveillance and reporting on the safety of SLIT. Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  4. Efficacy and safety of sublingual tablets of house dust mite allergen extracts in adults with allergic rhinitis

    NARCIS (Netherlands)

    Bergmann, Karl-Christian; Demoly, Pascal; Worm, Margitta; Fokkens, Wytske J.; Carrillo, Teresa; Tabar, Ana I.; Nguyen, Hélène; Montagut, Armelle; Zeldin, Robert K.

    2014-01-01

    Preliminary studies have suggested the efficacy of sublingual tablets of house dust mite (HDM) extracts in adults with allergic rhinitis. We sought to assess the efficacy and safety of 2 doses of HDM sublingual tablets over 1 treatment year and the subsequent immunotherapy-free year. Adults with

  5. SYNTHESIS AND STRUCTURE OF BIS(PHENYLTETRAMETHYLCYCLOPENTADIENYL)TITANIUM(III) HYDRIDE - THE FIRST MONOMERIC BIS(CYCLOPENTADIENYL)TITANIUM(III) HYDRIDE : The First Monomeric Bis(cyclopentadienyl)titanium(III) Hydride

    NARCIS (Netherlands)

    de Wolf, J.M.; Meetsma, A.; Teuben, J.H

    1995-01-01

    The first structurally characterized monomeric bis(cyclopentadienyl)titanium(III) hydride, (C(5)PhMe(4))(2)TiH (4), was synthesized by hydrogenolysis of (C(5)PhMe(4))(2)TiMe (5). Hydride 4 was found to be a monomeric bent sandwich by X-ray diffraction methods, and the pentamethylcyclopentadienyl

  6. Sharp tooth induced sublingual hematoma in a patient with elevated international normalized ratio

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    John Baliah

    2015-01-01

    Full Text Available Sublingual hematoma secondary to anticoagulation is a rare fatal condition. Hemorrhagic complications of warfarin are well-known. This particular case is unique because the patient was on warfarin for the past 2 years but did not develop the sublingual hematoma. However, a trauma by an attrited sharp cusp triggered the episode of the sublingual hematoma in this patient. Being a medical emergency, patient was promptly hospitalized in cardiac care unit and managed by medical team. The patient was transfused with 2 units of fresh frozen plasma and warfarin was temporarily stopped for 4 days. Alternate day regimen of warfarin was started after 4 days, and international normalized ratio dropped to 3. In dental management, enameloplasty of the mandibular first molar tooth was done to prevent trauma and ulcer development in the floor of the mouth. The hematoma resolved, and no new hematoma formation was observed for a period of 6 months.

  7. Monomeric insulins and their experimental and clinical implications.

    Science.gov (United States)

    Brange, J; Owens, D R; Kang, S; Vølund, A

    1990-09-01

    Due to the inherent pharmacokinetic properties of available insulins, normoglycemia is rarely, if ever, achieved in insulin-dependent diabetic patients without compromising their quality of life. Subcutaneous insulin absorption is influenced by many factors, among which the associated state of insulin (hexameric) in pharmaceutical formulation may be of importance. This review describes the development of a series of human insulin analogues with reduced tendency to self-association that, because of more rapid absorption, are better suited to meal-related therapy. DNA technology has made it possible to prepare insulins that remain dimeric or even monomeric at high concentration by introducing one or a few amino acid substitutions into human insulin. These analogues were characterized and used for elucidating the mechanisms involved in subcutaneous absorption and were investigated in preliminary clinical studies. Their relative receptor binding and in vitro potency (free-fat cell assay), ranging from 0.05 to 600% relative to human insulin, were strongly correlated (r = 0.97). In vivo, most of the analogues exhibited approximately 100% activity, explainable by a dominating receptor-mediated clearance. This was confirmed by clamp studies in which correlation between receptor binding and clearance was observed. Thus, an analogue with reduced binding and clearance gives higher circulating concentrations, counterbalancing the reduced potency at the cellular level. Absorption studies in pigs revealed a strong inverse correlation (r = 0.96) between the rate of subcutaneous absorption and the mean association state of the insulin analogues. These studies also demonstrated that monomeric insulins were absorbed three times faster than human insulin. In healthy subjects, rates of disappearance from subcutis were two to three times faster for dimeric and monomeric analogues than for human insulin. Concomitantly, a more rapid rise in plasma insulin concentration and an earlier

  8. The influence of a residual group in low-molecular-weight allergoids of Artemisia vulgaris pollen on their allergenicity, IgE- and IgG-binding properties.

    Science.gov (United States)

    Cirković, T; Gavrović-Jankulović, M; Prisić, S; Jankov, R M; Burazer, L; Vucković, O; Sporcić, Z; Paranos, S

    2002-11-01

    Reaction of epsilon-amino groups of lysine with potassium cyanate, maleic, or succinic anhydride leads to allergoids of low molecular weight. No study has been performed to compare their properties and investigate the influence of a residual group on allergenicity and human IgE- and IgG-binding of these derivatives. Allergoids of a pollen extract of Artemisia vulgaris were obtained by means of potassium cyanate, and succinic and maleic anhydride. Biochemical properties were investigated by determination of amino groups, enzyme activity, isoelectric focusing IEF and SDS-PAGE. IgE- and IgG-binding was determined using immunoblots and ELISA inhibition. Allergenicity was investigated by skin prick tests (SPT) on a group of 52 patients, of which 6 were control subjects, 30 were patients with no previous immunotherapy (IT), and 16 were patients undergoing immunotherapy. The same degree of amino-group modification (more than 85%), residual enzyme activity (less then 15%), IEF, and SDS-PAGE pattern were noted. In the immunoblots of IgE-binding, there was more pronounced reduction in the succinyl and maleyl derivatives than in the carbamyl one. IgG-binding was less affected by carbamylation than by acid anhydride modification. The SPT showed that the succinylated derivative had the most reduced allergenicity (98% showed a reduced wheal diameter when tested with the succinyl derivative, 87% with the maleyl allergoid, and 83% with the carbamyl allergoid). The most significant difference among allergoids could be seen in the group of patients with high skin reactivity (83% of patients showed no reaction to the succinyl derivative when compared to the value of 28% for the carbamyl derivative or 22% for the maleyl derivative). According to our results, all three modification procedures yielded allergoids with a similar extent of modification. No single biochemical parameter investigated in the study could predict the degree of reduced allergenicity in vivo. The most reduced

  9. Postmortem acinar autolysis in rat sublingual gland: a morphometric study.

    Science.gov (United States)

    Nery, Leticia Rodrigues; Moreira, Carla Ruffeil; Cestari, Tania Mary; Taga, Rumio; Damante, José Humberto

    2010-01-01

    To analyze and to quantify morphological acinar postmortem changes in rat sublingual glands (SLG). MATERIAL AND METHODSs: Fifty rats were divided into two groups of 25 animals each. Group I was used for morphological and morphometric evaluations and group II for the determination of gland density and processed gland volume. Acinar autolytic changes were studied at 0 (control group), 3, 6, 12 and 24 h postmortem periods. The morphometric analysis of the volume density (Vv) and total volume (Vt) of intact (ia) and autolyzed (aa) acini was performed under light microscopy using a Zeiss II integration grid with 100 symmetrically distributed points. Morphologically, temporal progressive nuclear alterations and gradual loss of the structural architecture of acinar cells were found. Regarding quantitative results, both the Vvaa and the Vvia showed statistically significant differences among all postmortem periods (p0.05), respectively. Vtaa increased from 0.18 mm³ at 0 h to 38.17 mm³ at 12 h, while Vtia showed a decrease from 33.47 mm³ to 0 mm³ between 3-24 h postmortem. Data concerning Vtaa were adjusted by two-variable linear regression, obtaining the equation: y=-3.54+3.38x (r²=0.90). The Vtaa growth rate calculated by this equation was 3.38 mm³/h between 0-12 h. Acinar autolysis on rat SLG demonstrated the most significant signs during the first 6 h postmortem and was widely spread through the gland at 12 h.

  10. [Cluster-immunotherapy in seasonal allergic rhinitis: safety aspects of induction therapy with depot allergoids (Purethal)].

    Science.gov (United States)

    Hansen, I; Hörmann, K; Stuck, B A; Schneider-Gêne, S; Mösges, R; Klimek, L

    2003-08-01

    Specific immunotherapy (SIT) represents the only specific treatment that can be offered to allergic patients apart from allergen avoidance. SIT has been widely used in pollen allergic rhinitis. Clinical efficacy has been demonstrated in several controlled clinical trials and depends on the specific allergen the individual patient is sensitive to, the quality and total amount of allergen applied, and the SIT schedule. In classic SIT, gradually increasing dosages of the allergen extract are injected subcutaneously. Several dosage schedules for subcutaneous SIT can be applied. In Cluster-SIT, 2 - 3 injections per day of treatment are given once a week during induction treatment. In this study, we investigated 64 patients (33 female, 31 male) from 18 to 54 years (26.9 +/- 5.1 years) in terms of side-effects of Cluster-SIT during induction treatment. The total amount of enlarged local reactions (> grade 1) was n = 77 or 15.2 % of all injections. Of these, 68 (88 %) were classified as immediate reactions, 8 (11 %) were late phase reactions and 1 (1 %) was immediate as well as late phase reaction. Of all enlarged local reactions, 48 (62 %) were grade 1 reactions, 13 (17 %) were grade 2 reactions, 13 (17 %) were grade 3 reactions and 1 (1 %) was a grade 4 reaction. The total amount of systemic reactions was n = 22 or 4.3 % of all injections. Of these, 19 (86 %) were classified as immediate reactions, 3 (14 %) were delayed reactions. Of all systemic reactions, 18 (82 %) were grade 1 reactions and 4 (18 %) grade 2 reactions. Grade 3 or grade 4 reactions did not occur. There were no differences in gender or age regarding the occurrence of side effects (all p > 0.05). Frequency and severity of adverse side effects in Cluster-SIT correspond to those in other dosage schedules. On behalf of security aspects, Cluster-SIT could become an interesting alternative dosage schedule for dose increase during SIT. Furthermore, in Cluster-SIT with allergoids, induction treatment can be

  11. Characterization of monomeric intermediates during VSV glycoprotein structural transition.

    Directory of Open Access Journals (Sweden)

    Aurélie A Albertini

    2012-02-01

    Full Text Available Entry of enveloped viruses requires fusion of viral and cellular membranes, driven by conformational changes of viral glycoproteins. Crystal structures provide static pictures of pre- and post-fusion conformations of these proteins but the transition pathway remains elusive. Here, using several biophysical techniques, including analytical ultracentrifugation, circular dichroïsm, electron microscopy and small angle X-ray scattering, we have characterized the low-pH-induced fusogenic structural transition of a soluble form of vesicular stomatitis virus (VSV glycoprotein G ectodomain (G(th, aa residues 1-422, the fragment that was previously crystallized. While the post-fusion trimer is the major species detected at low pH, the pre-fusion trimer is not detected in solution. Rather, at high pH, G(th is a flexible monomer that explores a large conformational space. The monomeric population exhibits a marked pH-dependence and adopts more elongated conformations when pH decreases. Furthermore, large relative movements of domains are detected in absence of significant secondary structure modification. Solution studies are complemented by electron micrographs of negatively stained viral particles in which monomeric ectodomains of G are observed at the viral surface at both pH 7.5 and pH 6.7. We propose that the monomers are intermediates during the conformational change and thus that VSV G trimers dissociate at the viral surface during the structural transition.

  12. Monomeric insulins obtained by protein engineering and their medical implications.

    Science.gov (United States)

    Brange, J; Ribel, U; Hansen, J F; Dodson, G; Hansen, M T; Havelund, S; Melberg, S G; Norris, F; Norris, K; Snel, L

    1988-06-16

    The use of insulin as an injected therapeutic agent for the treatment of diabetes has been one of the outstanding successes of modern medicine. The therapy has, however, had its associated problems, not least because injection of insulin does not lead to normal diurnal concentrations of insulin in the blood. This is especially true at meal times when absorption from subcutaneous tissue is too slow to mimic the normal rapid increments of insulin in the blood. In the neutral solutions used for therapy, insulin is mostly assembled as zinc-containing hexamers and this self-association, which under normal physiological circumstances functions to facilitate proinsulin transport, conversion and intracellular storage, may limit the rate of absorption. We now report that it is possible, by single amino-acid substitutions, to make insulins which are essentially monomeric at pharmaceutical concentrations (0.6 mM) and which have largely preserved their biological activity. These monomeric insulins are absorbed two to three times faster after subcutaneous injection than the present rapid-acting insulins. They are therefore capable of giving diabetic patients a more physiological plasma insulin profile at the time of meal consumption.

  13. Safety of ultrashort-term sit with pollen allergoids adjuvanted by monophosphoryl lipid A: a prospective Italian survey.

    Science.gov (United States)

    Crivellaro, M; Senna, G E; Pappacoda, A; Vanzelli, R; Spacal, B; Marchi, G; Recchia, G; Makatsori, M

    2011-03-01

    A 3-year prospective post marketing survey on the safety of the recently developed ultrashort pre-seasonal subcutaneous immunotherapy (uSCIT-MPL4) with pollen allergoids adjuvanted with monophosphoryl lipid A was performed. A total of 510 patients received uSCIT-MPL4, 61% for grass, 35.7% for birch, 13.2% for parietaria and 3% for other pollens (ragweed, mugwort, and olive). A total of 3308 injections were given and the mean duration of uSCIT-MPL-4 was 2.3 years. Overall, only 7 slight systemic reactions (SR) were observed in 510 patients (1.37%) and 2.11/1000 injections suggesting that this treatment is even safer than traditional depot injection SIT.

  14. Depigmented and polymerised house dust mite allergoid: allergen content, induction of IgG4 and clinical response.

    Science.gov (United States)

    Gallego, M T; Iraola, V; Himly, M; Robinson, D S; Badiola, C; García-Robaina, J C; Briza, P; Carnés, J

    2010-01-01

    Polymerised allergenic extracts (allergoids) are commonly used in allergen immunotherapy. Clinical efficacy and safety of these extracts have been demonstrated. Recently, allergen sequences have been identified by mass spectrometry in depigmented and polymerised (Dpg-Pol) extracts. The objectives of this study were to investigate the presence of allergens in Dpg-Pol extracts of house dust mite and to analyze the immunological changes induced by these extracts in asthmatic patients enrolled in a double-blind, placebo-controlled study. Dpg-Pol extracts were manufactured and vaccines with a composition of 50% Dermatophagoides pteronyssinus and 50% D. farinae (100 HEPL/ml) were prepared. Allergen composition was analyzed by mass spectrometry. Patients with asthma and rhinoconjunctivitis were treated in a 1-year, double-blind, placebo-controlled, parallel-group study with 6 up-dosing and monthly maintenance injections. Specific IgE and IgG4 titres to D. pteronyssinus, Der p 1 and Der p 2 were measured in patients' sera using the CAP system and direct ELISA experiments. Sequences from the major allergens Der p 1 and Der p 2 and from other allergens were identified in native and Dpg-Pol extracts. There was a statistically significant increase in specific IgG4, a decrease in the ratio of IgE/IgG4 to D. pteronyssinus and a significant increase in specific IgG4 to Der p 1 and Der p 2 in the patients allotted to active treatment. The detection of allergen sequences suggests preservation of major and minor allergens in Dpg-Pol allergoids from house dust mites. Efficacy in asthma treatment and the increase in specific IgG4 seem to be associated with the presence of major allergens in Dpg-Pol allergen extracts. Copyright (c) 2010 S. Karger AG, Basel.

  15. A functional and chemical study of radiation effects on rat parotid and submandibular/sublingual glands

    International Nuclear Information System (INIS)

    Vissink, A.; S-Gravenmade, E.J.; Ligeon, E.E.; Konings, W.T.

    1990-01-01

    The aim of this study was to monitor composition and rate of secretion of rat parotid and submandibular/sublingual saliva following local single doses of X-rays ranging from 5 to 20 Gy. Pilocarpine-stimulated samples of parotid and submandibular/sublingual saliva were simultaneously collected with miniaturized Lashley cups before and 1-30 days after irradiation. The lag phase (period between injection of pilocarpine and start of the secretion) and flow rate were recorded and the concentrations of sodium, potassium, calcium, phosphate, and amylase were measured. With increasing dose and time, the salivary flow rate as well as sodium concentration decreased, while potassium concentrations increased throughout the follow-up period. The lag phase and the concentration of amylase reached their maximum at 3 and 10 days after irradiation, respectively. The changes in lag phase and flow rate were most obvious after doses of 15 or 20 Gy and showed a great similarity for parotid and submandibular/sublingual saliva. No dose-response relationship was observed for the changes in concentrations of calcium and phosphate. It is concluded that for radiation doses of 10 Gy and above, irreversible changes (lag phase, flow rate, potassium, sodium) were observed. A saturation of the irradiation effects (lag phase, flow rate) seems to exist at doses larger than 15 Gy. No significant differences were observed between the radiation-induced functional changes in parotid and submandibular/sublingual salivary gland tissue

  16. 78 FR 34108 - Determination That SUBOXONE (Buprenorphine Hydrochloride and Naloxone Hydrochloride) Sublingual...

    Science.gov (United States)

    2013-06-06

    ... naloxone HCl) sublingual tablets, 2 mg/0.5 mg and 8 mg/2 mg, are the subject of NDA 20-733, held by Reckitt Benckiser Pharmaceuticals, Inc. (Reckitt), and initially approved on October 8, 2002. SUBOXONE is indicated...,'' http://www.rb.com/site/rkbr/templates/mediainvestorsgeneral2.aspx?pageid=1332&cc=GB , Reckitt Benckiser...

  17. Biopharmaceutical evaluation of transnasal, sublingual, and buccal disk dosage forms of butorphanol.

    Science.gov (United States)

    Shyu, W C; Mayol, R F; Pfeffer, M; Pittman, K A; Gammans, R E; Barbhaiya, R H

    1993-07-01

    A series of three-way crossover randomized studies were conducted to evaluate the absolute bioavailability of butorphanol, a potent agonist-antagonist analgesic, from transnasal, sublingual, and buccal disk formulations in order to identify a practical alternative to oral administration. In each study, healthy male volunteers received 2 mg doses of butorphanol tartrate intravenously and either transnasally, sublingually or buccally. Serial blood samples were collected over 12 h and butorphanol plasma concentrations were determined by radioimmunoassay. The plasma concentration data were subjected to non-compartmental pharmacokinetic analysis. The elimination half-life of butorphanol was about 3-5 h and was independent of the route of administration. Absorption of butorphanol following transnasal administration was faster than that observed following sublingual or buccal administration. Mean absolute bioavailabilities of sublingual tablet and buccal disk formulation were only 19 per cent and 29 per cent, respectively, but for transnasal administration the value rose significantly, to 70 per cent. Based on the results of these studies, transnasal dosage form of butorphanol was selected for further clinical trials of treatment of moderate to severe pain.

  18. Sublingual nitroglycerin administration in coronary computed tomography angiography: a systematic review

    Energy Technology Data Exchange (ETDEWEB)

    Takx, Richard A.P. [Harvard Medical School, Cardiac MR PET CT Program, Department of Radiology, Massachusetts General Hospital, Boston, MA (United States); University Medical Center Utrecht, Department of Radiology, Utrecht (Netherlands); Sucha, Dominika; Leiner, Tim [University Medical Center Utrecht, Department of Radiology, Utrecht (Netherlands); Park, Jakob [Harvard Medical School, Cardiac MR PET CT Program, Department of Radiology, Massachusetts General Hospital, Boston, MA (United States); University of Heidelberg, Department of Cardiology, Heidelberg (Germany); Hoffmann, Udo [Harvard Medical School, Cardiac MR PET CT Program, Department of Radiology, Massachusetts General Hospital, Boston, MA (United States)

    2015-12-15

    To systematically investigate the literature for the influence of sublingual nitroglycerin administration on coronary diameter, the number of evaluable segments, image quality, heart rate and blood pressure, and diagnostic accuracy of coronary computed tomography (CT) angiography. A systematic search was performed in PubMed, EMBASE and Web of Science. The studies were evaluated for the effect of sublingual nitroglycerin on coronary artery diameter, evaluable segments, objective and subjective image quality, systemic physiological effects and diagnostic accuracy. Due to the heterogeneous reporting of outcome measures, a narrative synthesis was applied. Of the 217 studies identified, nine met the inclusion criteria: seven reported on the effect of nitroglycerin on coronary artery diameter, six on evaluable segments, four on image quality, five on systemic physiological effects and two on diagnostic accuracy. Sublingual nitroglycerin administration resulted in an improved evaluation of more coronary segments, in particular, in smaller coronary branches, better image quality and improved diagnostic accuracy. Side effects were mild and were alleviated without medical intervention. Sublingual nitroglycerin improves the coronary diameter, the number of assessable segments, image quality and diagnostic accuracy of coronary CT angiography without major side effects or systemic physiological changes. (orig.)

  19. Efficacy and safety of 5-grass-pollen sublingual immunotherapy tablets in pediatric allergic rhinoconjunctivitis

    DEFF Research Database (Denmark)

    Wahn, Ulrich; Tabar, Ana; Kuna, Piotr

    2009-01-01

    BACKGROUND: The efficacy and safety of the 300-index of reactivity (IR) dose of 5-grass-pollen sublingual immunotherapy (SLIT) tablets (Stallergènes, Antony, France) have been demonstrated for the treatment of hay fever in adults. OBJECTIVE: We sought to assess the efficacy and safety of this tab...

  20. Sublingual immunotherapy in children with allergic rhinitis : quality of systematic reviews

    NARCIS (Netherlands)

    de Bot, Cindy M. A.; Moed, Heleen; Berger, Marjolein Y.; Roeder, Esther; van Wijk, Roy G.; van der Wouden, Johannes C.

    Systematic reviews have gained popularity as a way to combine the increasing amount of research information. This study assessed the quality of systematic reviews and meta-analyses of sublingual immunotherapy (SLIT) for allergic rhinitis in children, published since 2000. Eligible reviews were

  1. Intestinal and sublingual microcirculation are more severely compromised in hemodilution than in hemorrhage

    NARCIS (Netherlands)

    Ferrara, Gonzalo; Kanoore Edul, Vanina Siham; Martins, Enrique; Canales, Héctor Saúl; Canullán, Carlos; Murias, Gastón; Pozo, Mario Omar; Estenssoro, Elisa; Ince, Can; Dubin, Arnaldo

    2016-01-01

    The alterations in O2 extraction in hemodilution have been linked to fast red blood cell (RBC) velocity, which might affect the complete release of O2 from Hb. Fast RBC velocity might also explain the normal mucosal-arterial Pco2 (ΔPco2). Yet sublingual and intestinal microcirculation have not been

  2. Double-blind, placebo-controlled immunotherapy with mixed grass-pollen allergoids. II. Comparison between parameters assessing the efficacy of immunotherapy.

    Science.gov (United States)

    Bousquet, J; Maasch, H; Martinot, B; Hejjaoui, A; Wahl, R; Michel, F B

    1988-09-01

    Specific immunotherapy is effective in alleviating symptoms in grass pollen-induced rhinitis, but there are no clear data demonstrating a correlation between symptom-medication scores and objective parameters. Twenty-five patients taking part in a double-blind, placebo-controlled immunotherapy with mixed grass pollen-formalinized allergoids were studied. All patients had the same investigations. Symptom-medication scores were significantly (p less than 0.005, Mann-Whitney U test) reduced in the treated group by comparison to the placebo-treated patients. Nasal challenges performed with threefold increasing numbers of orchard grass-pollen grains demonstrated that patients treated with allergoid tolerated a significantly (p less than 0.005, Wilcoxon W test) greater number of grains after treatment, whereas there was no mean difference in the placebo-treated patients. There was a significant (p less than 0.005, Spearman rank-correlation) correlation between nasal challenges and symptom scores during the season. The skin prick test end point was significantly (p less than 0.001, Wilcoxon W test) reduced after treatment in the allergoid-treated group and remained unchanged in the placebo-treated group. There was a significant (p less than 0.001) correlation between the skin prick test end point and symptom scores during the season. Serum grass-pollen IgG titrated by a solid-phase radioimmunoassay with Staphylococcus A protein was significantly (p less than 0.01, Wilcoxon W test) increased after treatment with allergoid, but there was no significant correlation between IgG titer and symptom scores during the season. Serum grass-pollen IgE increased (p less than 0.04, Wilcoxon W test) in the treated group but there was no correlation with symptom scores.

  3. An accelerated dose escalation with a grass pollen allergoid is safe and well-tolerated: a randomized open label phase II trial.

    Science.gov (United States)

    Chaker, A M; Al-Kadah, B; Luther, U; Neumann, U; Wagenmann, M

    2015-01-01

    The number of injections in the dose escalation of subcutaneous immunotherapy (SCIT) is small for some currently used hypoallergenic allergoids, but can still be inconvenient to patients and can impair compliance. The aim of this trial was to compare safety and tolerability of an accelerated to the conventional dose escalation scheme of a grass pollen allergoid. In an open label phase II trial, 122 patients were 1:1 randomized for SCIT using a grass pollen allergoid with an accelerated dose escalation comprising only 4 weekly injections (Group I) or a conventional dose escalation including 7 weekly injections (Group II). Safety determination included the occurrence of local and systemic adverse events. Tolerability was assessed by patients and physicians. Treatment-related adverse events were observed in 22 (36.1 %) patients in Group I and 15 (24.6 %) in Group II. Local reactions were reported by 18 patients in Group I and 11 in Group II. Five Grade 1 systemic reactions (WAO classification) were observed in Group I and 2 in Group II. Grade 2 reactions occurred 3 times in Group I and 2 times in Group II. Tolerability was rated as "good" or "very good" by 53 (86.9 %) patients in Group I and 59 (100 %) in Group II by investigators. Forty-eight patients in Group I (80.0 %) and 54 in Group II (91.5 %) rated tolerability as "good" or "very good". The dose escalation of a grass pollen allergoid can be accelerated with safety and tolerability profiles comparable to the conventional dose escalation.

  4. IgG binding of mugwort pollen allergens and allergoids exposed to simulated gastrointestinal conditions measured by a self-developed ELISA test

    OpenAIRE

    RATKO M. JANKOV; OLGA VUCKOVIC; DANICA DJERGOVIC-PETROVIC; LIDIJA BURAZER; TANJA D. CIRKOVICVELICKOVIC; MARIJA DJ. GAVROVIC-JANKULOVIC; NATALIJA DJ. POLOVIC

    2004-01-01

    This study considers the influence of exposure to simulated gastrointestinal conditions (saliva, gut, intestine and acidic conditions of the gut) on IgG binding of unmodified allergens and three types of LMW allergoids of Artemisia vulgaris pollen extract obtained by means of potassium cyanate, succinic and maleic anhydride. It also concerns the optimization of a self-developed ELISA assay for comparison of the specific IgG binding of mugwort pollen extract and modified mugwort pollen derivat...

  5. Efficacy and tolerability of short-term specific immunotherapy with pollen allergoids adjuvanted by monophosphoryl lipid A (MPL) for children and adolescents.

    Science.gov (United States)

    Drachenberg, K J; Heinzkill, M; Urban, E; Woroniecki, S R

    2003-01-01

    Specific immunotherapy (SIT) with pollen allergoids formulated with the Th1-inducing adjuvant 3-deacylated monophosphoryl lipid A (MPL adjuvant, Corixa) has shown good efficacy and tolerability in the treatment of pollen allergies in adults. The aim of this study was to evaluate this treatment in children and adolescents aged 6-17 years old who were sensitive to grass/rye or tree pollens. An open, multicenter study was performed using 90 children and adolescents. The patients received four subcutaneous injections of grass/rye (n = 64) or tree pollen allergoids (n = 26) adsorbed to L-tyrosine and containing MPL adjuvant. Efficacy was measured by symptom and medication scoring, skin prick test reactivity and IgG/IgE antibody responses. Tolerability was monitored by recording adverse events. Both grass/rye and tree pollen treatment groups showed significant reductions in symptom scores and anti-allergic medication use compared with the previous pollen seasons (p allergoids adsorbed to L-tyrosine and with MPL adjuvant was shown to be effective with good tolerability. The treatment compared favorably with previous studies in adults.

  6. Formation of amyloid fibers by monomeric light chain variable domains.

    Science.gov (United States)

    Brumshtein, Boris; Esswein, Shannon R; Landau, Meytal; Ryan, Christopher M; Whitelegge, Julian P; Phillips, Martin L; Cascio, Duilio; Sawaya, Michael R; Eisenberg, David S

    2014-10-03

    Systemic light chain amyloidosis is a lethal disease characterized by excess immunoglobulin light chains and light chain fragments composed of variable domains, which aggregate into amyloid fibers. These fibers accumulate and damage organs. Some light chains induce formation of amyloid fibers, whereas others do not, making it unclear what distinguishes amyloid formers from non-formers. One mechanism by which sequence variation may reduce propensity to form amyloid fibers is by shifting the equilibrium toward an amyloid-resistant quaternary structure. Here we identify the monomeric form of the Mcg immunoglobulin light chain variable domain as the quaternary unit required for amyloid fiber assembly. Dimers of Mcg variable domains remain stable and soluble, yet become prone to assemble into amyloid fibers upon disassociation into monomers. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

  7. mKikGR, a monomeric photoswitchable fluorescent protein.

    Directory of Open Access Journals (Sweden)

    Satoshi Habuchi

    Full Text Available The recent demonstration and utilization of fluorescent proteins whose fluorescence can be switched on and off has greatly expanded the toolkit of molecular and cell biology. These photoswitchable proteins have facilitated the characterization of specifically tagged molecular species in the cell and have enabled fluorescence imaging of intracellular structures with a resolution far below the classical diffraction limit of light. Applications are limited, however, by the fast photobleaching, slow photoswitching, and oligomerization typical for photoswitchable proteins currently available. Here, we report the molecular cloning and spectroscopic characterization of mKikGR, a monomeric version of the previously reported KikGR that displays high photostability and switching rates. Furthermore, we present single-molecule imaging experiments that demonstrate that individual mKikGR proteins can be localized with a precision of better than 10 nanometers, suggesting their suitability for super-resolution imaging.

  8. Polyimide resin composites via in situ polymerization of monomeric reactants

    Science.gov (United States)

    Cavano, P. J.

    1974-01-01

    Thermo-oxidatively stable polyimide/graphite-fiber composites were prepared using a unique in situ polymerization of monomeric reactants directly on reinforcing fibers. This was accomplished by using an aromatic diamine and two ester-acids in a methyl alcohol solvent, rather than a previously synthesized prepolymer varnish, as with other A-type polyimides. A die molding procedure was developed and a composite property characterization conducted with high modulus graphite fiber tow. Flexure, tensile, compressive, and shear tests were conducted at temperatures from 72 to 650 F on laminates before and after exposures at the given temperatures in an air environment for times up to 1000 hours. The composite material was determined to be oxidatively, thermally, and hydrolytically stable.

  9. Prevention of postpartum haemorrhage with sublingual misoprostol or oxytocin: a double-blind randomised controlled trial.

    Science.gov (United States)

    Bellad, M B; Tara, D; Ganachari, M S; Mallapur, M D; Goudar, S S; Kodkany, B S; Sloan, N L; Derman, R

    2012-07-01

    Sublingual misoprostol produces a rapid peak concentration, and is more effective than oral administration. We compared the postpartum measured blood loss with 400 μg powdered sublingual misoprostol and after standard care using 10 iu intramuscular (IM) oxytocin. Double-blind randomised controlled trial. A teaching hospital: J N Medical College, Belgaum, India. A cohort of 652 consenting eligible pregnant women admitted to the labour room. Subjects were assigned to receive the study medications and placebos within 1 minute of clamping and cutting the cord by computer-generated randomisation. Chi-square and bootstrapped Student's t-tests were used to test categorical and continuous outcomes, respectively. Measured mean postpartum blood loss and haemorrhage (PPH, loss ≥ 500 ml), >10% pre- to post-partum decline in haemoglobin, and reported side effects. The mean blood loss with sublingual misoprostol was 192 ± 124 ml (n=321) and 366 ± 136 ml with oxytocin IM (n=331, P ≤ 0.001). The incidence of PPH was 3.1% with misoprostol and 9.1% with oxytocin (P=0.002). No woman lost ≥ 1000 ml of blood. We observed that 9.7% and 45.6% of women experienced a haemoglobin decline of >10% after receiving misoprostol and oxytocin, respectively (P ≤ 0.001). Side effects were significantly greater in the misoprostol group than in the oxytocin group. Unlike other studies, this trial found sublingual misoprostol more effective than intramuscular oxytocin in reducing PPH, with only transient side effects being greater in the misoprostol group. The sublingual mode and/or powdered formulation may increase the effectiveness of misoprostol, and render it superior to injectable oxytocin for the prevention of PPH. Further research is needed to confirm these results. © 2012 The Authors BJOG An International Journal of Obstetrics and Gynaecology © 2012 RCOG.

  10. A randomized trial of rectal indomethacin and sublingual nitrates to prevent post-ERCP pancreatitis.

    Science.gov (United States)

    Sotoudehmanesh, Rasoul; Eloubeidi, Mohamad Ali; Asgari, Ali Ali; Farsinejad, Maryam; Khatibian, Morteza

    2014-06-01

    Acute pancreatitis is the most common adverse event of endoscopic retrograde cholangiopancreatography (ERCP). Recent data suggest that indomethacin can reduce the risk of post-ERCP pancreatitis (PEP) in high-risk individuals. However, whether the combination of indomethacin and sublingual nitrates is superior to indomethacin alone is unknown. Therefore, we aimed to evaluate the efficacy of rectally administered indomethacin plus sublingual nitrate compared with indomethacin alone to prevent PEP. During a 17-month period, all eligible patients who underwent ERCP were enrolled in this study. We excluded patients who had undergone a prior endoscopic sphincterotomy. In a double-blind controlled randomized trial, patients received a suppository containing 100 mg of indomethacin, plus 5 mg of sublingual nitrate (group A), or a suppository containing 100 mg of indomethacin, plus sublingual placebo (group B), before ERCP. Serum amylase levels and clinically pertinent evaluations were measured in all patients after ERCP. Of the 300 enrolled patients, 150 received indomethacin plus nitrate. Thirty-three patients developed pancreatitis: 10 (6.7%) in group A and 23 (15.3%) in group B (P=0.016, risk ratio=0.39, 95% confidence intervals (CI): 0.18-0.86). More than 80% of the patients were at high risk of developing pancreatitis after ERCP. Absolute risk reduction, relative risk reduction, and number needed to treat for the prevention of PEP were 8.6% (95% CI: 4.7-14.5), 56.2% (95% CI: 50.6-60.8), and 12 (95% CI: 7-22), respectively. Combination of rectal indomethacin and sublingual nitrate given before ERCP was significantly more likely to reduce the incidence of PEP than indomethacin suppository alone. Multicenter trials to confirm these promising findings are needed.

  11. Sublingual fast dissolving niosomal films for enhanced bioavailability and prolonged effect of metoprolol tartrate

    Directory of Open Access Journals (Sweden)

    Allam A

    2016-08-01

    Full Text Available Ayat Allam, Gihan Fetih Department of Pharmaceutics, Faculty of Pharmacy, Assiut University, Assiut, Egypt Abstract: The aim of the present work was to prepare and evaluate sublingual fast dissolving films containing metoprolol tartrate-loaded niosomes. Niosomes were utilized to allow for prolonged release of the drug, whereas the films were used to increase the drug’s bioavailability via the sublingual route. Niosomes were prepared using span 60 and cholesterol at different drug to surfactant ratios. The niosomes were characterized for size, zeta-potential, and entrapment efficiency. The selected niosomal formulation was incorporated into polymeric films using hydroxypropyl methyl cellulose E15 and methyl cellulose as film-forming polymers and Avicel as superdisintegrant. The physical characteristics (appearance, texture, pH, uniformity of weight and thickness, disintegration time, and palatability of the prepared films were studied, in addition to evaluating the in vitro drug release, stability, and in vivo pharmacokinetics in rabbits. The release of the drug from the medicated film was fast (99.9% of the drug was released within 30 minutes, while the drug loaded into the niosomes, either incorporated into the film or not, showed only 22.85% drug release within the same time. The selected sublingual film showed significantly higher rate of drug absorption and higher drug plasma levels compared with that of commercial oral tablet. The plasma levels remained detectable for 24 hours following sublingual administration, compared with only 12 hours after administration of the oral tablet. In addition, the absolute bioavailability of the drug (ie, relative to intravenous administration following sublingual administration was found to be significantly higher (91.06%±13.28%, as compared with that after oral tablet administration (39.37%±11.4%. These results indicate that the fast dissolving niosomal film could be a promising delivery system to

  12. Premedication with benzodiazepines for upper gastrointestinal endoscopy: Comparison between oral midazolam and sublingual alprazolam

    Directory of Open Access Journals (Sweden)

    Vahid Sebghatollahi

    2017-01-01

    Full Text Available Background: Premedication with orally administered benzodiazepines is effective in reducing anxiety and discomfort related to endoscopic procedures. We evaluated the efficacy and safety of oral midazolam in comparison to sublingual alprazolam as premedication for esophagogastroduodenoscopy (EGD. Materials and Methods: Adult candidates for diagnostic EGD received either oral midazolam (7.5 mg in 15 cc apple juice or sublingual alprazolam (0.5 mg 30 min before EGD. Procedural anxiety and pain/discomfort were assessed using 11-point numerical rating scales. Patients' overall tolerance (using a four-point Likert scale and willingness to repeat the EGD, if necessary, were also assessed. Blood pressure, heart rate, and arterial oxygen saturation were monitored from medication to 30 min after the procedure. Results: Patients experienced a similar reduction in procedural anxiety after medication with oral midazolam and sublingual alprazolam; mean (standard deviation [SD] of 1.86 [1.63] and 2.02 [1.99] points, respectively, P = 0.91. Compared to oral midazolam, pain/discomfort scores were lower with sublingual alprazolam; mean (SD of 4.80 (3.01 versus 3.68 (3.28, P = 0.024. There was no significant difference between the two groups in patients' tolerance, willingness to repeat the procedure, or hemodynamic events. Conclusion: Oral midazolam and sublingual alprazolam are equally effective in reducing EGD-related anxiety; however, EGD-related pain/discomfort is lower with alprazolam. Both benzodiazepines are equally safe and can be used as premedication for patients undergoing diagnostic EGD.

  13. Sublingual fast dissolving niosomal films for enhanced bioavailability and prolonged effect of metoprolol tartrate.

    Science.gov (United States)

    Allam, Ayat; Fetih, Gihan

    2016-01-01

    The aim of the present work was to prepare and evaluate sublingual fast dissolving films containing metoprolol tartrate-loaded niosomes. Niosomes were utilized to allow for prolonged release of the drug, whereas the films were used to increase the drug's bioavailability via the sublingual route. Niosomes were prepared using span 60 and cholesterol at different drug to surfactant ratios. The niosomes were characterized for size, zeta-potential, and entrapment efficiency. The selected niosomal formulation was incorporated into polymeric films using hydroxypropyl methyl cellulose E15 and methyl cellulose as film-forming polymers and Avicel as superdisintegrant. The physical characteristics (appearance, texture, pH, uniformity of weight and thickness, disintegration time, and palatability) of the prepared films were studied, in addition to evaluating the in vitro drug release, stability, and in vivo pharmacokinetics in rabbits. The release of the drug from the medicated film was fast (99.9% of the drug was released within 30 minutes), while the drug loaded into the niosomes, either incorporated into the film or not, showed only 22.85% drug release within the same time. The selected sublingual film showed significantly higher rate of drug absorption and higher drug plasma levels compared with that of commercial oral tablet. The plasma levels remained detectable for 24 hours following sublingual administration, compared with only 12 hours after administration of the oral tablet. In addition, the absolute bioavailability of the drug (ie, relative to intravenous administration) following sublingual administration was found to be significantly higher (91.06%±13.28%), as compared with that after oral tablet administration (39.37%±11.4%). These results indicate that the fast dissolving niosomal film could be a promising delivery system to enhance the bioavailability and prolong the therapeutic effect of metoprolol tartrate.

  14. Double-blind, placebo-controlled immunotherapy with mixed grass-pollen allergoids. III. Efficacy and safety of unfractionated and high-molecular-weight preparations in rhinoconjunctivitis and asthma.

    Science.gov (United States)

    Bousquet, J; Maasch, H J; Hejjaoui, A; Skassa-Brociek, W; Wahl, R; Dhivert, H; Michel, F B

    1989-10-01

    Specific immunotherapy with unmodified formalinized allergoids is effective in grass-pollen allergy, but systemic reactions have been observed. A high-molecular-weight formalinized allergoid (HMW-GOID) was fractionated by gel filtration, retaining molecules of greater than 85,000 daltons in the expectation of improving safety without sacrificing efficacy. HMW-GOID and unfractionated allergoid (GOID) had a similar allergenic activity assessed by RAST inhibition, but the HMW-GOID preparation was 65 times less reactive when it was tested by skin prick test than the GOID preparation. A double-blind, placebo-controlled study was carried out in grass pollen-allergic patients with placebo (14 patients), GOID (15 patients), and HMW-GOID (13 patients). An additional group of 18 patients was treated by a rush schedule with a standardized orchard grass-pollen extract. A similar mean cumulative dose was administered with both allergoids. The fractionated allergoid only elicited minor systemic reactions similar to reactions elicited by placebo, whereas 20% of patients treated by GOID and 5.5% of patients receiving the standardized extract had a severe systemic reaction. For rhinitis, conjunctivitis, and asthma, the HMW-GOID and the standardized extract had a similar efficacy, significantly greater than placebo. GOID was less effective than the other two active treatments but was significantly more effective than placebo treatment for asthma and conjunctivitis.

  15. Sublingual flagellin protects against acute pneumococcal pneumonia in a TLR5-dependent and NLRC4-independent fashion.

    Science.gov (United States)

    Muñoz-Wolf, Natalia; Rial, Analía; Fougeron, Delphine; Tabareau, Julien; Sirard, Jean-Claude; Chabalgoity, José A

    2016-09-01

    To evaluate efficacy of sublingual flagellin to treat acute pneumonia. Mice were treated sublingually with flagellin and challenged intranasally with a lethal dose of pneumococcus. Flagellins lacking TLR5 or NLRC4 activation domains were used to assess their contribution to protection. Sublingual flagellin protected mice in a TLR5-dependent, NLRC4-independent fashion. Neutrophils were required for protection. Flagellin-stimulated lung epithelial cells recapitulated the lung's transcriptional profile suggesting they could be targeted by flagellin in vivo. Ligation of TLR5, a pathogen recognition receptor not naturally engaged by pneumococcus, protects mice from invasive pneumonia when administered via sublingual route. This can be a highly cost-effective alternative therapy against pneumonia.

  16. Warfarin-induced sublingual hematoma mimicking Ludwig angina: Conservative management of a potentially life-threatening condition.

    LENUS (Irish Health Repository)

    Cashman, Emma

    2012-02-01

    Sublingual hematoma secondary to excessive anticoagulation is a rare, life-threatening condition. Reports in the literature have emphasized the importance of a prompt reversal of the causative coagulopathy by intravenous administration of vitamin K and fresh frozen plasma. In the event of an unstable airway, surgical intervention via tracheostomy or cricothyroidectomy is advocated. We report a case of sublingual hematoma that was treated conservatively, and we discuss the presentation and management of this entity.

  17. Warfarin-induced sublingual hematoma mimicking Ludwig angina: Conservative management of a potentially life-threatening condition.

    LENUS (Irish Health Repository)

    Cashman, Emma

    2011-02-01

    Sublingual hematoma secondary to excessive anticoagulation is a rare, life-threatening condition. Reports in the literature have emphasized the importance of a prompt reversal of the causative coagulopathy by intravenous administration of vitamin K and fresh frozen plasma. In the event of an unstable airway, surgical intervention via tracheostomy or cricothyroidectomy is advocated. We report a case of sublingual hematoma that was treated conservatively, and we discuss the presentation and management of this entity.

  18. MR imaging of squamous cell carcinoma of the floor of the mouth. Appearance of the sublingual and submandibular glands

    International Nuclear Information System (INIS)

    Murakami, R.; Baba, Y.; Nishimura, R.; Baba, T.; Nakaura, T.; Takahashi, M.; Ishikawa, T.

    1999-01-01

    Purpose: To determine the diagnostic value of MR imaging for tumors of the floor of the mouth and the effects of the tumors on the sublingual and submandibular glands. Material and methods: Thirty-seven patients with proven squamous cell carcinoma of the floor of the mouth underwent MR imaging, including unenhanced T1-weighted, T2-weighted, dynamic, and contrast-enhanced T1-weighted images. The appearance of the tumor and the sublingual and submandibular glands was assessed qualitatively and quantitatively. Results: All tumors demonstrated replacement of the normal signal intensity in the adjacent sublingual gland. Twenty-one patients (57%) had abnormal signal intensity of the submandibular gland without tumor invasion, presumably secondary to submandibular duct obstruction by the tumor. Unenhanced T1-weighted images provided high contrast between tumor and sublingual gland. Tumors limited within the gland were well detected on unenhanced T1-weighted images. Large tumors extending beyond the gland were well delineated on dynamic images, but no better than on T2-weighted images. Conclusion: At MR imaging for tumor of the floor of the mouth, one must carefully evaluate the appearance of the sublingual and submandibular glands. Contrast-enhanced studies are unnecessary when the tumor is limited within the sublingual gland on precontrast MR images. (orig.)

  19. Mapping monomeric threading to protein-protein structure prediction.

    Science.gov (United States)

    Guerler, Aysam; Govindarajoo, Brandon; Zhang, Yang

    2013-03-25

    The key step of template-based protein-protein structure prediction is the recognition of complexes from experimental structure libraries that have similar quaternary fold. Maintaining two monomer and dimer structure libraries is however laborious, and inappropriate library construction can degrade template recognition coverage. We propose a novel strategy SPRING to identify complexes by mapping monomeric threading alignments to protein-protein interactions based on the original oligomer entries in the PDB, which does not rely on library construction and increases the efficiency and quality of complex template recognitions. SPRING is tested on 1838 nonhomologous protein complexes which can recognize correct quaternary template structures with a TM score >0.5 in 1115 cases after excluding homologous proteins. The average TM score of the first model is 60% and 17% higher than that by HHsearch and COTH, respectively, while the number of targets with an interface RMSD benchmark proteins. Although the relative performance of SPRING and ZDOCK depends on the level of homology filters, a combination of the two methods can result in a significantly higher model quality than ZDOCK at all homology thresholds. These data demonstrate a new efficient approach to quaternary structure recognition that is ready to use for genome-scale modeling of protein-protein interactions due to the high speed and accuracy.

  20. Development and evaluation of a sublingual film of the antiemetic granisetron hydrochloride.

    Science.gov (United States)

    Kalia, Vani; Garg, Tarun; Rath, Gautam; Goyal, Amit Kumar

    2016-05-01

    The objective of this study was to develop an oral transmucosal formulation of an antiemetic drug that can not only serve in the active form but also provide a controlled release profile. In this study, sublingual films based on the biodegradable and water-soluble polymers, that is HPMCK-4M and PVPK-30, were developed by the solvent casting method, and were loaded with the antiemetic drug granisetron hydrochloride (granisetron HCl). The entrapment efficiency of the developed formulation was found to be 86%. The in vitro profile showed an instant release of the drug from the sublingual film, in a pattern following the first order kinetics array. The in vivo studies showed that granisetron HCl was delivered in its active state and showed effective results, as compared to its activity in the marketed formulation.

  1. CHANGES OF IMMUNE INDEXES DURING SUBLINGUAL ALLERGEN-SPECIFIC IMMUNOTHERAPY IN CHILDREN WITH HAY FEVER

    Directory of Open Access Journals (Sweden)

    I. M. Gaiduk

    2013-01-01

    Full Text Available Aims of study: evaluation of immunological parameters in course of sublingual allergen-specific immunotherapy with tree pollen mixture in children with hay fever.Materials and methods: the study included one-hundred patients 5 to 18 years of age with hay fever (pollen rhinitis, rhinoconjunctivitis and/or asthma. Allergen-specific immunotherapy was administered pre-seasonally for three consecutive years. Cytokinechanges were studied in blood serum and in lavages from nasal cavity. Samples assessed before treatment and after 2nd and 3rd courses SLIT completion.Results: increased serum concentrations of IL-10, IFNγ, and decreased IL-4 contents were revealed in the course of treatment. No significant changes in cytokineconcentrations were detectable in nasal lavages.Conclusions: the changes revealed correspond to a shift of T cell response profile towards Th1 pathway, thus confirming pathogenetic effects of sublingual allergen-specific

  2. An accelerometric measure of the gait pattern in horses after the administration of sublingual detomidine.

    Science.gov (United States)

    López-Sanromán, F J; de la Riva Andrés, S; Holmbak-Petersen, R; Pérez-Nogués, M; Forés Jackson, P; Santos González, M

    2014-10-01

    The locomotor pattern alterations produced after the administration of a sublingual detomidine gel was measured by an accelerometric method in horses. Using a randomized two-way crossover design, all animals (n = 6) randomly received either detomidine gel or a placebo administered sublingually. A triaxial accelerometric device was used for gait assessment 15 minutes before (baseline) and every 10 minutes after each treatment for a period of 180 minutes. Eight different parameters were calculated, including speed, stride frequency, stride length, regularity, dorsoventral, propulsion, mediolateral, and total power. Force of acceleration and the three components of power were also calculated. Significant statistical differences were observed between groups in all the parameters but stride length. The majority of significant changes started between 30 and 70 minutes after drug administration and lasted for 160 minutes. This route of administration is definitely useful in horses in which a prolonged sedation is required, with stability being a major concern. Copyright © 2014 Elsevier Ltd. All rights reserved.

  3. Sublingual administration of detomidine to calves prior to disbudding: a comparison with the intravenous route.

    OpenAIRE

    Hokkanen, Ann-Helena; Raekallio, Marja R.; Salla, Kati; Hänninen, Laura; Viitasaari, Elina Anna Maria; Norring, Marianna; Raussi, Satu; Rinne, Valtteri; Scheinin, Mika; Vainio, Outi M.

    2014-01-01

    Objective To study the effects of oromucosal detomidine gel administered sublingually to calves prior to disbudding, and to compare its efficacy with intravenously (IV) administered detomidine. Study design Randomised, prospective clinical study. Animals Twenty dairy calves aged 12.4 ± 4.4days (mean ± SD), weight 50.5 ± 9.0 kg. Methods Detomidine at 80 μg kg−1 was administered to ten calves sublingually (GEL) and at 30 μg kg−1 to ten control calves IV (V. jugularis). Meloxicam (0.5 mg kg−1) a...

  4. Immunity of foot-and-mouth disease serotype Asia 1 by sublingual vaccination.

    Directory of Open Access Journals (Sweden)

    Hao-tai Chen

    Full Text Available Foot-and-mouth disease virus (FMDV causes vesicular disease of cloven-hoofed animals, with severe agricultural and economic losses. Here we present study using a sublingual (SL route with the killed serotype Asia 1 FMDV vaccine. Guinea pigs were vaccinated using a commercially available vaccine formulation at the manufacturer's recommended full, 1/4, and 1/16 antigen doses. Animals were challenged with homologous FMDV Asia1 strain at various times following vaccination. All control guinea pigs exhibited clinical disease, including fever, viremia, and lesions, specifically vesicle formation in feet. Animals vaccinated with the 1/16 and 1/4 doses were protected after challenge at days 7, 28, and 35 post vaccination. These data suggest that effective protection against foot-and-mouth disease can be achieved with 1/16 of the recommended vaccine dose using SL vaccination, indicating that the sublingual route is an attractive alternative for the administration of the FMDV vaccine.

  5. Substrate-Induced Dimerization of Engineered Monomeric Variants of Triosephosphate Isomerase from Trichomonas vaginalis.

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    Samuel Lara-Gonzalez

    Full Text Available The dimeric nature of triosephosphate isomerases (TIMs is maintained by an extensive surface area interface of more than 1600 Å2. TIMs from Trichomonas vaginalis (TvTIM are held in their dimeric state by two mechanisms: a ball and socket interaction of residue 45 of one subunit that fits into the hydrophobic pocket of the complementary subunit and by swapping of loop 3 between subunits. TvTIMs differ from other TIMs in their unfolding energetics. In TvTIMs the energy necessary to unfold a monomer is greater than the energy necessary to dissociate the dimer. Herein we found that the character of residue I45 controls the dimer-monomer equilibrium in TvTIMs. Unfolding experiments employing monomeric and dimeric mutants led us to conclude that dimeric TvTIMs unfold following a four state model denaturation process whereas monomeric TvTIMs follow a three state model. In contrast to other monomeric TIMs, monomeric variants of TvTIM1 are stable and unexpectedly one of them (I45A is only 29-fold less active than wild-type TvTIM1. The high enzymatic activity of monomeric TvTIMs contrast with the marginal catalytic activity of diverse monomeric TIMs variants. The stability of the monomeric variants of TvTIM1 and the use of cross-linking and analytical ultracentrifugation experiments permit us to understand the differences between the catalytic activities of TvTIMs and other marginally active monomeric TIMs. As TvTIMs do not unfold upon dimer dissociation, herein we found that the high enzymatic activity of monomeric TvTIM variants is explained by the formation of catalytic dimeric competent species assisted by substrate binding.

  6. Orally-dissolving film for sublingual and buccal delivery of ropinirole.

    Science.gov (United States)

    Lai, Ka Lun; Fang, Yuan; Han, Hao; Li, Qingqing; Zhang, Shuai; Li, Ho Yin; Chow, Shing Fung; Lam, Tai Ning; Lee, Wai Yip Thomas

    2018-03-01

    Ropinirole is a very important treatment option for Parkinson's disease (PD), a major threat to the aging population. However, this drug undergoes extensive first-pass metabolism, resulting in a low oral bioavailability. Moreover, the necessity of frequent administration due to the short half-life of ropinirole may jeopardize patient compliance. Indeed, taking this drug in solid oral dosage forms (e.g. Tablet) can be a challenge because of the tremor, rigidity, limited mobility, and impaired drug absorption experienced by PD patients. In light of these, there is a pressing need to devise formulations for the delivery of ropinirole that allow simple and easy administration and fast drug action, as well as avoidance of first-pass metabolism and overcoming the challenge of impaired absorption due to gastrointestinal dysfunctions, etc. Herein, we seek to overcome all these challenges via sublingual or buccal delivery of orally-dissolving films. Accordingly, we aimed to fabricate and characterize orally-dissolving films of ropinirole and assess their in vivo pharmacokinetics after sublingual and buccal administration. The ropinirole oral film was non-toxic and exhibited fast disintegration and dissolution and was physically stable for at least 28 days. Upon buccal/sublingual administration of the oral films, ropinirole reached the systemic circulation within 15 min and bioavailability was significantly improved, which may be attributable to avoidance of first-pass metabolism via absorption through the oral cavity. In conclusion, our ropinirole oral film improved bioavailability after sublingual or buccal administration. This formulation potentially overcomes biopharmaceutical challenges and provide a convenient means of administration of ropinirole or other anti-PD drugs. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. Adrenaline (epinephrine) microcrystal sublingual tablet formulation: enhanced absorption in a preclinical model.

    Science.gov (United States)

    Rawas-Qalaji, Mutasem; Rachid, Ousama; Mendez, Belacryst A; Losada, Annette; Simons, F Estelle R; Simons, Keith J

    2015-01-01

    For anaphylaxis treatment in community settings, adrenaline (epinephrine) administration using an auto-injector in the thigh is universally recommended. Despite this, many people at risk of anaphylaxis in community settings do not carry their prescribed auto-injectors consistently and hesitate to use them when anaphylaxis occurs.The objective of this research was to study the effect of a substantial reduction in adrenaline (Epi) particle size to a few micrometres (Epi microcrystals (Epi-MC)) on enhancing adrenaline dissolution and increasing the rate and extent of sublingual absorption from a previously developed rapidly disintegrating sublingual tablet (RDST) formulation in a validated preclinical model. The in-vivo absorption of Epi-MC 20 mg RDSTs and Epi 40 mg RDSTs was evaluated in rabbits. Epi 0.3 mg intramuscular (IM) injection in the thigh and placebo RDSTs were used as positive and negative controls, respectively. Epimean (standard deviation) area under the plasma concentration vs time curves up to 60 min and Cmax from Epi-MC 20 mg and Epi 40 mg RDSTs did not differ significantly (P > 0.05) from Epi 0.3 mg IM injection. After adrenaline, regardless of route of administration, pharmacokinetic parameters were significantly higher (P adrenaline levels). Epi-MC RDSTs facilitated a twofold increase in Epi absorption and a 50% reduction in the sublingual dose. This novel sublingual tablet formulation is potentially useful for the first-aid treatment of anaphylaxis in community settings. © 2014 Royal Pharmaceutical Society.

  8. Sublingual sugar for hypoglycaemia in children with severe malaria: A pilot clinical study

    Science.gov (United States)

    Graz, Bertrand; Dicko, Moussa; Willcox, Merlin L; Lambert, Bernard; Falquet, Jacques; Forster, Mathieu; Giani, Sergio; Diakite, Chiaka; Dembele, Eugène M; Diallo, Drissa; Barennes, Hubert

    2008-01-01

    Background Hypoglycaemia is a poor prognostic indicator in severe malaria. Intravenous infusions are rarely feasible in rural areas. The efficacy of sublingual sugar (SLS) was assessed in a pilot randomized controlled trial among hypoglycaemic children with severe malaria in Mali. Methods Of 151 patients with presumed severe malaria, 23 children with blood glucose concentrations = 3.3 mmol/l (60 mg/dl) within 40 minutes after admission. Secondary outcome measures were early treatment response at 20 minutes, relapse (early and late), maximal BGC gain (CGmax), and treatment delay. Results There was no significant difference between the groups in the primary outcome measure. Treatment response occurred in 71% and 67% for SLS and IVG, respectively. Among the responders, relapses occurred in 30% on SLS at 40 minutes and in 17% on IVG at 20 minutes. There was one fatality in each group. Treatment failures in the SLS group were related to children with clenched teeth or swallowing the sugar, whereas in the IVG group, they were due to unavoidable delays in beginning an infusion (median time 17.5 min (range 3–40). Among SLS, the BGC increase was rapid among the nine patients who really kept the sugar sublingually. All but one increased their BGC by 10 minutes with a mean gain of 44 mg/dl (95%CI: 20.5–63.4). Conclusion Sublingual sugar appears to be a child-friendly, well-tolerated and effective promising method of raising blood glucose in severely ill children. More frequent repeated doses are needed to prevent relapse. Children should be monitored for early swallowing which leads to delayed absorption, and in this case another dose of sugar should be given. Sublingual sugar could be proposed as an immediate "first aid" measure while awaiting intravenous glucose. In many cases it may avert the need for intravenous glucose. PMID:19025610

  9. Sublingual sugar for hypoglycaemia in children with severe malaria: A pilot clinical study

    Directory of Open Access Journals (Sweden)

    Giani Sergio

    2008-11-01

    Full Text Available Abstract Background Hypoglycaemia is a poor prognostic indicator in severe malaria. Intravenous infusions are rarely feasible in rural areas. The efficacy of sublingual sugar (SLS was assessed in a pilot randomized controlled trial among hypoglycaemic children with severe malaria in Mali. Methods Of 151 patients with presumed severe malaria, 23 children with blood glucose concentrations = 3.3 mmol/l (60 mg/dl within 40 minutes after admission. Secondary outcome measures were early treatment response at 20 minutes, relapse (early and late, maximal BGC gain (CGmax, and treatment delay. Results There was no significant difference between the groups in the primary outcome measure. Treatment response occurred in 71% and 67% for SLS and IVG, respectively. Among the responders, relapses occurred in 30% on SLS at 40 minutes and in 17% on IVG at 20 minutes. There was one fatality in each group. Treatment failures in the SLS group were related to children with clenched teeth or swallowing the sugar, whereas in the IVG group, they were due to unavoidable delays in beginning an infusion (median time 17.5 min (range 3–40. Among SLS, the BGC increase was rapid among the nine patients who really kept the sugar sublingually. All but one increased their BGC by 10 minutes with a mean gain of 44 mg/dl (95%CI: 20.5–63.4. Conclusion Sublingual sugar appears to be a child-friendly, well-tolerated and effective promising method of raising blood glucose in severely ill children. More frequent repeated doses are needed to prevent relapse. Children should be monitored for early swallowing which leads to delayed absorption, and in this case another dose of sugar should be given. Sublingual sugar could be proposed as an immediate "first aid" measure while awaiting intravenous glucose. In many cases it may avert the need for intravenous glucose.

  10. A randomised controlled trial of sublingual misoprostol and intramuscular oxytocin for prevention of postpartum haemorrhage.

    Science.gov (United States)

    Al-Sawaf, A; El-Mazny, A; Shohayeb, A

    2013-04-01

    This study aims to evaluate the efficacy and side-effects of 200 μg sublingual misoprostol vs 5 IU i.m. oxytocin, administered immediately following cord clamping in normal non-augmented vaginal delivery, in prevention of postpartum haemorrhage (PPH). A total of 104 women were randomised into three groups: misoprostol group (28 patients); oxytocin group (37 patients) and control group (39 patients). Misoprostol and oxytocin significantly minimised the blood loss during the third stage of labour and reduced the need for additional treatments for PPH as compared with the control group. Oxytocin was more effective than misoprostol in minimising blood loss and the need for additional uterotonic treatments. However, a significant decrease in systolic and diastolic blood pressure, associated with tachycardia was observed in the oxytocin group. In conclusion, sublingual misoprostol appears to be less effective than i.m. oxytocin in the prevention of PPH; however, it has the potential advantages of being easily used, cost-effective and stable at room temperature. Therefore, sublingual misoprostol is still a feasible drug for routine management of third stage, especially in areas with limited medical facilities.

  11. [Efficacy of the dust mites drops sublingual immunotherapy in pediatric allergic rhinitis].

    Science.gov (United States)

    Xie, Lisheng; Jiang, Yinzhu; Li, Qi

    2016-03-01

    To observe the role of the dust mites drops sublingual immunotherapy(SLIT) in pediatric allergic rhiriitis caused by dust mites and compare its efficacy between monosensitized and polysensitized children. A total of 77 pediatric allergic rhinitis patients received Dermatophagoides farina extracts sublingual immunotherapy for 2 years were enrolled as desensitization group and were allocated into monosensitized group (41 cases) and polysensitized group (36 cases) according to the number of coexisting allergens. Meanwhile another 33 allergic rhinitis children treated by pharmacotherapy during the period were collected as control group. The total symptom scores (TNSS), total medication scores (TMS) and visual analogue scale(VAS) were assessed at the beginning, six months, 1 year and 2 years of the treatment. SPSS 13. 0 software was used to analyze the data. the score of TNSS and VAS in desensitization was slightly higher than the control after six months treatment, but without difference at l year and 2 years; the score of TMS had significantly improved in desensitization compared with the corresponding points in control. All the parameters in monosensitized group were equivalent with polysensitizend group, except the score of TMS was slightly lower than the polysensitizend group at six months. Dust mite drops sublingual immunotherapy is effective for the allergic rhinitis children caused by mites. And it has similar immunotherapy efficacy between monosensitized and polysensitized children.

  12. Bioavailability of detomidine administered sublingually to horses as an oromucosal gel.

    Science.gov (United States)

    Kaukinen, H; Aspegrén, J; Hyyppä, S; Tamm, L; Salonen, J S

    2011-02-01

    The objective of the study was to determine the absorption, bioavailability and sedative effect of detomidine administered to horses as an oromucosal gel compared to intravenous and intramuscular administration of detomidine injectable solution. The study was open and randomized, with three sequences crossover design. Nine healthy horses were given 40 μg/kg detomidine intravenously, intramuscularly or administered under the tongue with a 7-day wash-out period between treatments. Blood samples were collected before and after drug administration for the measurement of detomidine concentrations in serum. The effects of the route of administration on heart rate and rhythm were evaluated and the depth of sedation assessed. Mean (±SD) bioavailability of detomidine was 22% (±5.3%) after sublingual administration and 38.2% (±7.9%) after intramuscular administration. The sedative effects correlated with detomidine concentrations regardless of the route of administration. We conclude that less detomidine is absorbed when given sublingually than when given intramuscularly, because part of it does not reach the circulation. Sublingual administration of detomidine oromucosal gel at 40 μg/kg produces safe sedation in horses. Slow absorption leads to fewer and less pronounced adverse effects than the more rapid absorption after intramuscular injection. © 2010 Blackwell Publishing Ltd.

  13. Novel vaccines targeting dendritic cells by coupling allergoids to nonoxidized mannan enhance allergen uptake and induce functional regulatory T cells through programmed death ligand 1.

    Science.gov (United States)

    Sirvent, Sofía; Soria, Irene; Cirauqui, Cristina; Cases, Bárbara; Manzano, Ana I; Diez-Rivero, Carmen M; Reche, Pedro A; López-Relaño, Juan; Martínez-Naves, Eduardo; Cañada, F Javier; Jiménez-Barbero, Jesús; Subiza, Javier; Casanovas, Miguel; Fernández-Caldas, Enrique; Subiza, José Luis; Palomares, Oscar

    2016-08-01

    Allergen immunotherapy (AIT) is the only curative treatment for allergy. AIT faces pitfalls related to efficacy, security, duration, and patient compliance. Novel vaccines overcoming such inconveniences are in demand. We sought to study the immunologic mechanisms of action for novel vaccines targeting dendritic cells (DCs) generated by coupling glutaraldehyde-polymerized grass pollen allergoids to nonoxidized mannan (PM) compared with glutaraldehyde-polymerized allergoids (P) or native grass pollen extracts (N). Skin prick tests and basophil activation tests with N, P, or PM were performed in patients with grass pollen allergy. IgE-blocking experiments, flow cytometry, confocal microscopy, cocultures, suppression assays, real-time quantitative PCR, ELISAs, and ELISpot assays were performed to assess allergen capture by human DCs and T-cell responses. BALB/c mice were immunized with PM, N, or P. Antibody levels, cytokine production by splenocytes, and splenic forkhead box P3 (FOXP3)(+) regulatory T (Treg) cells were quantified. Experiments with oxidized PM were also performed. PM displays in vivo hypoallergenicity, induces potent blocking antibodies, and is captured by human DCs much more efficiently than N or P by mechanisms depending on mannose receptor- and dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin-mediated internalization. PM endorses human DCs to generate functional FOXP3(+) Treg cells through programmed death ligand 1. Immunization of mice with PM induces a shift to nonallergic responses and increases the frequency of splenic FOXP3(+) Treg cells. Mild oxidation impairs these effects in human subjects and mice, demonstrating the essential role of preserving the carbohydrate structure of mannan. Allergoids conjugated to nonoxidized mannan represent suitable vaccines for AIT. Our findings might also be of the utmost relevance to development of therapeutic interventions in other immune tolerance-related diseases. Copyright

  14. Measurement of basophil-activating capacity of grass pollen allergens, allergoids and hypoallergenic recombinant derivatives by flow cytometry using anti-CD203c.

    Science.gov (United States)

    Kahlert, H; Cromwell, O; Fiebig, H

    2003-09-01

    The assessment of the basophil-activating potential is an important aspect in the development of improved preparations for specific immunotherapy. The aim of the study was to evaluate the suitability of CD203c expression as a measure of basophil activation to compare allergoids with original allergen extracts, and recombinant hypoallergenic allergen derivatives with recombinant wild-type and natural allergens. Heparinized whole blood samples from grass pollen allergic subjects were stimulated with grass pollen allergens and allergen derivatives followed by labelling of the basophils with PE-conjugated anti-CD203c. After lysis of the erythrocytes and fixation, the basophils were detected by flow cytometry. In some experiments, histamine release was determined simultaneously. Grass pollen allergoids revealed a 10-10 000-fold reduction of basophil-activating capacity measured by CD203c expression. The deletion mutant DM4 of rPhl p 5b showed stronger hypoallergenic characteristics in a range of 50-10 000-fold reduction, whereas a combination mutant of rPhl p 5b and Phl p 6 revealed less hypoallergenic features. Histamine release experiments led to a similar outcome as CD203c measurement. The measurement of CD203c expression on basophils by flow cytometry provides a rapid and sensitive method for the estimation of the allergic or hypoallergenic features of allergen preparations. The results demonstrated the hypoallergenicity of grass pollen allergoids and of the rPhl p 5b variant DM4, which may be a candidate in future preparations for specific immunotherapy.

  15. Anthocyanins and Their Variation in Red Wines I. Monomeric Anthocyanins and Their Color Expression

    OpenAIRE

    Chang-Qing Duan; Malcolm J. Reeves; Qiu-Hong Pan; Lin Mu; Na-Na Liang; Fei He; Jun Wang

    2012-01-01

    Originating in the grapes, monomeric anthocyanins in young red wines contribute the majority of color and the supposed beneficial health effects related to their consumption, and as such they are recognized as one of the most important groups of phenolic metabolites in red wines. In recent years, our increasing knowledge of the chemical complexity of the monomeric anthocyanins, their stability, together with the phenomena such as self-association and copigmentation that can stabilize and enha...

  16. A Three-Year Course of House Dust Mite Sublingual Immunotherapy Appears Effective in Controlling the Symptoms of Allergic Rhinitis.

    Science.gov (United States)

    Novakova, Silviya M; Novakova, Plamena I; Yakovliev, Plamen H; Staevska, Maria T; Mateva, Nonka G; Dimcheva, Teodora D; Peichev, Jivko L

    2018-05-01

    Background Allergic rhinitis is the most common allergic disorder. Although the management of the disease is successful in many patients, based on guidelines, some of them remain with symptoms uncontrolled with pharmacotherapy. Presently, there is no substantiated information on the control of allergic rhinitis in patients who underwent sublingual immunotherapy. Objective The purpose of this prospective follow-up study was to assess the control of allergic rhinitis in adults after a three-year course of house dust mite sublingual immunotherapy. Methods This prospective real-life study was designed to include adults with moderate to severe allergic rhinitis sensitized to house dust mite who underwent a three-year course of sublingual immunotherapy. Control of symptoms was assessed by Rhinitis Control Assessment Test (RCAT) after three years of house dust mite sublingual immunotherapy. Additionally, patients assessed their symptoms by utilizing a visual analog scale. Results A total number of 86 consecutively enrolled patients (46 (53.49%) men; mean age 26.10 years (SD = 5.85)) with moderate to severe allergic rhinitis and clinically relevant sensitization to house dust mite were evaluated. When assessed by RCAT on the third year, 74 (86.05%) had well-controlled symptoms and 20 (27.03%) of them were completely controlled. A significant reduction in visual analog scale scores-from 7.52 cm at baseline to 2.31 cm-was established ( P house dust mite sublingual immunotherapy appears effective in controlling the symptoms of allergic rhinitis.

  17. Design Function and Structure of a Monomeric CLC Transporter

    Energy Technology Data Exchange (ETDEWEB)

    L Robertson; L Kolmakova-Partensky; C Miller

    2011-12-31

    Channels and transporters of the ClC family cause the transmembrane movement of inorganic anions in service of a variety of biological tasks, from the unusual - the generation of the kilowatt pulses with which electric fish stun their prey - to the quotidian - the acidification of endosomes, vacuoles and lysosomes. The homodimeric architecture of ClC proteins, initially inferred from single-molecule studies of an elasmobranch Cl{sup -} channel and later confirmed by crystal structures of bacterial Cl{sup -}/H{sup +} antiporters, is apparently universal. Moreover, the basic machinery that enables ion movement through these proteins - the aqueous pores for anion diffusion in the channels and the ion-coupling chambers that coordinate Cl{sup -} and H{sup +} antiport in the transporters - are contained wholly within each subunit of the homodimer. The near-normal function of a bacterial ClC transporter straitjacketed by covalent crosslinks across the dimer interface and the behaviour of a concatemeric human homologue argue that the transport cycle resides within each subunit and does not require rigid-body rearrangements between subunits. However, this evidence is only inferential, and because examples are known in which quaternary rearrangements of extramembrane ClC domains that contribute to dimerization modulate transport activity, we cannot declare as definitive a 'parallel-pathways picture in which the homodimer consists of two single-subunit transporters operating independently. A strong prediction of such a view is that it should in principle be possible to obtain a monomeric ClC. Here we exploit the known structure of a ClC Cl{sup -}/H{sup +} exchanger, ClC-ec1 from Escherichia coli, to design mutants that destabilize the dimer interface while preserving both the structure and the transport function of individual subunits. The results demonstrate that the ClC subunit alone is the basic functional unit for transport and that cross-subunit interaction is not

  18. A monomeric variant of insulin degrading enzyme (IDE loses its regulatory properties.

    Directory of Open Access Journals (Sweden)

    Eun Suk Song

    2010-03-01

    Full Text Available Insulin degrading enzyme (IDE is a key enzyme in the metabolism of both insulin and amyloid beta peptides. IDE is unique in that it is subject to allosteric activation which is hypothesized to occur through an oligomeric structure.IDE is known to exist as an equilibrium mixture of monomers, dimers, and higher oligomers, with the dimer being the predominant form. Based on the crystal structure of IDE we deleted the putative dimer interface in the C-terminal region, which resulted in a monomeric variant. Monomeric IDE retained enzymatic activity, however instead of the allosteric behavior seen with wild type enzyme it displayed Michaelis-Menten kinetic behavior. With the substrate Abz-GGFLRKHGQ-EDDnp, monomeric IDE retained approximately 25% of the wild type activity. In contrast with the larger peptide substrates beta-endorphin and amyloid beta peptide 1-40, monomeric IDE retained only 1 to 0.25% of wild type activity. Unlike wild type IDE neither bradykinin nor dynorphin B-9 activated the monomeric variant of the enzyme. Similarly, monomeric IDE was not activated by polyphosphates under conditions in which the activity of wild type enzyme was increased more than 50 fold.These findings serve to establish the dimer interface in IDE and demonstrate the requirement for an oligomeric form of the enzyme for its regulatory properties. The data support a mechanism where the binding of activators to oligomeric IDE induces a conformational change that cannot occur in the monomeric variant. Since a conformational change from a closed to a more open structure is likely the rate-determining step in the IDE reaction, the subunit induced conformational change likely shifts the structure of the oligomeric enzyme to a more open conformation.

  19. Depigmented-polymerised allergoids favour regulatory over effector T cells: enhancement by 1α, 25-dihydroxyvitamin D3.

    Science.gov (United States)

    Urry, Zoe L; Richards, David F; Black, Cheryl; Morales, Maria; Carnés, Jerónimo; Hawrylowicz, Catherine M; Robinson, Douglas S

    2014-05-29

    Allergen immunotherapy (SIT) is the only treatment for allergic disease capable of modifying disease long term. To reduce the risk of anaphylaxis from SIT, allergen-extracts have been modified by polymerisation with glutaraldehyde to reduce IgE binding. It is suggested that these allergoid extracts also have reduced T cell activity, which could compromise clinical efficacy. Effective SIT is thought to act through regulatory T cells (Tregs) rather than activation of effector T cells. There is no published data on the activity of modified extracts on Tregs. We compared the capacity of modified (depigmented-polymerised) versus unmodified (native) allergen extracts of grass pollen and house dust mite to stimulate proliferation/cytokine production and to modulate Treg/effector T cell frequency in cultures of peripheral blood mononuclear cells (PBMC), from volunteers sensitised to both allergens in vitro. Depigmented-polymerised allergen extracts stimulated less proliferation of PBMC, and reduced effector cell numbers after 7 days in culture than did native extracts. However, the frequency of Foxp3+ Tregs in cultures were similar to those seen with native extract so that ratios of regulatory to effector T cells were significantly increased in cultures stimulated with depigmented-polymerised extracts. Addition of 1α, 25-dihydroxyvitamin D3 further favoured Treg, and reduced effector cytokine production, but not interleukin-10. Depigmented-polymerised allergen extracts appear to favour Treg expansion over activation of effector T cells and this may relate to their demonstrated efficacy and safety in SIT. 1α, 25-dihydroxyvitamin D3 further reduces effector T cell activation by allergen extracts and may be a useful adjuvant for SIT.

  20. Airway function indicators and blood indicators in children with dust mite allergic rhinitis after sublingual immunotherapy

    Directory of Open Access Journals (Sweden)

    Hua Xiang

    2016-07-01

    Full Text Available Objective: To evaluate the airway function indicators and blood indicators in children with dust mite allergic rhinitis after sublingual immunotherapy. Methods: A total of 68 children with dust mite allergic rhinitis treated in our hospital from November, 2012 to October, 2015 were selected as the research subjects and randomly divided into observation group 34 cases and control group 34 cases. The control group received clinical routine therapy for allergic rhinitis, the observation group received sublingual immunotherapy, and then differences in basic lung function indicator values, small airway function indicator values and levels of serum inflammatory factors as well as serum ECP, TARC, Eotaxin-2 and VCAM were compared between two groups after treatment. Results: The FVC, FEV1, PEF and FEV1/FVC values of the observation group after treatment were higher than those of the control group (P<0.05; the MMEF, MEF50% and MEF25% values of the observation group were higher than those of the control group, and the proportion of AHR was lower than that of the control group (P<0.05; the serum IL-4, IL-9, IL-12, IL-13 and IL-16 levels of the observation group after treatment were lower than those of the control group, and the IL-10 and IL-12 levels are higher than those of the control group (P<0.05; the serum ECP, TARC, Eotaxin-2 and VCAM levels of the observation group children after treatment were lower than those of the control group (P<0.05. Conclusions: Sublingual immunotherapy for children with dust mite allergic rhinitis can optimize the airway function, reduce the systemic inflammatory response and eventually improve the children’s overall state, and it’s has positive clinical significance.

  1. In vitro and in vivo evaluation of a sublingual fentanyl wafer formulation

    Directory of Open Access Journals (Sweden)

    Lim SCB

    2013-04-01

    Full Text Available Stephen CB Lim,1,3 Michael J Paech,2 Bruce Sunderland,3 Yandi Liu3 1Pharmacy Department, Armadale Health Service, Armadale, 2School of Medicine and Pharmacology, University of Western Australia, and Department of Anaesthesia and Pain Medicine, King Edward Memorial Hospital for Women, Subiaco, 3School of Pharmacy, Curtin Health Innovation Research Institute, Curtin University, Perth, WA, Australia Background: The objective of this study was to prepare a novel fentanyl wafer formulation by a freeze-drying method, and to evaluate its in vitro and in vivo release characteristics, including its bioavailability via the sublingual route. Methods: The wafer formulation was prepared by freeze-drying an aqueous dispersion of fentanyl containing sodium carboxymethylcellulose and amylogum as matrix formers. Uniformity of weight, friability, and dissolution testing of the fentanyl wafer was achieved using standard methods, and the residual moisture content was measured. The fentanyl wafer was also examined using scanning electron microscopy and x-ray diffraction. The absolute bioavailability of the fentanyl wafer was evaluated in 11 opioid-naïve adult female patients using a randomized crossover design. Results: In vitro release showed that almost 90% of the fentanyl dissolved in one minute. In vivo, the first detectable plasma fentanyl concentration was observed after 3.5 minutes and the peak plasma concentration between 61.5 and 67 minutes. The median absolute bioavailability was 53.0%. Conclusion: These results indicate that this wafer has potential as an alternative sublingual fentanyl formulation. Keywords: absolute bioavailability, fentanyl wafer, in vitro dissolution, in vivo study, pharmacokinetics, sublingual

  2. ROLE OF 400 MCG INTRAOPERATIVE SUBLINGUAL MISOPROSTOL FOR REDUCTION OF CAESAREAN BLOOD LOSS

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    Lalmohan Nayak

    2017-02-01

    Full Text Available BACKGROUND Lower segment caesarean section is a common surgical procedure. Postpartum haemorrhage incidence after LSCS is 4%. Misoprostol is a prostaglandin E1 analogue with good uterotonic properties, easy availability, low cost, thermostability, long shelf life, easy administration and few adverse effects at therapeutic dose. It is readily absorbed by oral, sublingual, buccal, vaginal or rectal route. Sublingual route attains quickest concentration. Dose of 400 mcg was chosen in this study to minimise adverse effects with optimal therapeutic benefit. The aim of the study is to determine the efficacy of sublingual misoprostol in reducing caesarean blood loss. MATERIALS AND METHODS It is a prospective experimental study done in VSSIMSAR, Burla. Women undergoing LSCS were randomly assigned to study and control groups of equal strength of 100 each. In all cases, preoperative Hb%, haematocrit, pulse, BP was noted. Study group were given 400 mcg misoprostol at the time of cord clamping. In control group, nothing was given. In all patients, active management of third stage of labour was done by using oxytocin 10 IU (IV along with uterine massage. Blood loss soaked by tetra was calculated using formula, blood loss = wet weight-dry weight/1.05 (1.05 is constant. Amount of blood loss, postoperative Hb%, haematocrit, pulse rate, BP was noted in both groups and compared. BP and pulse were noted after 1 hour and Hb%, haematocrit were noted after 24 hours. RESULTS Study group showed significant decrease in total blood loss (around 117.9 mL as compared to control group. There was significant decrease in the postoperative fall in Hb in the study group as compared to control, the mean difference being 0.631 gm%. Study group also showed decrease in postoperative fall in haematocrit as compared to control, the mean difference being 0.055. CONCLUSION Misoprostol significantly reduced caesarean blood loss and doesn’t affect foetal outcome without significant

  3. Ultrastructural changes in the sublingual salivary gland of prenatal buffalo (Bubalus bubalis

    Directory of Open Access Journals (Sweden)

    A. D. Singh

    2016-03-01

    Full Text Available Aim: The present study was aimed to elucidate ultrastructural changes in the development of sublingual salivary gland of buffalo during prenatal life. Materials and Methods: The study was carried out on sublingual salivary gland of 36 buffalo fetuses ranging from 13.2 cm curved crown-rump length (CVRL (88th day to full term. The fetuses were categorized into three groups based on their CVRL. Results: The cells lining the terminal tubules were undifferentiated with poorly developed cytoplasmic organelles but lacked secretory granules (SGs at 13.2 cm CVRL (88th day. The SGs appeared first in the form of membrane-bound secretory vesicles with homogeneous electron-dense as well as electron-lucent contents at 21.2 cm CVRL (122nd day; however, mucous acinar cells contained electron-lucent granules, while serous secretory cells as well as serous demilunes showed electron-dense granules at 34 cm CVRL (150th day of prenatal life. At 53.5 cm CVRL (194th day, both mucous and serous acini were differentiated by the density of SGs. Conclusion: The cytoplasm of acinar cells was filled with mitochondria, rough endoplasmic reticulum, and Golgi profiles in mid and late fetal age groups. The SGs were increased in number during the late fetal age group. The myoepithelial cells (MECs were located at the base of the acinar cells as well as intercalated and striated ducts and were stellate in shape. The ultrastructure of MEC revealed a parallel stream of myofilaments in the cytoplasm and its processes. The mucous cells were predominantly present in the sublingual salivary gland and were pyramidal in shape.

  4. Sedation and mechanical hypoalgesia after sublingual administration of detomidine hydrochloride gel to donkeys.

    Science.gov (United States)

    Lizarraga, Ignacio; Castillo-Alcala, Fernanda; Varner, Kelley M; Robinson, Lauren S

    2016-07-01

    OBJECTIVE To compare sedative and mechanical hypoalgesic effects of sublingual administration of 2 doses of detomidine gel to donkeys. DESIGN Randomized blinded controlled trial. ANIMALS 6 healthy castrated male donkeys. PROCEDURES In a crossover study design, donkeys received each of the following sublingual treatments 1 week apart in a randomly assigned order: 1 mL of molasses (D0) or detomidine hydrochloride gel at 20 μg/kg (9 μg/lb; D20) or 40 μg/kg (18 μg/lb; D40). Sedation score (SS), head height above the ground (HHAG), and mechanical nociceptive threshold (MNT) were assessed before and for 180 minutes after treatment. Areas under the effect change-versus-time curves (AUCs) from 0 to 30, 30 to 60, 60 to 120, and 120 to 180 minutes after administration were computed for SS, HHAG, and MNT and compared among treatments. RESULTS D20 and D40 resulted in greater SS AUCs from 60 to 120 minutes and smaller HHAG AUCs from 30 through 180 minutes than did D0. The D40 resulted in smaller HHAG AUCs from 60 to 120 minutes than did D20. Compared with D0 values, MNT AUCs from 60 to 120 minutes were higher for D20, whereas MNT AUCs from 30 through 180 minutes were higher for D40. CONCLUSIONS AND CLINICAL RELEVANCE D20 and D40 induced sedation and mechanical hypoalgesia in donkeys by > 30 minutes after administration, but only sedation was dose dependent. Sublingual administration of detomidine gel at 40 μg/kg may be useful for sedation of standing donkeys prior to potentially painful minor procedures.

  5. Disintegration of sublingual tablets: proposal for a validated test method and acceptance criterion.

    Science.gov (United States)

    Weda, M; van Riet-Nales, D A; van Aalst, P; de Kaste, D; Lekkerkerker, J F F

    2006-12-01

    In the Netherlands the market share of isosorbide dinitrate 5 mg sublingual tablets is dominated by 2 products (A and B). In the last few years complaints have been received from health care professionals on product B. During patient use the disintegration of the tablet was reported to be slow and/or incomplete, and ineffectiveness was experienced. In the European Pharmacopoeia (Ph. Eur.) no requirement is present for the disintegration time of sublingual tablets. The purpose of this study was to compare the in vitro disintegration time of products A and B, and to establish a suitable test method and acceptance criterion. A and B were tested with the Ph. Eur. method described in the monograph on disintegration of tablets and capsules as well as with 3 modified tests using the same Ph. Eur. apparatus, but without movement of the basket-rack assembly. In modified test 1 and modified test 2 water was used as medium (900 ml and 50 ml respectively), whereas in modified test 3 artificial saliva was used (50 ml). In addition, disintegration was tested in Nessler tubes with 0.5 and 2 ml of water. Finally, the Ph. Eur. method was also applied to other sublingual tablets with other drug substances on the Dutch market. With modified test 3 no disintegration could be achieved within 20 min. With the Ph. Eur. method and modified tests 1 and 2 product A and B differed significantly (p disintegration times. These 3 methods were capable of discriminating between products and between batches. The time measured with the Ph. Eur. method was significantly lower compared to modified tests 1 and 2 (p tablets the disintegration time should be tested. The Ph. Eur. method is considered suitable for this test. In view of the products currently on the market and taking into consideration requirements in the United States Pharmacopeia and Japanese Pharmacopoeia, an acceptance criterion of not more than 2 min is proposed.

  6. Reduced sublingual endothelial glycocalyx in type 1 diabetic patients with diabetic nephropathy

    DEFF Research Database (Denmark)

    Winther, Signe Abitz; Frimodt-Møller, Marie; Zobel, Emilie Hein

    thickness was assessed by 5 measurements with the GlucoCheck device (GlucoCheck BV, The Netherlands), a non-invasive hand-held microscope generating video recordings of the sublingual capillaries. Endothelial glycocalyx thickness was estimated from the PBR in capillaries with a diameter range of 5-25 μm......- and macroalbuminuric patients (p=0.020) and micro- and macroalbuminuric patients (p=0.042) were significant, but the difference between normo- and microalbuminuric patients was not (p=0.74). After adjustment for age, sex, HbA1c, diabetes duration and systolic blood pressure, differences between normo...

  7. Multislice CT coronary angiography: effect of sublingual nitroglycerine on the diameter of coronary arteries

    International Nuclear Information System (INIS)

    Dewey, M.; Hamm, B.; Hoffmann, H.

    2006-01-01

    Purpose: to investigate the influence of sublingual glycerol trinitrate (1.2 mg, Nitrate [nitroglycerine], Nitrolingual N spray) on the coronary artery diameter on multislice computed tomography (MSCT) coronary angiography. Materials and methods: out of our database of patients who underwent MSCT (slice thickness of 0.5 mm, Aquilion, Toshiba) coronary angiography between July 2003 and November 2005 (950 patients) we retrospectively identified patients with follow-up examinations who received Nitrate for one examination while another examination was performed without Nitrate (10 patients). Another 10 patients who underwent two MSCT examinations with sublingual Nitrate administration were randomly selected from this database to serve as control group. For the resulting 40 MSCT examinations, blinded MSCT datasets were prepared, which were randomly evaluated by a reader blinded to the patient information and whether or not Nitrate had been given. The proximal coronary artery diameters were measured for the left main coronary artery (LMA), the left anterior descending coronary artery (LAD), the left circumflex coronary artery (LCX), and the right coronary artery (RCA) in all 40 datasets, resulting in altogether 160 measurements. Results: the proximal diameters of all four coronary arteries were significantly larger on the MSCT coronary angiograms obtained after sublingual administration of Nitrate compared with the examinations in the same 10 patients without Nitrate (p < 0.001). The average diameters without and with Nitrate for the LMA, LAD, LCX, and RCA were 4.3 ± 1.1 vs. 4.8 ± 0.9 mm (12% increase, p < 0.005), 3.0 ± 0.6 vs. 3.5 ± 0.5 mm (17% increase, p < 0.001), 2.7 ± 0.6 vs. 3.2 ± 0.7 mm (19% increase, p < 0.005), and 2.9 ± 0.9 vs. 3.5 ± 0.7 mm (21% increase, p < 0.005), respectively. In the control group of 10 patients who underwent two MSCT coronary angiographies after sublingual Nitrate, no significant difference in the proximal diameter of all four

  8. Distinct modulation of allergic T cell responses by subcutaneous versus sublingual allergen-specific immunotherapy

    DEFF Research Database (Denmark)

    Schulten, Véronique; Tripple, Victoria; Andersen, Kristian Aasbjerg

    2016-01-01

    mechanisms involved have not been fully explored. OBJECTIVE: To compare changes in the allergen-specific T cell response induced by subcutaneous versus sublingual administration of allergen-specific immunotherapy (AIT). METHODS: Grass pollen allergic patients were randomized into groups receiving either SCIT...... injections, or SLIT tablets or neither. PBMC were tested for Timothy grass (TG)-specific cytokine production by ELISPOT after in vitro expansion with TG peptide pools. Phenotypic characterization of cytokine producing cells was performed by FACS. RESULTS: In the SCIT group, decreased IL-5 production...

  9. Anthocyanins and Their Variation in Red Wines I. Monomeric Anthocyanins and Their Color Expression

    Directory of Open Access Journals (Sweden)

    Chang-Qing Duan

    2012-02-01

    Full Text Available Originating in the grapes, monomeric anthocyanins in young red wines contribute the majority of color and the supposed beneficial health effects related to their consumption, and as such they are recognized as one of the most important groups of phenolic metabolites in red wines. In recent years, our increasing knowledge of the chemical complexity of the monomeric anthocyanins, their stability, together with the phenomena such as self-association and copigmentation that can stabilize and enhance their color has helped to explain their color representation in red wine making and aging. A series of new enological practices were developed to improve the anthocyanin extraction, as well as their color expression and maintenance. This paper summarizes the most recent advances in the studies of the monomeric anthocyanins in red wines, emphasizing their origin, occurrence, color enhancing effects, their degradation and the effect of various enological practices on them.

  10. Acinar autolysis and mucous extravasation in human sublingual glands: a microscopic postmortem study.

    Science.gov (United States)

    Azevedo-Alanis, Luciana Reis; Tolentino, Elen de Souza; de Assis, Gerson Francisco; Cestari, Tânia Mary; Lara, Vanessa Soares; Damante, José Humberto

    2015-10-01

    Although some morphological investigations on aged human sublingual glands (HSG) found eventual phenomena identified as autolysis and mucous extravasation, the exact meaning of these findings has not been elucidated. The aim of this work is to investigate whether acinar autolysis and mucous extravasation are related to the aging process in human sublingual glands. We also speculate if autolytic changes may assist forensic pathologists in determining time of death. 186 cadavers' glands were allocated to age groups: I (0-30 years); II (31-60), and III (61-90). Time and mode of death were also recorded. Acinar autolysis and mucous extravasation were classified as present or absent. Ultrastructural analysis was performed using transmission electron microscopy (TEM). Data were compared using Mann-Whitney U, Spearman's correlation coefficient, Kruskal-Wallis, and Dunn tests (pautolysis (r=0.38; p=0.0001). However, there was no correlation between autolysis and time of death. No differences were observed between genders. TEM showed mucous and serous cells presenting nuclear and membrane alterations and mucous cells were more susceptible to autolysis. Acinar autolysis occurred in all age groups and increased with age while mucous extravasation was rarely found. Both findings are independent. Autolysis degrees in HSG could not be used to determine time of death.

  11. Spontaneous sublingual and intramural small-bowel hematoma in a patient on oral anticoagulation

    Directory of Open Access Journals (Sweden)

    Mohamed Moftah

    2012-08-01

    Full Text Available Spontaneous sublingual hematoma and intramural small bowel hematoma are rare and serious complications of anticoagulant therapy. Though previously reported individually, there has been no previous report of the same two complications occurring in a single patient. A 71-year-old Caucasian man, who was on warfarin for atrial fibrillation, presented with difficulty in swallowing due to a sublingual hematoma. He was observed in our intensive care unit, his warfarin was held and he recovered with conservative management. He represented two months later with a two day history of abdominal pain and distension. An abdominopelvic computed tomography (CT scan now showed small bowel obstruction due to intramural small bowel hematoma and haemorrhagic ascites. Again, this was treated expectantly with a good outcome. In conclusion, life threatening haemorrhagic complications of oral anticoagulant therapy can recur. Conservative treatment is successful in most cases, but an accurate diagnosis is mandatory to avoid unnecessary surgery. CT scan is the investigation of choice for the diagnosis of suspected haemorrhagic complications of over coagulation.

  12. In vitro and in vivo evaluation of a sublingual fentanyl wafer formulation

    Science.gov (United States)

    Lim, Stephen CB; Paech, Michael J; Sunderland, Bruce; Liu, Yandi

    2013-01-01

    Background The objective of this study was to prepare a novel fentanyl wafer formulation by a freeze-drying method, and to evaluate its in vitro and in vivo release characteristics, including its bioavailability via the sublingual route. Methods The wafer formulation was prepared by freeze-drying an aqueous dispersion of fentanyl containing sodium carboxymethylcellulose and amylogum as matrix formers. Uniformity of weight, friability, and dissolution testing of the fentanyl wafer was achieved using standard methods, and the residual moisture content was measured. The fentanyl wafer was also examined using scanning electron microscopy and x-ray diffraction. The absolute bioavailability of the fentanyl wafer was evaluated in 11 opioid-naïve adult female patients using a randomized crossover design. Results In vitro release showed that almost 90% of the fentanyl dissolved in one minute. In vivo, the first detectable plasma fentanyl concentration was observed after 3.5 minutes and the peak plasma concentration between 61.5 and 67 minutes. The median absolute bioavailability was 53.0%. Conclusion These results indicate that this wafer has potential as an alternative sublingual fentanyl formulation. PMID:23596347

  13. Sublingual administration of detomidine in horses: sedative effect, analgesia and detection time.

    Science.gov (United States)

    L'Ami, Jiske J; Vermunt, Lian E; van Loon, Johannes P A M; Sloet van Oldruitenborgh-Oosterbaan, Marianne M

    2013-05-01

    A single dose of 40 μg/kg bodyweight (BW) of oromucosal detomidine gel was administered sublingually to 10 healthy Dutch Warmblood mares aged 7 ± 4 years (mean ± SD) and BW 580 ± 69 kg. Blood and urine samples were collected before and for 8 days following administration and evaluated qualitatively in an FEI Reference Laboratory and quantitatively in a research laboratory. Clinical effects were evaluated at baseline and for 24 h after administration. Sedation was determined using head height and scores of reaction to auditory and mixed auditory/sensory stimuli. Mechanical nociceptive thresholds (MNTs) were assessed using pressure algometry to evaluate analgesia. Heart rate (HR) was measured and ataxia scored. All horses were considered negative for detomidine in blood samples by 48 h post-administration and in urine by 60 h. These results indicated that a safe withdrawal time for detomidine oromucosal gel may be 72 h following a single sublingual administration of 40 μg/kgBW. Decreases in HR and head height were maximal at 40 and 60 min post-administration, respectively. The maximal decrease in response to stimuli was observed at 100 min. Ataxia was maximal at 60 min. At 40 and 80 min MNTs were significantly increased compared to baseline. All parameters, except the MNTs of two locations, which were decreased, returned to baseline values within 24 h post-administration. Copyright © 2012 Elsevier Ltd. All rights reserved.

  14. Acinar autolysis and mucous extravasation in human sublingual glands: a microscopic postmortem study

    Directory of Open Access Journals (Sweden)

    Luciana Reis AZEVEDO-ALANIS

    2015-10-01

    Full Text Available Although some morphological investigations on aged human sublingual glands (HSG found eventual phenomena identified as autolysis and mucous extravasation, the exact meaning of these findings has not been elucidated.Objective The aim of this work is to investigate whether acinar autolysis and mucous extravasation are related to the aging process in human sublingual glands. We also speculate if autolytic changes may assist forensic pathologists in determining time of death.Material and Methods 186 cadavers’ glands were allocated to age groups: I (0–30 years; II (31–60, and III (61–90. Time and mode of death were also recorded. Acinar autolysis and mucous extravasation were classified as present or absent. Ultrastructural analysis was performed using transmission electron microscopy (TEM. Data were compared using Mann-Whitney U, Spearman’s correlation coefficient, Kruskal-Wallis, and Dunn tests (p<0.05.Results There was correlation between age and acinar autolysis (r=0.38; p=0.0001. However, there was no correlation between autolysis and time of death. No differences were observed between genders. TEM showed mucous and serous cells presenting nuclear and membrane alterations and mucous cells were more susceptible to autolysis.Conclusion Acinar autolysis occurred in all age groups and increased with age while mucous extravasation was rarely found. Both findings are independent. Autolysis degrees in HSG could not be used to determine time of death.

  15. Congenital hypothyroidism due to ectopic sublingual thyroid gland in Prader-Willi Syndrome: a case report.

    Science.gov (United States)

    Bocchini, Sarah; Fintini, Danilo; Grugni, Graziano; Boiani, Arianna; Convertino, Alessio; Crinò, Antonino

    2017-09-22

    Thyroid gland disorders are variably associated with Prader-Willi syndrome (PWS). Many of the clinical features in newborns with PWS are similar to those found in congenital hypothyroidism (CH). We report a case of a girl with CH and PWS. At the age of 9 months CH caused by an ectopic sublingual thyroid was diagnosed, and hormone replacement therapy was started. In spite of this treatment a decrease in growth velocity, weight excess and delayed development were observed. At the age of 9 years PWS was suspected on the basis of phenotype and genetic tests confirmed a maternal uniparental disomy of chromosome 15. This is the second reported case of hypothyroidism due to an ectopic sublingual thyroid gland in PWS suggesting that, although rare, an association between CH and PWS may exist. In our case diagnosis of PWS was delayed because mental retardation, hypotonia, obesity and short stature were initially attributed to hypothyroidism. In this context PWS should be considered in obese children with CH who do not improve adequately with l-thyroxine therapy. Also, thyroid function in all PWS children should be assessed regularly in order to avoid delayed diagnosis of hypothyroidism.

  16. Direct labelling of monomeric antibody fragments Fab' with 99mTc

    International Nuclear Information System (INIS)

    Li Jun; Wang Shizhen; Yang Ziyi

    1994-01-01

    Direct labelling method and conditions of monomeric antibody Fab' with 99m Tc were investigated. Polyclonal antibody IgG was digested with ficin to produce dimeric fragments F(ab') 2 , which was subsequently reduced to monomeric fragments Fab' with 2-mercaptoethylamine. Finally, Fab' was incubated with sodium gluconate (Sn(II)) kit solution and 99m TcO 4 - eluted at room temperature to form 99m Tc-Fab'. The labelling efficiency was 85%-95%. The stability of labelled products was satisfactory and the elimination rate was faster than 99m Tc-IgG

  17. Direct action of the X-ray on the submandibular and sublingual glands. Histologic and histochemical study in rats

    International Nuclear Information System (INIS)

    Santos-Pinto, M.C. dos; Martinelli, C.; Santos-Pinto, R. dos

    1991-01-01

    The submandibular and sublingual glands of rats are surgically exposed and irradiated by X-ray. A simulated group with surgical exposition of the glands is performed. In the irradiated submandibular glands occurred atrophy, architectural disorder and degenerative processes. RNA reduction in the nucleus, nucleolus and cytoplasm of the acini cells and a decrease of protein synthesis are described. (M.A.C.)

  18. Comparative Study Between Different Ready-Made Orally Disintegrating Platforms for the Formulation of Sumatriptan Succinate Sublingual Tablets.

    Science.gov (United States)

    Tayel, Saadya A; El Nabarawi, Mohamed A; Amin, Maha M; AbouGhaly, Mohamed H H

    2017-02-01

    Sumatriptan succinate (SS) is a selective serotonin receptor agonist used for the treatment of migraine attacks, suffering from extensive first-pass metabolism and low oral bioavailability (∼14%). The aim of this work is to compare the performance of different ready-made co-processed platforms (Pharmaburst®, Prosolv ODT®, Starlac®, Pearlitol Flash®, or Ludiflash®) in the formulation of SS sublingual orodispersible tablets (ODTs) using direct compression technique. The prepared SS ODT formulae were evaluated regarding hardness, friability, simulated wetting time, and in vitro disintegration and dissolution tests. Different mucoadhesive polymers-HPMC K4M, Carbopol®, chitosan, or Polyox®-were tested aiming to increase the residence time in the sublingual area. A pharmacokinetic study on healthy human volunteers was performed, using LC/MS/MS assay, to compare the optimum sublingual formula (Ph25/HPMC) with the conventional oral tablet Imitrex®. Results showed that tablets prepared using Pharmaburst® had significantly (p disintegration times of 17.17 and 23.50 s, respectively, with Q 5 min of 83.62%. HPMC showed a significant (p tablet Imitrex®. In conclusion, Pharmaburst® was chosen as the optimum ready-made co-processed platform that can be successfully used in the preparation of SS sublingual tablets for the rapid relief of migraine attacks.

  19. Sublingual injection of microparticles containing glycolipid ligands for NKT cells and subunit vaccines induces antibody responses in oral cavity.

    Science.gov (United States)

    DeLyria, Elizabeth S; Zhou, Dapeng; Lee, Jun Soo; Singh, Shailbala; Song, Wei; Li, Fenge; Sun, Qing; Lu, Hongzhou; Wu, Jinhui; Qiao, Qian; Hu, Yiqiao; Zhang, Guodong; Li, Chun; Sastry, K Jagannadha; Shen, Haifa

    2015-03-20

    Natural Killer T (NKT) cells are a unique type of innate immune cells which exert paradoxical roles in animal models through producing either Th1 or Th2 cytokines and activating dendritic cells. Alpha-galactosylceramide (αGalCer), a synthetic antigen for NKT cells, was found to be safe and immune stimulatory in cancer and hepatitis patients. We recently developed microparticle-formulated αGalCer, which is selectively presented by dendritic cells and macrophages, but not B cells, and thus can avoid the anergy of NKT cells. In this study, we have examined the immunogenicity of microparticles containing αGalCer and protein vaccine components through sublingual injection in mice. The results showed that sublingual injection of microparticles containing αGalCer and ovalbumin triggered IgG responses in serum (titer >1:100,000), which persisted for more than 3months. Microparticles containing ovalbumin alone also induced comparable level of IgG responses. However, immunoglobulin subclass analysis showed that sublingually injected microparticles containing αGalCer and ovalbumin induced 20 fold higher Th1 biased antibody (IgG2c) than microparticles containing OVA alone (1:20,000 as compared to 1:1000 titer). Sublingual injection of microparticles containing αGalCer and ovalbumin induced secretion of both IgG (titer >1:1000) and IgA (titer=1:80) in saliva secretion, while microparticles containing ovalbumin alone only induced secretion of IgG in saliva. Our results suggest that sublingual injection of microparticles and their subsequent trafficking to draining lymph nodes may induce adaptive immune responses in mucosal compartments. Ongoing studies are focused on the mechanism of antigen presentation and lymphocyte biology in the oral cavity, as well as the toxicity and efficacy of these candidate microparticles for future applications. Copyright © 2014 Elsevier Ltd. All rights reserved.

  20. Generation and Characterization of an IgG4 Monomeric Fc Platform.

    Directory of Open Access Journals (Sweden)

    Lu Shan

    Full Text Available The immunoglobulin Fc region is a homodimer consisted of two sets of CH2 and CH3 domains and has been exploited to generate two-arm protein fusions with high expression yields, simplified purification processes and extended serum half-life. However, attempts to generate one-arm fusion proteins with monomeric Fc, with one set of CH2 and CH3 domains, are often plagued with challenges such as weakened binding to FcRn or partial monomer formation. Here, we demonstrate the generation of a stable IgG4 Fc monomer with a unique combination of mutations at the CH3-CH3 interface using rational design combined with in vitro evolution methodologies. In addition to size-exclusion chromatography and analytical ultracentrifugation, we used multi-angle light scattering (MALS to show that the engineered Fc monomer exhibits excellent monodispersity. Furthermore, crystal structure analysis (PDB ID: 5HVW reveals monomeric properties supported by disrupted interactions at the CH3-CH3 interface. Monomeric Fc fusions with Fab or scFv achieved FcRn binding and serum half-life comparable to wildtype IgG. These results demonstrate that this monomeric IgG4 Fc is a promising therapeutic platform to extend the serum half-life of proteins in a monovalent format.

  1. Iontophoresis of monomeric insulin analogues in vitro: effects of insulin charge and skin pretreatment.

    Science.gov (United States)

    Langkjaer, L; Brange, J; Grodsky, G M; Guy, R H

    1998-01-23

    The aim of this study was to investigate the influence of association state and net charge of human insulin analogues on the rate of iontophoretic transport across hairless mouse skin, and the effect of different skin pretreatments on said transport. No insulin flux was observed with anodal delivery probably because of degradation at the Ag/AgCl anode. The flux during cathodal iontophoresis through intact skin was insignificant for human hexameric insulin, and only low and variable fluxes were observed for monomeric insulins. Using stripped skin on the other hand, the fluxes of monomeric insulins with two extra negative charges were 50-100 times higher than that of hexameric human insulin. Introducing three additional charges led to a further 2-3-fold increase in flux. Wiping the skin gently with absolute alcohol prior to iontophoresis resulted in a 1000-fold increase in transdermal transport of insulin relative to that across untreated skin, i.e. to almost the same level as stripping the skin. The alcohol pretreatment reduced the electrical resistance of the skin, presumably by lipid extraction. In conclusion, monomeric insulin analogues with at least two extra negative charges can be iontophoretically delivered across hairless mouse skin, whereas insignificant flux is observed with human, hexameric insulin. Wiping the skin with absolute alcohol prior to iontophoresis gave substantially improved transdermal transport of monomeric insulins resulting in clinically relevant delivery rates for basal treatment.

  2. Bioavailability of House Dust Mite Allergens in Sublingual Allergy Tablets Is Highly Dependent on the Formulation.

    Science.gov (United States)

    Ohashi-Doi, Katsuyo; Kito, Hirokazu; Du, Weibin; Nakazawa, Hiroshi; Ipsen, Henrik; Gudmann, Pernille; Lund, Kaare

    2017-01-01

    In sublingual immunotherapy (SLIT), the immune system is addressed by solubilized allergen that interacts with immunocompetent cells of the oral mucosa, the efficiency of which is governed by 2 main factors of SLIT allergen bioavailability: the allergen concentration and the mucosal contact time. Recently, 3 house dust mite (HDM) SLIT tablets were developed that differ with regard to allergen content, nominal strength (maintenance doses: 6 SQ-HDM/10,000 Japanese Allergen Units [JAU], 12 SQ-HDM/ 20,000 JAU, and 300 IR/57,000 JAU), and formulation (freeze-dried/compressed). Here, the importance of the SLIT tablet formulation for HDM major allergen bioavailability is examined. The HDM major allergen content, tablet disintegration times, and allergen release kinetics were determined. Dissolution kinetics (allergen concentration vs. time) of Der f 1, Der p 1, and Der 2 were measured. Area under the curve (AUC) was used as a surrogate parameter for allergen bioavailability. The release of HDM major allergens from the freeze-dried tablets was complete after 30 s, while only partial release was achieved with the compressed tablets, even after prolonged dissolution. At 1 min, i.e., the recommended sublingual holding time for the freeze-dried tablets, the allergen bioavailability (AUC) of the compressed 300 IR/57,000 JAU tablet was 4.7-fold (Der f 1), 10.8-fold (Der p 1), and 23.6-fold (Der 2) lower than that of the freeze-dried 12 SQ-HDM/20,000 JAU tablet and similar to (Der f 1) and 5.3-fold (Der p 1) and 12.5-fold (Der 2) lower than that of the freeze-dried 6 SQ-HDM/10,000 JAU tablet. SLIT tablet allergen bioavailability depends highly on the tablet formulation. Only the fast-dissolving freeze-dried tablets provide maximal delivery of soluble allergens and achieve allergen concentrations that reflect the nominal tablet strengths within the recommended sublingual holding time. © 2017 S. Karger AG, Basel.

  3. Mite allergoids coupled to nonoxidized mannan from Saccharomyces cerevisae efficiently target canine dendritic cells for novel allergy immunotherapy in veterinary medicine.

    Science.gov (United States)

    Soria, Irene; Alvarez, Javier; Manzano, Ana I; López-Relaño, Juan; Cases, Bárbara; Mas-Fontao, Ana; Cañada, F Javier; Fernández-Caldas, Enrique; Casanovas, Miguel; Jiménez-Barbero, Jesús; Palomares, Oscar; Viñals-Flórez, Luis M; Subiza, José L

    2017-08-01

    We have recently reported that grass pollen allergoids conjugated with nonoxidized mannan of Saccharomyces cerevisae using glutaraldehyde results in a novel hypoallergenic mannan-allergen complex with improved properties for allergen vaccination. Using this approach, human dendritic cells show a better allergen uptake and cytokine profile production (higher IL-10/IL-4 ratio) for therapeutic purposes. Here we aim to address whether a similar approach can be extended to dogs using canine dendritic cells. Six healthy Spanish Greyhound dogs were used as blood donors to obtain canine dendritic cells (DC) derived from peripheral blood monocytes. Allergens from Dermatophagoides farinae mite were polymerized and conjugated with nonoxidized mannan. Nuclear magnetic resonance (NMR), gel electrophoresis (SDS-PAGE), immunoblotting and IgE-ELISA inhibition studies were conducted to evaluate the main characteristics of the allergoid obtained. Mannan-allergen conjugate and controls were assayed in vitro for canine DC uptake and production of IL-4 and IL-10. The results indicate that the conjugation of D. farinae allergens with nonoxidized mannan was feasible using glutaraldehyde. The resulting product was a polymerized structure showing a high molecular weight as detected by NMR and SDS-PAGE analysis. The mannan-allergen conjugate was hypoallergenic with a reduced reactivity with specific dog IgE. An increase in both allergen uptake and IL-10/IL-4 ratio was obtained when canine DCs were incubated with the mannan-allergen conjugate, as compared with the control allergen preparations (unmodified D. farinae allergens and oxidized mannan-allergen conjugate). We conclude that hypoallergenic D. farinae allergens coupled to nonoxidized mannan is a novel allergen preparation suitable for canine allergy immunotherapy targeting dendritic cells. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  4. Fentanyl sublingual spray for breakthrough cancer pain in patients receiving transdermal fentanyl.

    Science.gov (United States)

    Alberts, David S; Smith, Christina Cognata; Parikh, Neha; Rauck, Richard L

    2016-10-01

    To investigate the relationship between effective fentanyl sublingual spray (FSS) doses for breakthrough cancer pain (BTCP) and around-the-clock (ATC) transdermal fentanyl patch (TFP). Adults tolerating ATC opioids received open-label FSS for 26 days, followed by a 26-day double-blind phase for patients achieving an effective dose (100-1600 µg). Out of 50 patients on ATC TFP at baseline, 32 (64%) achieved an effective dose. FSS effective dose moderately correlated with mean TFP dose (r = 0.4; p = 0.03). Patient satisfaction increased during the study. Common adverse event included nausea (9%) and peripheral edema (9%). FSS can be safely titrated to an effective dose for BTCP in patients receiving ATC TFP as chronic cancer pain medication. ClinicalTrials.gov identifier: NCT00538850.

  5. SQ grass sublingual allergy immunotherapy tablet for disease-modifying treatment of grass pollen allergic rhinoconjunctivitis

    DEFF Research Database (Denmark)

    Dahl, Ronald; Roberts, Graham; de Blic, Jacques

    2016-01-01

    BACKGROUND: Allergy immunotherapy is a treatment option for allergic rhinoconjunctivitis (ARC). It is unique compared with pharmacotherapy in that it modifies the immunologic pathways that elicit an allergic response. The SQ Timothy grass sublingual immunotherapy (SLIT) tablet is approved in North...... America and throughout Europe for the treatment of adults and children (≥5 years old) with grass pollen-induced ARC. OBJECTIVE: The clinical evidence for the use of SQ grass SLIT-tablet as a disease-modifying treatment for grass pollen ARC is discussed in this review. METHODS: The review included...... the suitability of SQ grass SLIT-tablet for patients with clinically relevant symptoms to multiple Pooideae grass species, single-season efficacy, safety, adherence, coseasonal initiation, and cost-effectiveness. The data from the long-term SQ grass SLIT-tablet clinical trial that evaluated a clinical effect 2...

  6. Post-treatment efficacy of discontinuous treatment with 300IR 5-grass pollen sublingual tablet in adults with grass pollen-induced allergic rhinoconjunctivitis

    DEFF Research Database (Denmark)

    Didier, A; Malling, H-J; Worm, Marcel

    2013-01-01

    Sustained efficacy over three pollen seasons of pre- and co-seasonal treatment with 300IR 5-grass pollen sublingual tablet has been demonstrated in adults with moderate-severe grass pollen-associated allergic rhinoconjunctivitis.......Sustained efficacy over three pollen seasons of pre- and co-seasonal treatment with 300IR 5-grass pollen sublingual tablet has been demonstrated in adults with moderate-severe grass pollen-associated allergic rhinoconjunctivitis....

  7. Histological study of human sublingual gland with special emphasis on intercalated and striated ducts

    International Nuclear Information System (INIS)

    Rana, R.; Minhas, L.A.; Mubarik, A.

    2012-01-01

    Objective: To study the histomorphological characteristics of human sublingual gland, specially of intercalated and striated ducts. Study design: Descriptive study Place and duration of study: Army Medical College from Jan 2002 to Dec 2002 Materials and methods: Fifteen sublingual glands (right and left) from postmortem cases were obtained from District Headquarter Hospital Rawalpindi, within twelve hours of death. Five micrometer thick sections were made and stained with Haematoxylin and Eosin (H and E). Morphology of intercalated and striated ducts was studied and their number was counted. Results: The mean number of intercalated ducts in the right gland 'a'and 'b' parts, and in the left gland 'a' and 'b' parts was 1.45+-0.14, 1.39+-.009, 1.31+-0.11 and 1.18+-0.10 respectively. The mean diameter of intercalated ducts in the same parts was 19.76+-0.44 micro m, 20.6+-0.53 micro m, 20.34+-0.49 micro m and 19.84+-0.98 micro m respectively. The mean number of striated ducts in the right gland ''a'' and ''b'' parts, and in the left gland ''a'' and ''b'' parts was 0.55+-.008, 0.57+-.008, 0.80+-0.14 and 0.80+-0.14 while mean diameter of striated ducts in the right gland ''a'' and ''b'' parts, and in the left gland ''a'' and ''b'' parts was 49.90+-4.70 micro m, 53.23+-2.50 micro m, 61.68+-3.93 micro m and 57.73+-2.85 micro m respectively. Conclusion: The difference between the mean number and diameter of the ducts of right and left glands was statistically insignificant. (author)

  8. Sublingual piroxicam in the management of postoperative pain after surgical removal of impacted mandibular third molar.

    Science.gov (United States)

    Mohammad, Shadab; Singh, Vibha; Wadhwani, Puneet; Tayade, Himanshu P; Rathod, Onkar K

    2012-01-01

    Surgical removal of impacted mandibular third molar is one of the most commonly performed procedures in oral and maxillofacial surgical practice. The role of preoperative and postoperative medications for management of postoperative complications has been extensively evaluated. To assess the therapeutic effect of a single dose of 40 mg sublingual piroxicam (study group) vs 150 mg oral diclofenac (50 mg thrice a day) (control group) in patients undergoing surgical removal of impacted mandibular third molar. A total of 100 patients with asymptomatic impacted mandibular third molars were randomized into two groups. One group received two 20-mg tablets of piroxicam once daily on the first and second postoperative days, followed by one 20-mg tablet on the third post-operative day. The other group received one tablet of diclofenac 50 mg orally thrice daily on the first, second, and third post-operative days. Repeated extraoral examinations were done for continuous assessment of swelling, trismus, and reduction in pain. Overall impression of the treating physician and the patient regarding efficacy of study drugs were recorded at the end of the study. In the piroxicam group there was >50% reduction in pain on all three days postoperatively. The incidence of swelling and trismus was found to be higher in the control group as compared to the study group. Adverse events, such as gastrointestinal (GI) disturbances, were significantly higher in the diclofenac group (11%) as compared to the piroxicam group (0%). Two sublingual piroxicam 20 mg tablets once daily has better efficacy and tolerability profile than diclofenac 50 mg one tablet thrice daily in the management of pain after surgical removal of impacted mandibular third molar.

  9. Uso y abuso del nifedipino por vía sublingual en nuestros sistemas de urgencia

    Directory of Open Access Journals (Sweden)

    Nancy Guinart Zayas

    1998-04-01

    Full Text Available Se observa que el incremento de la prevalencia de pacientes hipertensos en nuestras comunidades, y la implantación del Programa Nacional para el control de la hipertensión arterial, no han podido disminuir la cantidad de pacientes que acuden con cifras altas de su presión arterial a nuestros servicios de urgencia con decisiones terapéuticas indiscriminadas y agresivas. Se ha generalizado el uso del nifedipino sublingual, incluso en pacientes de la tercera edad, lo que produce bajadas bruscas de la presión arterial por disminución en la sensibilidad de los barorreceptores y con ellas una alteración de los mecanismos de autorregulación del flujo hístico. Se señala que las complicaciones producidas no son alarmantes, pero con un uso racional y si se cumplen algunas normas, podrían disminuirse aún másIt is observed that the prevalence increase of hypertensive patients in our communities and the implementation of the National Program for the Hypertension Control have not so far been able to reduce the number of hypertensive patients going to our emergency medical services by applying indiscriminate and aggressive therapeutical methods. The use of sublingual administered nifedipine is extensive even in elderly patients, which may cause a sharp blood pressure drop and also a change in the hystic flow self-regulating mechanisms. It is stressed that complications are not serious but if this drug is more rationally used and some directions are fulfilled, then these complications will be further reduced

  10. Sublingual administration of detomidine to calves prior to disbudding: a comparison with the intravenous route.

    Science.gov (United States)

    Hokkanen, Ann-Helena; Raekallio, Marja R; Salla, Kati; Hänninen, Laura; Viitasaari, Elina; Norring, Marianna; Raussi, Satu; Rinne, Valtteri M; Scheinin, Mika; Vainio, Outi M

    2014-07-01

    To study the effects of oromucosal detomidine gel administered sublingually to calves prior to disbudding, and to compare its efficacy with intravenously (IV) administered detomidine. Randomised, prospective clinical study. Twenty dairy calves aged 12.4 ± 4.4days (mean ± SD), weight 50.5 ± 9.0 kg. Detomidine at 80 μg kg(-1) was administered to ten calves sublingually (GEL) and at 30 μg kg(-1) to ten control calves IV (V. jugularis). Meloxicam (0.5 mg kg(-1) ) and local anaesthetic (lidocaine 3 mg kg(-1) ) were administered before heat cauterization of horn buds. Heart rate (HR), body temperature and clinical sedation were monitored over 240 minutes. Blood was collected from the V. cephalica during the same period for drug concentration analysis. Pharmacokinetic variables were calculated from the plasma detomidine concentration-time data using non-compartmental methods. Statistical analyses compared routes of administration by Student's t-test and linear mixed models as relevant. The maximum plasma detomidine concentration after GEL was 2.1 ± 1.2 ng mL(-1) (mean ±SD) and the time of maximum concentration was 66.0 ± 36.9 minutes. The bioavailability of detomidine was approximately 34% with GEL. Similar sedation scores were reached in both groups after administration of detomidine, but maximal sedation was reached earlier in the IV group (10 minutes) than in the GEL group (40 minutes). HR was lower after IV than GEL from 5 to 10 minutes after administration. All animals were adequately sedated, and we were able to administer local anaesthetic without resistance to all of the calves before disbudding. Oromucosally administered detomidine is an effective sedative agent for calves prior to disbudding. © 2014 The Authors Veterinary Anaesthesia and Analgesia published by John Wiley & Sons Ltd on behalf of Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia.

  11. Buprenorphine Implants for Treatment of Opioid Dependence: Randomized Comparison to Placebo and Sublingual Buprenorphine/Naloxone

    Science.gov (United States)

    Rosenthal, Richard N.; Ling, Walter; Casadonte, Paul; Vocci, Frank; Bailey, Genie L.; Kampman, Kyle; Patkar, Ashwin; Chavoustie, Steven; Blasey, Christine; Sigmon, Stacey; Beebe, Katherine L.

    2015-01-01

    Aims To evaluate safety and efficacy of buprenorphine implants (BI) versus placebo implants (PI) for the treatment of opioid dependence. A secondary aim compared BI to open-label sublingual buprenorphine/naloxone tablets (BNX). Design Randomized, double-blind, placebo-controlled trial. Subjects received either 4 buprenorphine implants (80 mg/implant) (n=114), 4 placebo implants (n=54), or open-label BNX (12–16 mg/d) (n=119). Setting 20 addiction treatment centers. Participants Adult outpatients (ages 18 to 65) with DSM-IV-TR opioid dependence. Measurements The primary efficacy endpoint was the percent of urine samples negative for opioids collected from weeks 1 to 24, examined as a cumulative distribution function (CDF). Findings The BI CDF was significantly different from placebo (P<.0001). Mean (95% CI) proportions of urines negative for opioids were: BI: 31.2% (25.3, 37.1) and PI: 13.4% (8.3, 18.6). BI subjects had a higher study completion rate relative to placebo (64% vs. 26%, P<.0001), lower clinician-rated (P<.0001) and patient-rated (P<.0001) withdrawal, lower patient-ratings of craving (P<.0001), and better subjects’ (P=.031) and clinicians’ (P=.022) global ratings of improvement. BI also resulted in significantly lower cocaine use (P=.0016). Minor implant-site reactions were comparable in the buprenorphine (27.2% [31/114]) and placebo groups (25.9% [14/54]). BI were non-inferior to BNX on percent urines negative for opioids [mean (95% CI): 33.5 (27.3, 39.6); CI for the difference of proportions, (−10.7, 6.2)]. Conclusions Compared with placebo, buprenorphine implants result in significantly less frequent opioid use, and are non-inferior to sublingual buprenorphine/naloxone tablets. PMID:23919595

  12. Development and evaluation of fixed dose bi therapy sublingual tablets for treatment stress hypertension and anxiety

    Directory of Open Access Journals (Sweden)

    Mohamed A El-Nabarawi

    2013-01-01

    Full Text Available Objective: A stress induced rise in the blood pressure. Some believe that patients with hypertension are characterized by a generalized state of increased anxiety. Aim: The purpose of this study is to prepare a fixed dose bi therapy using bisoprolol hemifumarate (BH as antihypertensive drug and buspirone hydrochloride (BuHCl as anxiolytic drug, which can be used to treat both diseases concomitantly. Using sublingual tablets is hopeful to improve the BuHCl poor oral bioavailability and to facilitate administration to patients experiencing problems with swallowing. Materials and Methods: A total of 5mg BH and 10mg BuHCl were selected based on compatibility study. A 3×22 full factorial design was adopted for the optimization of the tablets prepared by direct compression method. The effects of the filler type, the binder molecular weight, and the binder type were studied. The prepared formulae were evaluated according to their physical characters as hardness, friability, disintegration time (new modified method and in vivo disintegration time and wetting properties. In vitro drugs dissolute, permeation through the buccal mucosa and the effect of storage were analyzed by a new valid high pressure liquid chromatography (HPLC method. Bioavailability study of the selected formula study was carried out and followed by the clinical. Results: The optimized tablet formulation showed accepted average weight, hardness, wetting time, friability, content uniformity, disintegration time (less than 3 min. Maximum drug release could be achieved with in 10 min. In addition enhancing drug permeation through the buccal mucosa and, the maximum concentration of the drug that reached the blood was in the first 10 min which means a rapid onset of action and improved the extent of both drug′s absorption. Conclusion: The results revealed that sublingual (F6 tablets containing both drugs would maintain rapid onset of action, and increase bioavailability. BuHCl with BH

  13. Impact of mean arterial pressure on sublingual microcirculation during cardiopulmonary bypass - secondary outcome from a randomised clinical trial

    DEFF Research Database (Denmark)

    Holmgaard, Frederik; Vedel, Anne G; Ravn, Hanne Berg

    2018-01-01

    . METHODS: Thirty-six cardiac surgery patients undergoing coronary artery bypass grafting were included and randomised to either low (40-50 mmHg) or high (70-80 mmHg) mean arterial pressure during cardiopulmonary bypass. Sidestream Dark Field video images were recorded from the sublingual mucosa. Recordings...... were analysed in a blinded fashion to quantify microcirculatory variables. RESULTS: Mean arterial pressure during cardiopulmonary bypass in the low target group was 45.0 mmHg (SD 5.3) vs. 67.2 mmHg (SD 8.9) in the high target group. We found no significant difference between the two groups......OBJECTIVE: In this substudy of a randomised, clinical trial, we explored the sublingual microcirculation during cardiac surgery at two different levels of blood pressure. We hypothesised that a higher mean arterial pressure during cardiopulmonary bypass would cause higher Microvascular Flow Index...

  14. Results from the 5-year SQ grass sublingual immunotherapy tablet asthma prevention (GAP) trial in children with grass pollen allergy

    DEFF Research Database (Denmark)

    Valovirta, Erkka; Petersen, Thomas H; Piotrowska, Teresa

    2018-01-01

    BACKGROUND: Allergy immunotherapy targets the immunological cause of allergic rhinoconjunctivitis and allergic asthma and has the potential to alter the natural course of allergic disease. OBJECTIVE: The primary objective was to investigate the effect of the SQ grass sublingual immunotherapy tablet...... compared with placebo on the risk of developing asthma. METHODS: A total of 812 children (5-12 years), with a clinically relevant history of grass pollen allergic rhinoconjunctivitis and no medical history or signs of asthma, were included in the randomized, double-blind, placebo-controlled trial......, comprising 3 years of treatment and 2 years of follow-up. RESULTS: There was no difference in time to onset of asthma, defined by prespecified asthma criteria relying on documented reversible impairment of lung function (primary endpoint). Treatment with the SQ grass sublingual immunotherapy tablet...

  15. New approaches for the management of bipolar disorder: role of sublingual asenapine in the treatment of mania

    Directory of Open Access Journals (Sweden)

    Warren CG

    2013-05-01

    Full Text Available Calvert G Warren,1 Steven L Dubovsky1,21Department of Psychiatry, State University of New York at Buffalo, Buffalo, NY, USA; 2Departments of Psychiatry and Medicine, University of Colorado, Boulder, CO, USAAbstract: Bipolar disorder is a prevalent disorder that tends to become progressive without treatment and with inadequate treatment. Second generation (atypical antipsychotic drugs have increasingly been used as adjunctive treatment or monotherapy for mania, but they have the potential for significant adverse effects and their role in maintenance treatment remains unclear. Asenapine is a new atypical antipsychotic medication formulated in a sublingual preparation that has been studied for mania but not maintenance therapy. Evidence indicating efficacy, adverse effects, and potential benefits and drawbacks of using asenapine in the treatment of bipolar disorder based on currently available published data are summarized.Keywords: bipolar disorder, antipsychotic drug, mania, maintenance, sublingual

  16. Efficacy and safety of 5-grass pollen sublingual immunotherapy tablets in patients with different clinical profiles of allergic rhinoconjunctivitis

    DEFF Research Database (Denmark)

    Malling, Hans-Jørgen; Montagut, A; Melac, M

    2009-01-01

    pollen sublingual tablets of 100 IR (index of reactivity), 300 IR or 500 IR, or placebo starting 4 months before the pollen season. OBJECTIVE: The aim of this complementary analysis was to determine whether 300 IR 5-grass pollen SLIT-tablets is effective in different subtypes of patients who are allergic......BACKGROUND: The optimal dose of grass pollen tablets for sublingual immunotherapy (SLIT) in allergic rhinoconjunctivitis patients was previously established in a multinational, randomized, double-blind, placebo-controlled study in 628 adults. Patients were randomized to receive once-daily 5-grass...... to grass pollen. METHODS: Different subgroups could be identified regarding comorbidities (with or without asthma during the grass-pollen season), sensitization (mono/polysensitization) and symptom severity. An additional exploratory analysis was performed within four subgroups based on pre...

  17. Preparation of a highly concentrated, completely monomeric, active sarcoplasmic reticulum Ca2+-ATPase.

    Science.gov (United States)

    Lüdi, H; Hasselbach, W

    1985-11-21

    Sarcoplasmic reticulum vesicles from fast skeletal muscle were partially delipidated with sodium cholate at high ionic strength and sedimented in a discontinuous sucrose gradient. Phospholipid content was reduced from 0.777 mumol/mg protein to 0.242 mumol/mg protein. As judged from gel electrophoresis and high pressure liquid gel chromatography, accessory proteins were removed during centrifugation and the Ca2+-ATPase was obtained in an almost pure form. Addition of myristoylglycerophosphocholine (1 mg/mg protein) reactivates ATPase and dinitrophenylphosphatase activity to the same degree obtained with native vesicles. Using the analytical ultracentrifuge it could be demonstrated that the reactivated Ca2+-ATPase was present exclusively in a monomeric state. These results were obtained at high and low ionic strength and up to a protein concentration of 10 mg/ml. Therefore this preparation should be very useful to investigate differences between oligomeric and monomeric Ca2+-ATPase.

  18. An evaluation of total disintegration time for three different doses of sublingual fentanyl tablets in patients with breakthrough pain.

    Science.gov (United States)

    Nalamachu, Srinivas

    2013-12-01

    Breakthrough pain is common among patients with cancer and presents challenges to effective pain management. Breakthrough pain is characterized by rapid onset, severe intensity, and duration typically lasting disintegration time of three different doses of sublingual fentanyl tablets in opioid-tolerant patients. This was a single-center, non-randomized, open-label study. Opioid-tolerant adult patients (N = 30) with chronic pain were assigned to one of three dose groups and self-administered a single 100, 200, or 300 μg sublingual fentanyl tablet (Abstral(®), Galena Biopharma, Portland, OR, USA). Time to complete disintegration was measured by each patient with a stopwatch and independently verified by study personnel. Disintegration time (mean ± SD) for sublingual fentanyl tablets (all doses) was 88.2 ± 55.1 s. Mean disintegration times tended to be slightly longer for the 200 μg (96.7 ± 57.9 s) and 300 μg doses (98.6 ± 64.8 s) compared to the 100 μg dose (69.5 ± 40.5 s). Differences were not statistically significant. Disintegration time was not significantly different between men and women and was not affected by age. Sublingual fentanyl tablets dissolved rapidly (average time <2 min) in all patients, with the higher doses taking slightly more time to dissolve.

  19. Comparison of Intravenous Morphine with Sublingual Buprenorphine in Management of Postoperative Pain after Closed Reduction Orthopedic Surgery.

    Science.gov (United States)

    Soltani, Ghasem; Khorsand, Mahmood; Shamloo, Alireza Sepehri; Jarahi, Lida; Zirak, Nahid

    2015-10-01

    Postoperative pain is a common side effect following surgery that can significantly reduce surgical quality and patient's satisfaction. Treatment options are morphine and buprenorphine. We aimed to compare the efficacy of a single dose of intravenous morphine with sublingual buprenorphine in postoperative pain control following closed reduction surgery. This triple blind clinical trial was conducted on 90 patients referred for closed reduction orthopedic surgery. They were older than 18 years and in classes I and II of the American Society of Anesthesiologists (ASA) with an operation time of 30-90 minutes. Patients were divided into two groups of buprenorphine (4.5µg/kg sublingually) and morphine (0.2mg/kg intravenously). Baseline characteristics, vital signs, pain score, level of sedation and pharmacological side effects were recorded in the recovery room (at 0 and 30 minutes), and in the ward (at 3, 6 and 12 hours). SPSS version 19 software was used for data analysis and the significance level was set at P<0.05. Ninety patients were studied, 60 males and 30 females with a mean age of 37.7±16.2 years. There was no significant difference between the two groups in terms of baseline characteristics. Pain score in the morphine group was significantly higher than the buprenorphine group with an average score of 2.5 (P<0.001). Postoperative mean heart rate in the buprenorphine group was four beats lower than the morphine group (P<0.001). Also, in the buprenorphine 48.6% and in the morphine group 86.7% of cases were conscious in recovery (P=0.001) with a higher rate of pruritus in the latter group (P=0.001). Sublingual buprenorphine administration before anesthesia induction in closed reduction surgery can lead to better postoperative pain control in comparison to intravenous morphine. Due to simple usage and longer postoperative sedation, sublingual buprenorphine is recommended as a suitable drug in closed reduction surgery.

  20. Comparison of Intravenous Morphine with Sublingual Buprenorphine in Management of Postoperative Pain after Closed Reduction Orthopedic Surgery

    OpenAIRE

    Ghasem Soltani; Mahmood Khorsand; ALireza Sepehri Shamloo; Lida Jarahi; Nahid Zirak

    2015-01-01

    Background: Postoperative pain is a common side effect following surgery that can significantly reduce surgical quality and patient’s satisfaction. Treatment options are morphine and buprenorphine. We aimed to compare the efficacy of a single dose of intravenous morphine with sublingual buprenorphine in postoperative pain control following closed reduction surgery. Methods: This triple blind clinical trial was conducted on 90 patients referred for closed reduction orthopedic surgery. They wer...

  1. Food-specific sublingual immunotherapy is well tolerated and safe in healthy dogs : a blind, randomized, placebo-controlled study

    OpenAIRE

    Maina, Elisa; Pelst, Michael; Hesta, Myriam; Cox, Eric

    2017-01-01

    Background: Food allergies are increasing in prevalence but no treatment strategies are currently available to cure dogs with food allergy. Over the past decade, experimental food allergen-specific sublingual immunotherapy (FA-SLIT) has emerged as a potential treatment for food allergies in human medicine. However, FA-SLIT has not been investigated in dogs. Therefore, the objective of this study was to prospectively evaluate the safety, tolerability and dispenser sterility of FA-SLIT in healt...

  2. Multistage modeling of protein dynamics with monomeric Myc oncoprotein as an example.

    Science.gov (United States)

    Liu, Jiaojiao; Dai, Jin; He, Jianfeng; Niemi, Antti J; Ilieva, Nevena

    2017-03-01

    We propose to combine a mean-field approach with all-atom molecular dynamics (MD) into a multistage algorithm that can model protein folding and dynamics over very long time periods yet with atomic-level precision. As an example, we investigate an isolated monomeric Myc oncoprotein that has been implicated in carcinomas including those in colon, breast, and lungs. Under physiological conditions a monomeric Myc is presumed to be an example of intrinsically disordered proteins that pose a serious challenge to existing modeling techniques. We argue that a room-temperature monomeric Myc is in a dynamical state, it oscillates between different conformations that we identify. For this we adopt the Cα backbone of Myc in a crystallographic heteromer as an initial ansatz for the monomeric structure. We construct a multisoliton of the pertinent Landau free energy to describe the Cα profile with ultrahigh precision. We use Glauber dynamics to resolve how the multisoliton responds to repeated increases and decreases in ambient temperature. We confirm that the initial structure is unstable in isolation. We reveal a highly degenerate ground-state landscape, an attractive set towards which Glauber dynamics converges in the limit of vanishing ambient temperature. We analyze the thermal stability of this Glauber attractor using room-temperature molecular dynamics. We identify and scrutinize a particularly stable subset in which the two helical segments of the original multisoliton align in parallel next to each other. During the MD time evolution of a representative structure from this subset, we observe intermittent quasiparticle oscillations along the C-terminal α helix, some of which resemble a translating Davydov's Amide-I soliton. We propose that the presence of oscillatory motion is in line with the expected intrinsically disordered character of Myc.

  3. Structural Characterization of Monomeric/Dimeric State of p59fyn SH2 Domain.

    Science.gov (United States)

    Huculeci, Radu; Kieken, Fabien; Garcia-Pino, Abel; Buts, Lieven; van Nuland, Nico; Lenaerts, Tom

    2017-01-01

    Src homology 2 (SH2) domains are key modulators in various signaling pathways allowing the recognition of phosphotyrosine sites of different proteins. Despite the fact that SH2 domains acquire their biological functions in a monomeric state, a multitude of reports have shown their tendency to dimerize. Here, we provide a technical description on how to isolate and characterize by gel filtration, circular dichroism (CD), and nuclear magnetic resonance (NMR) each conformational state of p59 fyn SH2 domain.

  4. Improved detection of a staphylococcal infection by monomeric and protein A-purified polyclonal human immunoglobulin

    International Nuclear Information System (INIS)

    Calame, W.

    1993-01-01

    The present study was undertaken to compare the technetium-99m labelled non-specific polyclonal human immunoglobulin (Ig) with 99m Tc-labelled monomeric human immunoglobulin (m-Ig), 99m Tc-labelled, protein A-purified, human immunoglobulin (A-IG) and 99m Tc-labelled monomeric, protein A-purified, human immunoglobulin (mA-Ig) as tracer agents for the detection of a thigh infection with Staphylococcus aureus. In vitro the binding of the various tracer agents to bacteria at various intervals was determined. For the in vivo evaluation, mice were infected and received one of the various labelled proteins. Scintigrams were made 0.25, 1, 4 and 24 h later. All 99m Tc-labelled Igs bound to bacteria in vitro: The percentages of binding for the m-Ig (from 1 h onwards) and A-Ig and mA-Ig (from 3 h onwards) were significantly higher than that for Ig. The in vivo target-to-non-target (T/NT) ratios were significantly higher from 4 h onwards for all purified Igs than for Ig. Protein A-purified Ig yielded higher T/NT ratios than m-Ig. Furthermore, the amount of activity in the liver was significantly lower 24 h after administration of m-Ig, A-Ig and mA-Ig than after administration of Ig. It is concluded that in this experimental infection 99m Tc-labelled monomeric Ig localizes a staphylococcal thigh infection better and faster than 99m Tc-labelled unpurified Ig. However, the accumulation obtained with protein A-purified Ig or protein A-purified monomeric Ig was the highest of all tracer agents tested. (orig.)

  5. Two mechanisms for dissipation of excess light in monomeric and trimeric light-harvesting complexes

    Energy Technology Data Exchange (ETDEWEB)

    Dall' Osto, Luca [Univ. di Verona, Verona (Italy). Dipartimento di Biotecnologie; Cazzaniga, Stefano [Univ. di Verona, Verona (Italy). Dipartimento di Biotecnologie; Bressan, Mauro [Univ. di Verona, Verona (Italy). Dipartimento di Biotecnologie; Paleček, David [Lund Univ. (Sweden). Dept. of Chemical Physics; Židek, Karel [Lund Univ. (Sweden). Dept. of Chemical Physics; Niyogi, Krishna K. [Univ. of California, Berkeley, CA (United States). Howard Hughes Medical Inst., Dept. of Plant and Microbial Biology; Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Molecular Biophysics and Integrated Bioimaging Division; Fleming, Graham R. [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Molecular Biophysics and Integrated Bioimaging Division; Univ. of California, Berkeley, CA (United States). Dept. of Chemistry, Graduate Group in Applied Science and Technology; Zigmantas, Donatas [Lund Univ. (Sweden). Dept. of Chemical Physics; Bassi, Roberto [Univ. di Verona, Verona (Italy). Dipartimento di Biotecnologie; Consiglio Nazionale delle Ricerche (CNR), Firenze (Italy). Istituto per la Protezione delle Piante (IPP)

    2017-04-10

    Oxygenic photoautotrophs require mechanisms for rapidly matching the level of chlorophyll excited states from light harvesting with the rate of electron transport from water to carbon dioxide. These photoprotective reactions prevent formation of reactive excited states and photoinhibition. The fastest response to excess illumination is the so-called non-photochemical quenching which, in higher plants, requires the luminal pH sensor PsbS and other yet unidentified components of the photosystem II antenna. Both trimeric light-harvesting complex II (LHCII) and monomeric LHC proteins have been indicated as site(s) of the heat-dissipative reactions. Different mechanisms have been proposed: Energy transfer to a lutein quencher in trimers, formation of a zeaxanthin radical cation in monomers. Here, we report on the construction of a mutant lacking all monomeric LHC proteins but retaining LHCII trimers. Its non-photochemical quenching induction rate was substantially slower with respect to the wild type. A carotenoid radical cation signal was detected in the wild type, although it was lost in the mutant. Here, we conclude that non-photochemical quenching is catalysed by two independent mechanisms, with the fastest activated response catalysed within monomeric LHC proteins depending on both zeaxanthin and lutein and on the formation of a radical cation. Trimeric LHCII was responsible for the slowly activated quenching component whereas inclusion in supercomplexes was not required. Finally, this latter activity does not depend on lutein nor on charge transfer events, whereas zeaxanthin was essential.

  6. Peracetic Acid Depolymerization of Biorefinery Lignin for Production of Selective Monomeric Phenolic Compounds

    Energy Technology Data Exchange (ETDEWEB)

    Ma, Ruoshui [Voiland School of Chemical Engineering and Bioengineering, Bioproducts, Science & Engineering Laboratory, Washington State University, 2710 Crimson Way Richland WA 99354 USA; Guo, Mond [Voiland School of Chemical Engineering and Bioengineering, Bioproducts, Science & Engineering Laboratory, Washington State University, 2710 Crimson Way Richland WA 99354 USA; Lin, Kuan-ting [Voiland School of Chemical Engineering and Bioengineering, Bioproducts, Science & Engineering Laboratory, Washington State University, 2710 Crimson Way Richland WA 99354 USA; Hebert, Vincent R. [Food and Environmental Laboratory, Washington State, University-TriCities, 2710 Crimson Way Richland WA 99354 USA; Zhang, Jinwen [Wood Materials and Engineering Laboratory, Washington State University, Pullman WA 99164 USA; Wolcott, Michael P. [Wood Materials and Engineering Laboratory, Washington State University, Pullman WA 99164 USA; Quintero, Melissa [Voiland School of Chemical Engineering and Bioengineering, Bioproducts, Science & Engineering Laboratory, Washington State University, 2710 Crimson Way Richland WA 99354 USA; Ramasamy, Karthikeyan K. [Chemical and Biological Process Development Group, Pacific Northwest National Laboratory, Richland WA 99354 USA; Chen, Xiaowen [National Bioenergy Center, National Renewable Energy Lab, 1617 Cole Blvd Golden CO 80127 USA; Zhang, Xiao [Voiland School of Chemical Engineering and Bioengineering, Bioproducts, Science & Engineering Laboratory, Washington State University, 2710 Crimson Way Richland WA 99354 USA

    2016-07-04

    Lignin is the largest source of renewable material with an aromatic skeleton. However, due to the recalcitrant and heterogeneous nature of the lignin polymer, it has been a challenge to effectively depolymerize lignin and produce high-value chemicals with high selectivity. In this study, a highly efficient lignin-to-monomeric phenolic compounds (MPC) conversion method based on peracetic acid (PAA) treatment was reported. PAA treatment of two biorefinery lignin samples, diluted acid pretreated corn stover lignin (DACSL) and steam exploded spruce lignin (SESPL), led to complete solubilization and production of selective hydroxylated monomeric phenolic compounds (MPC-H) and monomeric phenolic acid compounds (MPC-A) including 4-hydroxy-2-methoxyphenol, p-hydroxybenzoic acid, vanillic acid, syringic acid, and 3,4-dihydroxybenzoic acid. The maximized MPC yields obtained were 18 and 22 % based on the initial weight of the lignin in SESPL and DACSL, respectively. However, we found that the addition of niobium pentoxide catalyst to PAA treatment of lignin can significantly improve the MPC yields up to 47 %. The key reaction steps and main mechanisms involved in this new lignin-to-MPC valorization pathway were investigated and elucidated.

  7. Peracetic Acid Depolymerization of Biorefinery Lignin for Production of Selective Monomeric Phenolic Compounds

    Energy Technology Data Exchange (ETDEWEB)

    Ma, Ruoshui [Voiland School of Chemical Engineering and Bioengineering, Bioproducts, Science & Engineering Laboratory, Washington State University, 2710 Crimson Way Richland WA 99354 USA; Guo, Mond [Voiland School of Chemical Engineering and Bioengineering, Bioproducts, Science & Engineering Laboratory, Washington State University, 2710 Crimson Way Richland WA 99354 USA; Lin, Kuan-ting [Voiland School of Chemical Engineering and Bioengineering, Bioproducts, Science & Engineering Laboratory, Washington State University, 2710 Crimson Way Richland WA 99354 USA; Hebert, Vincent R. [Food and Environmental Laboratory, Washington State, University-TriCities, 2710 Crimson Way Richland WA 99354 USA; Zhang, Jinwen [Wood Materials and Engineering Laboratory, Washington State University, Pullman WA 99164 USA; Wolcott, Michael P. [Wood Materials and Engineering Laboratory, Washington State University, Pullman WA 99164 USA; Quintero, Melissa [Voiland School of Chemical Engineering and Bioengineering, Bioproducts, Science & Engineering Laboratory, Washington State University, 2710 Crimson Way Richland WA 99354 USA; Ramasamy, Karthikeyan K. [Chemical and Biological Process Development Group, Pacific Northwest National Laboratory, Richland WA 99354 USA; Chen, Xiaowen [National Bioenergy Center, National Renewable Energy Lab, 1617 Cole Blvd Golden CO 80127 USA; Zhang, Xiao [Voiland School of Chemical Engineering and Bioengineering, Bioproducts, Science & Engineering Laboratory, Washington State University, 2710 Crimson Way Richland WA 99354 USA

    2016-07-04

    Lignin is the largest source of renewable material with an aromatic skeleton. However, due to the recalcitrant and heterogeneous nature of the lignin polymer as well as its complex side chain structures, it has been a challenge to effectively depolymerize lignin and produce high value chemicals with high selectivity. In this study, a highly efficient lignin-to-monomeric phenolic compounds (MPC) conversion method based on peracetic acid (PAA) treatment was reported. PAA treatment of two biorefinery lignin samples, diluted acid pretreated corn stover lignin (DACSL) and steam exploded spruce lignin (SESPL), led to complete solubilization and production of selective hydroxylated monomeric phenolic compounds (MPC-H) and monomeric phenolic acid compounds (MPC-A) inclduing 4-hydroxy-2-methoxyphenol, p-hydroxybenzoic acid, vanillic acid, syringic acid, and 3,4-dihydroxybenzoic acid. The maximized MPCs yields obtained were 18% and 22% based on the initial weight of the lignin in SESPL and DACSL respectively. However, we found that the addition of niobium pentoxide catalyst to PAA treatment of lignin can significantly improve the MPC yields up to 47%. The key reaction steps and main mechanisms involved in this new lignin-to-MPC valorization pathway were investigated and elucidated.

  8. Peracetic Acid Depolymerization of Biorefinery Lignin for Production of Selective Monomeric Phenolic Compounds.

    Science.gov (United States)

    Ma, Ruoshui; Guo, Mond; Lin, Kuan-Ting; Hebert, Vincent R; Zhang, Jinwen; Wolcott, Michael P; Quintero, Melissa; Ramasamy, Karthikeyan K; Chen, Xiaowen; Zhang, Xiao

    2016-07-25

    Lignin is the largest source of renewable material with an aromatic skeleton. However, due to the recalcitrant and heterogeneous nature of the lignin polymer, it has been a challenge to effectively depolymerize lignin and produce high-value chemicals with high selectivity. In this study, a highly efficient lignin-to-monomeric phenolic compounds (MPC) conversion method based on peracetic acid (PAA) treatment was reported. PAA treatment of two biorefinery lignin samples, diluted acid pretreated corn stover lignin (DACSL) and steam exploded spruce lignin (SESPL), led to complete solubilization and production of selective hydroxylated monomeric phenolic compounds (MPC-H) and monomeric phenolic acid compounds (MPC-A) including 4-hydroxy-2-methoxyphenol, p-hydroxybenzoic acid, vanillic acid, syringic acid, and 3,4-dihydroxybenzoic acid. The maximized MPC yields obtained were 18 and 22 % based on the initial weight of the lignin in SESPL and DACSL, respectively. However, we found that the addition of niobium pentoxide catalyst to PAA treatment of lignin can significantly improve the MPC yields up to 47 %. The key reaction steps and main mechanisms involved in this new lignin-to-MPC valorization pathway were investigated and elucidated. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  9. The Influence of Low Salivary Flow Rates on the Absorption of a Sublingual Fentanyl Citrate Formulation for Breakthrough Cancer Pain.

    Science.gov (United States)

    Davies, Andrew; Mundin, Gill; Vriens, Joanna; Webber, Kath; Buchanan, Alison; Waghorn, Melanie

    2016-03-01

    Salivary gland hypofunction may affect the absorption of drugs through the oral mucosa, which in turn may affect their clinical efficacy (e.g., onset of action). The aim of this study was to assess the pharmacokinetics of a sublingual fentanyl orally disintegrating tablet (Abstral, Prostrakan Inc.) in a group of cancer patients with salivary gland hypofunction. Nine cancer patients with salivary gland hypofunction underwent a series of three pharmacokinetic studies with the sublingual fentanyl orally disintegrating tablet. In the first phase, the patients received no pretreatment; in the second phase, the patients were allowed to moisten the oral cavity before dosing; in the third phase, the patients were given pilocarpine hydrochloride (saliva stimulant) before dosing. Fentanyl concentrations were measured using a method of high-performance liquid chromatography with validated tandem mass spectrometric detection. The Tmax was longer, the Cmax was lower, the AUC0-30 lower, and the AUClast lower in the phase involving no pretreatment; the Tmax/Cmax/AUC0-30/AUClast were similar in the phase involving moistening of the oral cavity and the phase involving giving pilocarpine hydrochloride. The pharmacokinetics of the sublingual fentanyl orally disintegrating tablet appear to be negatively affected by the presence of salivary gland hypofunction, although the moistening of the oral cavity before dosing results in a pharmacokinetic profile similar to that seen with the giving of pilocarpine hydrochloride. Copyright © 2016 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.

  10. Formulation and evaluation of sublingual delivery of piroxicam using thermosensitive polymer with an inverted Franz diffusion cell.

    Science.gov (United States)

    Sivaraman, Arunprasad; Banga, Ajay K

    2016-01-01

    The aim of the study was to prepare a sublingual formulation for piroxicam using a thermosensitive polymer and to evaluate its permeation through porcine sublingual mucosa. Formulation technique utilized the transition property of poloxamer from solution state at room temperature to gel state at oromucosal temperature (37 °C). The permeation of the drug was evaluated using an inverted Franz diffusion cell technique that allowed the dosage form to be directly applied onto the substrate with required volume of saliva. The formulation was characterized for microscopy of the piroxicam crystals, sol-gel transition property and in-vitro diffusion study. Poloxamer-based formulation enhanced solubility and increased permeability of the piroxicam. Poloxamer formulation with 0.1% w/w piroxicam delivered a cumulative amount of 11.99 ± 7.82 and 11.23 ± 1.79 μg/cm(2), while non-poloxamer formulation delivered 3.57 ± 2.20 and 4.60 ± 6.90 μg/cm(2) with 0.1 and 0.5 ml artificial saliva, respectively, through porcine sublingual tissue in 6 h. A similar delivery profile was observed for 0.05% w/w piroxicam formulation as well. © 2015 Royal Pharmaceutical Society.

  11. Recombinant Mal d 1 facilitates sublingual challenge tests of birch pollen-allergic patients with apple allergy.

    Science.gov (United States)

    Kinaciyan, T; Nagl, B; Faustmann, S; Kopp, S; Wolkersdorfer, M; Bohle, B

    2016-02-01

    It is still unclear whether allergen-specific immunotherapy (AIT) with birch pollen improves birch pollen-related food allergy. One reason for this may be the lack of standardized tests to assess clinical reactions to birch pollen-related foods, for example apple. We tested the applicability of recombinant (r) Mal d 1, the Bet v 1-homolog in apple, for oral challenge tests. Increasing concentrations of rMal d 1 in 0.9% NaCl were sublingually administered to 72 birch pollen-allergic patients with apple allergy. The dose of 1.6 μg induced oral allergy syndromes in 26.4%, 3.2 μg in 15.3%, 6.3 μg in 27.8%, 12.5 μg in 8.3%, 25 μg in 11.1%, and 50 μg in 4.2% of the patients. No severe reactions occurred. None of the patients reacted to 0.9% NaCl alone. Sublingual administration of 50 μg of rMal d 1 induced no reactions in three nonallergic individuals. Our approach allows straight forward, dose-defined sublingual challenge tests in a high number of birch pollen-allergic patients that inter alia can be applied to evaluate the therapeutic efficacy of birch pollen AIT on birch pollen-related food allergy. © 2015 The Authors. Allergy Published by John Wiley & Sons Ltd.

  12. Current issues on sublingual allergen-specific immunotherapy in children with asthma and allergic rhinitis

    Directory of Open Access Journals (Sweden)

    Živković Zorica

    2016-01-01

    Full Text Available In 1993 the European Academy of Allergy and Clinical Immunology was the first official organization to recognize that sublingual administration could be “promising route” for allergic desensitization. A few years later, the World Health Organization recommended this therapy as “a viable alternative to the injection route in adults.” The first meta-analysis showed sublingual allergen specific immunotherapy (SLIT effectiveness for allergic rhinitis and another study showed SLIT can actually help prevent the development of asthma both in adults and in children. The main goal of this review article is to present insight into the most up-to-date understanding of the clinical efficacy and safety of immunotherapy in the treatment of pediatric patients with allergic rhinitis and asthma. A literature review was performed on PubMed from 1990 to 2015 using the terms “asthma,” “allergic rhinitis,” “children,” “allergen specific immune therapy.” Evaluating data from double-blind placebo-controlled randomized clinical trials (DB-PC-RCTs, the clinical efficacy (assessed as the reduction of symptom score and the need of rescue medicament of SLIT for allergic rhinitis and allergic asthma, has been confirmed in various meta-analysis Outcomes such as rhinoconjunctivitis score and medication scores, combined scores, quality of life, days with severe symptoms, immunological endpoints, and safety parameters were all improved in the SLIT-tablet compared with placebo group. SLIT safety has been already proven in many DB-PC-RCTs and real-life settings. In accordance with all of the above mentioned, the goals for future trials and studies are the development of comprehensive guidelines for clinical practice on immunotherapy, embracing all the different potential participants. The importance of allergen immunotherapy is of special relevance in the pediatric age, when the plasticity and modulability of the immune system are maximal, and when

  13. Sublingual immunotherapy in patients with house dust mite allergic rhinitis: prospective study of clinical outcomes over a two-year period.

    Science.gov (United States)

    Soh, J Y; Thalayasingam, M; Ong, S; Loo, E X L; Shek, L P; Chao, S S

    2016-03-01

    Sublingual immunotherapy in patients with allergic rhinitis sensitised to house dust mites is safe, but its efficacy is controversial and sublingual immunotherapy with Blomia tropicalis has not yet been studied. This study sought to evaluate the efficacy of sublingual immunotherapy with house dust mite extract in children and adults with house dust mite allergic rhinitis over a period of two years. A prospective observational study was conducted of children and adults diagnosed with house dust mite allergic rhinitis who were treated with sublingual immunotherapy from 2008 to 2012. Total Nasal Symptom Scores, Mini Rhinoconjunctivitis Quality of Life scores and medication usage scores were assessed prospectively. Thirty-nine patients, comprising 24 children and 15 adults, were studied. Total Nasal Symptom Scores and Mini Rhinoconjunctivitis Quality of Life scores dropped significantly at three months into therapy, and continued to improve. Medication usage scores improved at one year into immunotherapy. Sublingual immunotherapy with house dust mite extracts, including B tropicalis, is efficacious as a treatment for patients with house dust mite allergic rhinitis.

  14. [Breakthrough pain treatment with sublingual fentanyl in patients with chronic cutaneous ulcers].

    Science.gov (United States)

    Domingo-Triadó, V; López Alarcón, M D; Villegas Estévez, F; Alba Moratillas, C; Massa Domínguez, B; Palomares Payá, F; Mínguez Martí, A; Debón Vicent, L

    2014-10-01

    The aim of the study was to assess the efficacy and safety of opioids in the management of pain in those patients with chronic cutaneous ulcers and breakthrough/incidental pain. An open-label, multicentre, prospective, uncontrolled study was conducted in the pain and ulcer units of 5 hospitals across the Comunidad Valenciana. Eligibility criteria were baseline pain 4 in the visual analogue scale or breakthrough procedural pain 4. Exclusion criteria were cognitive impairment, opioid intolerance, or patient refusal to provide informed consent. The protocol scheduled 5 controls: baseline (enrolment), 15 days, one month, 2 months, and 3 months. The main outcome measure of the study was the visual analogue scale score during rest, movement and procedures. Opioids were administered for release of the baseline pain, and sublingual fentanyl for breakthrough pain. A total of 32 patients (86.5%) completed the study. Baseline pain achieved a mean improvement of 3.6 visual analogue scale points (SD 2.3), movement pain improved by 3.9 points (SD 2.5) and procedural pain improved by 4.5 points (SD 2.8), and the mean pain intensity improvement was statistically significant from the first control and at all controls thereafter (PDolor. Published by Elsevier España. All rights reserved.

  15. Fast-Acting Sublingual Zolpidem for Middle-of-the-Night Wakefulness

    Directory of Open Access Journals (Sweden)

    Joseph V. Pergolizzi

    2014-01-01

    Full Text Available Sleep disorders (somnipathies are conditions characterized by disruptions of sleep quality or of sleep pattern. They can involve difficulty falling asleep (prolonged sleep onset latency, difficulty staying asleep (disturbance of sleep maintenance, sleep of poor quality (unrefreshing, or combinations of these and can lead to poor health and quality of life problems. A subtype of sleep-maintenance insomnia is middle-of-the-night wakefulness, a relatively common occurrence. Zolpidem, a nonbenzodiazepine benzodiazepine receptor agonist, allosterically modulates an ion channel and increases the influx of Cl−, thereby dampening the effect of excitatory (sleep disrupting input. Recently, product label changes to some zolpidem containing products have been implemented by the FDA in order to reduce the risk associated with their morning after residual side effects. A new formulation of zolpidem tartrate (Intermezzo sublingual tablet, an approved product indicated exclusively for the treatment of middle-of-the-night wakefulness and difficulty returning to sleep, did not have its label changed. We present a short summary of its basic science and clinical attributes in light of the recent regulatory changes for zolpidem products.

  16. Specific IgE response to different grass pollen allergen components in children undergoing sublingual immunotherapy

    Directory of Open Access Journals (Sweden)

    Marcucci Francesco

    2012-06-01

    Full Text Available Abstract Background Grass pollen is a major cause of respiratory allergy worldwide and contain a number of allergens, some of theme (Phl p 1, Phl p 2, Phl p 5, and Phl 6 from Phleum pratense, and their homologous in other grasses are known as major allergens. The administration of grass pollen extracts by immunotherapy generally induces an initial rise in specific immunoglobulin E (sIgE production followed by a progressive decline during the treatment. Some studies reported that immunotherapy is able to induce a de novo sensitisation to allergen component previously unrecognized. Methods We investigated in 30 children (19 males and 11 females, mean age 11.3 years, 19 treated with sublingual immunotherapy (SLIT by a 5-grass extract and 11 untreated, the sIgE and sIgG4 response to the different allergen components. Results Significant increases (p  Conclusions These findings confirm that the initial phase of SLIT with a grass pollen extract enhances the sIgE synthesis and show that the sIgE response concerns the same allergen components which induce IgE reactivity during natural exposure.

  17. Suppression of TIM-1 predicates clinical efficacy of sublingual immunotherapy for allergic rhinitis in children.

    Science.gov (United States)

    Lin, Zhibin; Zhou, Lifeng; Luo, Xi; Xia, Wentong; Chen, Dehua; Xu, Rui; Wang, Jie; Luo, Renzhong; Xu, Geng; Li, Huabin

    2013-08-01

    To evaluate the clinical efficacy of sublingual immunotherapy (SLIT) with house-dust mite (HDM) extract and to examine the change of biomarkers (TIM-1, IL-5 and IL-10) after 6-month SLIT in children with allergic rhinitis (AR). One hundred and sixteen HDM-sensitized children with persistent AR were enrolled to assess the clinical efficacy of SLIT by determining the individual nasal symptom score (INSS) and total nasal symptom scores (TNSS) after 6-month SLIT. Moreover, the mRNA expression of TIM-1, IL-5 and IL-10 in peripheral blood mononuclear cells (PBMCs) was examined in 16 well-controlled and 12 uncontrolled AR patients using quantitative reverse transcription polymerase chain reaction (qRT-PCR). After 6-month SLIT, both TNSS and INSS scores were significantly decreased compared with the baseline value (p < 0.01). The rates for well-controlled, partly controlled and uncontrolled children were 43.1%, 32.8% and 24.1%, respectively. Accordingly, the mRNA levels of TIM-1 and IL-5 decreased significantly and IL-10 mRNA level increased significantly compared with the baseline value in well-controlled children (p < 0.05). Our findings suggest SLIT with HDM extract is effective and safe for AR children and TIM-1 may be considered as an indicator for evaluating the clinical efficacy of SLIT. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  18. Tumour localization and pharmacokinetics of iodine-125 human monoclonal IgM antibody (COU-1) and its monomeric and half-monomeric fragments analysed in nude mice grafted with human tumour

    International Nuclear Information System (INIS)

    Ditzel, H.; Erb, K.; Rasmussen, J.W.; Jensenius, J.C.

    1992-01-01

    Human monoclonal IgM antibodies reactive with cancer-associated antigens may not have the optimal imaging capability due to their large size. Fragmentation of human IgM is less than straight-forward due to the loss of immunoreactivity. From the human monoclonal IgM antibody COU-1 we have prepared monomeric and half-monomeric fragments, which retain the ability to bind to colon cancer cells in vitro. The pharmacokinetics and tumour localization were evaluated in nude mice bearing human colon adenocarcinoma and human melanoma grafts. Faster clearance from the circulation was seen for the smaller half-monomeric fragment with a half-life (rapid phase/slow phase) of 2 h/16 h compared with the intact antibody, 4 h/25 h, and the monomeric fragment, 3 h/27 h. Intact COU-1 as well as the fragments accumulated in the colon tumour graft. Higher amounts of radioactivity were found in the colon tumour as compared to normal organs for intact COU-1 at days 4 and 6, for the monomeric fragment at day 4, and for the half-monomeric fragment at day 2 after injection. This investigation demonstrates the favourable biodistribution of the half monomeric COU-1 fragment. The fast clearance of this fragment resulted in a tumour-to-muscle ratio as high as 22 on day 2 after injection. Also, only this fragment gave a positive tumour-to-blood ratio. Normal IgM and its fragments were used as controls. Radioimmunoscintigraphy demonstrated the colon tumour discriminatory properties of each of the three iodine-labelled antibody preparations. The results compare favourably with previously reported investigations of the localization of human monoclonal antibodies and suggest that fragments of human monoclonal IgM antibodies may be useful tools for the immunodetection of cancer in patients. (orig.)

  19. Natural monomeric form of fetal bovine serum acetylcholinesterase lacks the C-terminal tetramerization domain.

    Science.gov (United States)

    Saxena, Ashima; Hur, Regina S; Luo, Chunyuan; Doctor, Bhupendra P

    2003-12-30

    Acetylcholinesterase isolated from fetal bovine serum (FBS AChE) was previously characterized as a globular tetrameric form. Analysis of purified preparations of FBS AChE by gel permeation chromatography revealed the presence of a stable, catalytically active, monomeric form of this enzyme. The two forms could be distinguished from each other based on their molecular weight, hydrodynamic properties, kinetic properties, thermal stability, and the type of glycans they carry. No differences between the two forms were observed for the binding of classical inhibitors such as edrophonium and propidium or inhibitors that are current or potential drugs for the treatment of Alzheimer's disease such as (-) huperzine A and E2020; tacrine inhibited the monomeric form 2-3-fold more potently than the tetrameric form. Sequencing of peptides obtained from an in-gel tryptic digest of the monomer and tetramer by tandem mass spectrometry indicated that the tetramer consists of 583 amino acid residues corresponding to the mature form of the enzyme, whereas the monomer consists of 543-547 amino acid residues. The subunit molecular weight of the protein component of the monomer (major species) was determined to be 59 414 Da and that of the tetramer as 64 239 Da. The N-terminal of the monomer and the tetramer was Glu, suggesting that the monomer is not a result of truncation at the N-terminal. The only differences detected were at the C-terminus. The tetramer yielded the expected C-terminus, CSDL, whereas the C-terminus of the monomer yielded a mixture of peptides, of which LLSATDTLD was the most abundant. These results suggest that monomeric FBS AChE is trimmed at the C-terminus, and the results are consistent with the involvement of C-terminal amino acids in the assembly of monomers into tetramers.

  20. Monomeric banana lectin at acidic pH overrules conformational stability of its native dimeric form.

    Directory of Open Access Journals (Sweden)

    Javed M Khan

    Full Text Available Banana lectin (BL is a homodimeric protein categorized among jacalin-related family of lectins. The effect of acidic pH was examined on conformational stability of BL by using circular dichroism, intrinsic fluorescence, 1-anilino-8-napthalene sulfonate (ANS binding, size exclusion chromatography (SEC and dynamic light scattering (DLS. During acid denaturation of BL, the monomerization of native dimeric protein was found at pH 2.0. The elution profile from SEC showed two different peaks (59.65 ml & 87.98 ml at pH 2.0 while single peak (61.45 ml at pH 7.4. The hydrodynamic radii (R h of native BL was 2.9 nm while at pH 2.0 two species were found with R h of 1.7 and 3.7 nm. Furthermore at, pH 2.0 the secondary structures of BL remained unaltered while tertiary structure was significantly disrupted with the exposure of hydrophobic clusters confirming the existence of molten globule like state. The unfolding of BL with different subunit status was further evaluated by urea and temperature mediated denaturation to check their stability. As inferred from high Cm and ΔG values, the monomeric form of BL offers more resistance towards chemical denaturation than the native dimeric form. Besides, dimeric BL exhibited a Tm of 77°C while no loss in secondary structures was observed in monomers even up to 95°C. To the best of our knowledge, this is the first report on monomeric subunit of lectins showing more stability against denaturants than its native dimeric state.

  1. Influence of preseasonal treatment with L-tyrosine-adsorbed allergoids on IgE-mediated histamine release from basophils of children suffering from allergic diseases.

    Science.gov (United States)

    Wegner, F; Fenkes, A; Stemmann, E A; Reinhardt, D

    1981-04-01

    In 10 children suffering from allergic pollinosis and/or asthma, a preseasonal hyposensitization scheme with 3 weekly injections of a glutaraldehyde-modified, tyrosine-adsorbed grass-pollen allergen reduced the histamine release from basophils in response to increasing concentrations of antigen. The decrease in histamine release which occurred 1 week after the injection course was even maintained during the pollen season. The inhibition was only obtained when basophils were incubated with the serum of patients, but not with the serum of normals, indicating that blocking antibodies may have occurred. In contrast to what has been observed in the treated patients' group, 5 patients, who were not included in the hyposensitization scheme, showed identical histamine release curves during the whole investigation period. Specific IgE did not increase after the treatment course and shows the same behaviour as the untreated patients. Thus, as treatment with glutaraldehyde modified, tyrosine-adsorbed allergoids is safe to administer, requires only 3 injections, reduces histamine release from basophils by production of "blocking" antibodies, it appears to be a useful tool in the hyposensitization treatment.

  2. A de novo designed monomeric, compact three helix bundle protein on a carbohydrate template

    DEFF Research Database (Denmark)

    Malik, Leila; Nygård, Jesper; Christensen, Niels Johan

    2015-01-01

    De novo design and chemical synthesis of proteins and of other artificial structures, which mimic them, is a central strategy for understanding protein folding and for accessing proteins with novel functions. We have previously described carbohydrates as templates for the assembly of artificial...... the template could facilitate protein folding. Here we report the design and synthesis of 3-helix bundle carboproteins on deoxy-hexopyranosides. The carboproteins were analyzed by CD, AUC, SAXS, and NMR, which revealed the formation of the first compact, and folded monomeric carboprotein distinctly different...

  3. The Beckman DxI 800 prolactin assay demonstrates superior specificity for monomeric prolactin.

    LENUS (Irish Health Repository)

    Byrne, Brendan

    2010-02-01

    Commercially available prolactin immunoassays detect macroprolactin to variable degrees. Best practice requires laboratories to assess the cross-reactivity of their prolactin assay with macroprolactin, and where appropriate, introduce a screen for the presence of macroprolactin. Our policy has been to reanalyse hyperprolactinaemic samples following polyethylene glycol (PEG) precipitation and to report the resultant value as the monomeric prolactin content of the sample. The goal of this study was to determine the need to continue PEG precipitation when prolactin measurements with the Wallac AutoDELFIA were replaced by the Beckman DxI 800.

  4. Monomeric adiponectin modulates nitric oxide release and calcium movements in porcine aortic endothelial cells in normal/high glucose conditions.

    Science.gov (United States)

    Grossini, Elena; Farruggio, Serena; Qoqaiche, Fatima; Raina, Giulia; Camillo, Lara; Sigaudo, Lorenzo; Mary, David; Surico, Nicola; Surico, Daniela

    2016-09-15

    Perivascular adipose tissue can be involved in the process of cardiovascular pathology through the release of adipokines, namely adiponectins. Monomeric adiponectin has been shown to increase coronary blood flow in anesthetized pigs through increased nitric oxide (NO) release and the involvement of adiponectin receptor 1 (AdipoR1). The present study was therefore planned to examine the effects of monomeric adiponectin on NO release and Ca(2+) transients in porcine aortic endothelial cells (PAEs) in normal/high glucose conditions and the related mechanisms. PAEs were treated with monomeric adiponectin alone or in the presence of intracellular kinases blocker, AdipoR1 and Ca(2+)-ATPase pump inhibitors. The role of Na(+)/Ca(2+) exchanger was examined in experiments performed in zero Na(+) medium. NO release and intracellular Ca(2+) were measured through specific probes. In PAE cultured in normal glucose conditions, monomeric adiponectin elevated NO production and [Ca(2+)]c. Similar effects were observed in high glucose conditions, although the response was lower and not transient. The Ca(2+) mobilized by monomeric adiponectin originated from an intracellular pool thapsigargin- and ATP-sensitive and from the extracellular space. Moreover, the effects of monomeric adiponectin were prevented by kinase blockers and AdipoR1 inhibitor. Finally, in normal glucose condition, a role for Na(+)/Ca(2+) exchanger and Ca(2+)-ATPase pump in restoring Ca(2+) was found. Our results add new information about the control of endothelial function elicited by monomeric adiponectin, which would be achieved by modulation of NO release and Ca(2+) transients. A signalling related to Akt, ERK1/2 and p38MAPK downstream AdipoR1 would be involved. Copyright © 2016 Elsevier Inc. All rights reserved.

  5. Results from the 5-year SQ grass sublingual immunotherapy tablet asthma prevention (GAP) trial in children with grass pollen allergy.

    Science.gov (United States)

    Valovirta, Erkka; Petersen, Thomas H; Piotrowska, Teresa; Laursen, Mette K; Andersen, Jens S; Sørensen, Helle F; Klink, Rabih

    2018-02-01

    Allergy immunotherapy targets the immunological cause of allergic rhinoconjunctivitis and allergic asthma and has the potential to alter the natural course of allergic disease. The primary objective was to investigate the effect of the SQ grass sublingual immunotherapy tablet compared with placebo on the risk of developing asthma. A total of 812 children (5-12 years), with a clinically relevant history of grass pollen allergic rhinoconjunctivitis and no medical history or signs of asthma, were included in the randomized, double-blind, placebo-controlled trial, comprising 3 years of treatment and 2 years of follow-up. There was no difference in time to onset of asthma, defined by prespecified asthma criteria relying on documented reversible impairment of lung function (primary endpoint). Treatment with the SQ grass sublingual immunotherapy tablet significantly reduced the risk of experiencing asthma symptoms or using asthma medication at the end of trial (odds ratio = 0.66, P year posttreatment follow-up, and during the entire 5-year trial period. Also, grass allergic rhinoconjunctivitis symptoms were 22% to 30% reduced (P years). At the end of the trial, the use of allergic rhinoconjunctivitis pharmacotherapy was significantly less (27% relative difference to placebo, P < .001). Total IgE, grass pollen-specific IgE, and skin prick test reactivity to grass pollen were all reduced compared to placebo. Treatment with the SQ grass sublingual immunotherapy tablet reduced the risk of experiencing asthma symptoms and using asthma medication, and had a positive, long-term clinical effect on rhinoconjunctivitis symptoms and medication use but did not show an effect on the time to onset of asthma. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  6. Efficacy of sublingual administration of detomidine gel for sedation of horses undergoing veterinary and husbandry procedures under field conditions.

    Science.gov (United States)

    Gardner, Rachel B; White, Gary W; Ramsey, Deborah S; Boucher, Joseph F; Kilgore, W Randal; Huhtinen, Mirja K

    2010-12-15

    To determine whether sublingual detomidine gel administration to horses would be effective in providing an appropriate degree of sedation and restraint to facilitate completion of veterinary and husbandry procedures under field conditions. Multicenter, prospective, randomized, blinded, placebo-controlled clinical study. 270 client-owned horses known to require sedation or strong restraint to enable veterinary and husbandry procedures to be performed. Horses randomly received a single dose of detomidine gel (0.04 mg/kg [0.018 mg/lb]) or placebo gel administered sublingually. Horses were sedated to facilitate cleaning the prepuce, cutting of hair with electric clippers, hoof trimming or application of shoes, manual dental floating (ie, rasping or filing of the teeth to remove irregularities), nasogastric passage of a stomach tube or endoscope, and radiography. The primary determinant of efficacy was an assessment by a veterinarian on the ability or inability to successfully conduct the procedure. 171 horses met all the study protocol criteria. One hundred twenty-nine horses were treated with detomidine. The procedure was completed successfully for 76% (98/129) of the detomidine-treated horses, while the procedure was completed successfully for only 7% (3/42) of the placebo-treated horses. The percentage of horses in which the procedure was successfully completed was significantly different between detomidine-treated horses and placebo-treated horses. No serious adverse effects were reported. Detomidine gel administered to horses sublingually at a dose of 0.04 mg/kg provided an appropriate degree of sedation and restraint to facilitate completion of veterinary and husbandry procedures in horses known to require sedation for such procedures.

  7. Monomeric, Oligomeric and Polymeric Proteins in Huntington Disease and Other Diseases of Polyglutamine Expansion

    Directory of Open Access Journals (Sweden)

    Guylaine Hoffner

    2014-03-01

    Full Text Available Huntington disease and other diseases of polyglutamine expansion are each caused by a different protein bearing an excessively long polyglutamine sequence and are associated with neuronal death. Although these diseases affect largely different brain regions, they all share a number of characteristics, and, therefore, are likely to possess a common mechanism. In all of the diseases, the causative protein is proteolyzed, becomes abnormally folded and accumulates in oligomers and larger aggregates. The aggregated and possibly the monomeric expanded polyglutamine are likely to play a critical role in the pathogenesis and there is increasing evidence that the secondary structure of the protein influences its toxicity. We describe here, with special attention to huntingtin, the mechanisms of polyglutamine aggregation and the modulation of aggregation by the sequences flanking the polyglutamine. We give a comprehensive picture of the characteristics of monomeric and aggregated polyglutamine, including morphology, composition, seeding ability, secondary structure, and toxicity. The structural heterogeneity of aggregated polyglutamine may explain why polyglutamine-containing aggregates could paradoxically be either toxic or neuroprotective.

  8. Selective defunctionalization by TiO2 of monomeric phenolics from lignin pyrolysis into simple phenols.

    Science.gov (United States)

    Mante, Ofei D; Rodriguez, Jose A; Babu, Suresh P

    2013-11-01

    This study is focused on defunctionalizing monomeric phenolics from lignin into simple phenols for applications such as phenol/formaldehyde resins, epoxidized novolacs, adhesives and binders. Towards this goal, Titanium dioxide (TiO2) was used to selectively remove hydroxyl, methoxy, carbonyl and carboxyl functionalities from the monomeric phenolic compounds from lignin to produce mainly phenol, cresols and xylenols. The results showed that anatase TiO2 was more selective and active compared to rutile TiO2. Catechols were found to be the most reactive phenolics and 4-ethylguaiacol the least reactive with anatase TiO2. An overall conversion of about 87% of the phenolics was achieved at 550°C with a catalyst-to-feed ratio of 5 w/w. Over 97% conversion of phenolics is achievable at moderate temperatures (550°C or ≤ 600°C) and a moderate catalyst-to-feed ratio of 6.5:1. The reactivity of catechols on TiO2 suggests that titania is a promising catalyst in the removal of hydroxyl moiety. Published by Elsevier Ltd.

  9. Extracellular Monomeric and Aggregated Tau Efficiently Enter Human Neurons through Overlapping but Distinct Pathways

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    Lewis D. Evans

    2018-03-01

    Full Text Available Summary: In Alzheimer’s disease, neurofibrillary tangle pathology appears to spread along neuronal connections, proposed to be mediated by the release and uptake of abnormal, disease-specific forms of microtubule-binding protein tau MAPT. It is currently unclear whether transfer of tau between neurons is a toxic gain-of-function process in dementia or reflects a constitutive biological process. We report two entry mechanisms for monomeric tau to human neurons: a rapid dynamin-dependent phase typical of endocytosis and a second, slower actin-dependent phase of macropinocytosis. Aggregated tau entry is independent of actin polymerization and largely dynamin dependent, consistent with endocytosis and distinct from macropinocytosis, the major route for aggregated tau entry reported for non-neuronal cells. Anti-tau antibodies abrogate monomeric tau entry into neurons, but less efficiently in the case of aggregated tau, where internalized tau carries antibody with it into neurons. These data suggest that tau entry to human neurons is a physiological process and not a disease-specific phenomenon. : In contrast with predictions that transfer of the microtubule-associated protein tau between neurons is a toxic gain-of-function process in dementia, Evans et al. show that healthy human neurons efficiently take up both normal and aggregated tau, by distinct but overlapping uptake mechanisms. Keywords: Alzheimer’s disease, frontotemporal dementia, Tau, MAPT, iPSC, endocytosis, human neurons, intracellular transport

  10. Effectiveness of sublingual nitroglycerin before puncture compared with conventional intra-arterial nitroglycerin in transradial procedures: a randomized trial

    Energy Technology Data Exchange (ETDEWEB)

    Turan, Burak, E-mail: drburakturan@gmail.com; Daşlı, Tolga; Erkol, Ayhan; Erden, İsmail

    2015-10-15

    Aim: Sublingual (SL) nitroglycerin administered before radial artery puncture can improve cannulation success and decrease the incidence of radial artery spasm (RAS) compared with intra-arterial (IA) nitroglycerin in transradial procedures. Methods: Patients undergoing diagnostic transradial angiography were randomized to IA (200 mcg) or SL (400 mcg) nitroglycerin. Primary endpoints were puncture time and puncture attempts. Secondary endpoint was the incidence of RAS. Results: Total of 101 participants (mean age 60 ± 11 years, 53% male) were randomized (51 in IA and 50 in SL groups). Puncture time (50 [36–75] vs 50 [35–90] sec), puncture attempts (1.18 ± 0.48 vs 1.20 ± 0.49), multiple punctures (13.7 vs 16.0%) and RAS (19.6 vs 24.0%) were not statistically different between IA vs SL groups respectively. A composite endpoint of all adverse events related to transradial angiography (multiple punctures, RAS, access site crossover, hypotension/bradycardia associated with nitroglycerin and radial artery occlusion) was very similar in IA vs SL groups (39 vs 40%, respectively). However puncture time was significantly longer with SL nitroglycerin in patients < 1.65 m height (47 [36–66] vs 63 [41–110] sec, p = 0.042). Multiple punctures seemed higher with SL nitroglycerin in patients with diabetes (0 vs 30%, p = 0.028) or in patients < 1.65 m height (7.4 vs 25%, p = 0.085). Likewise, RAS with SL nitroglycerin seemed more frequent in smokers compared to IA nitroglycerin (0 vs 27%, p = 0.089). Conclusions: SL nitroglycerin was not different from IA nitroglycerin in terms of efficiency and safety in overall study population. However it may be inferior to IA nitroglycerin in certain subgroups (shorter individuals, diabetics and smokers). - Highlights: • Improvement in radial artery puncture time and success with subcutaneous nitrate was reported. • Giving nitrate sublingually may have vasodilation along entire length of radial artery and may prevent RAS

  11. Efficacy of Sublingual Misoprostol versus Intramuscular Methylergometrine in Prevention of Primary Postpartum Hemorrhage

    International Nuclear Information System (INIS)

    Anwar, R.; Ambreen, A.; Khuram, A.; Mushtaq, M.

    2013-01-01

    Post partum hemorrhage still remains a major cause of maternal morbidity and mortality in developing countries. Most of oxytocics like methylergometrine require parenteral administration, which requires special storage. Misoprostol is thermo stable, has a long shelf life and is widely recommended for prevention of postpartum hemorrhage. This can be a choice of oxytocic in developing countries like ours, where storage facilities and resources are limited. Objectives: To compare efficacy of sublingual Misoprostol versus intramuscular Methylergometrine in prevention of primary postpartum hemorrhage after delivery. Study Design: Quasi experimental study Place and Duration of Study: Department of Gynae/Obs, Military Hospital and Combined Military Hospital Rawalpindi cantt. December 2007 to July 2008. Material and Methods: One hundred and thirty six pregnant ladies were selected. On arrival each patient was examined thoroughly along with baseline investigations. Therapeutic option was allocated to the patients simply by using a table of random numbers and dividing them in two equal groups. Informed written consent was taken. Each patient was observed for blood loss estimation and hematocrit drop. All the data was analyzed using SPSS version 10.0. Mean +- SD for age, pre-delivery and post-delivery hematocrit, percentage of drop in hematocrit and blood loss during labour was calculated. Results: Mean drop of hematocrit and blood loss were compared among two groups. At the end, it was revealed that there was no significant difference among two groups in blood loss (p=0.49) and hematocrit drop (p=0.14). Conclusion: There is no significant better effect in preventing post partum hemorrhage among the two drugs. (author)

  12. Sublingual buprenorphine is effective in the treatment of chronic pain syndrome.

    Science.gov (United States)

    Malinoff, Herbert L; Barkin, Robert L; Wilson, Geoffrey

    2005-01-01

    Many patients with chronic pain have less than optimal therapeutic outcomes after prolonged treatment with opiate analgesics. Worsening of pain perception, functional capacity, and mood often result. Medical detoxification is often undertaken in this situation. Ninety-five consecutive patients (49 men and 46 women; age range, 26-84) with chronic noncancer pain (maldynia) were referred by local pain clinics for detoxification from long-term opiate analgesic (LTOA) therapy. All patients had failed treatment as manifest by increasing pain levels, worsening functional capacity, and, in 8%, the emergence of opiate addiction. Length of prior LTOA therapy ranged from 1.5 to 27 years (mean, 8.8 years). After a minimum of 12 hours of abstinence from all opiate analgesics, patients were given low doses of sublingual (SL) buprenorphine or buprenorphine/naloxone (Reckitt Benckiser). Maintenance dosing was individualized to treat chronic pain. Daily SL dose of buprenorphine ranged from 4 to 16 mg (mean, 8 mg) in divided doses. Mean duration of treatment is 8.8 months (range, 2.4-16.6 months). At clinic appointments, patients were assessed for pain reports, functional capacity, and mood inventory. Eighty-six percent of patients experienced moderate to substantial relief of pain accompanied by both improved mood and functioning. Patient and family satisfaction was robust. Only 6 patients discontinued therapy secondary to side effects and/or exacerbation of pain. In this open-label study, SL buprenorphine and buprenorphine/naloxone were well tolerated and safe and appeared to be effective in the treatment of chronic pain patients refractory to LTOA.

  13. [Onset time and efficacy of sublingual immunotherapy with Dermatophagoides farinae drops in children with allergic rhinitis].

    Science.gov (United States)

    Chen, Zhiling; Qian, Yasheng; Liu, Suqin; Huang, Liqin; Xu, Shiying; Yin, Wenhua; Chen, Yanchun; Wu, Huawei; Wang, Gan

    2015-08-01

    To investigate the onset time and efficacy of sublingual immunotherapy (SLIT) with Dermatophagoides farinae drops in children with house dust mites (HDM)-induced allergic rhinitis (AR). One hundred and forty three children with perennial moderate to severe HDM-induced AR were treated by SLIT with standardized Dermatophagoides farinae extract. One hundred children who finally completed two years treatment were divided into two groups according to the age: younger children group (aged 4-8 years, n = 52) and older children group (aged 9-14 years, n = 48). Respectively, Each children was assessed before and after 1st, 2nd, 3rd, 6th, 12th, 24th months of the treatment. Total nasal symptom score (TNSS), total medication score (TMS) and visual analogue scale (VAS) were evaluated at each visit. All clinical data were analyzed retrospectively with the SPSS 19.0 software. TNSS, TMS and VAS of two groups decreased significantly after three months of the treatment compared with before (younger children group: Z value was -3.843, -3.534, -3.940, older children group: Z value was -3.938, -3.405, -3.953, all P < 0.05). TNSS and VAS of younger children group decreased significantly after two months of the treatment compared with before (6.4 ± 1.6, 5.3 ± 1.4 vs 8.6 ± 1.2, 7.9 ± 1.6, Z value was -3.843, -3.940, both P < 0.05). Five children (5%) experienced local adverse events and 2 children (2%) experienced mild systemic adverse events. No severe adverse events happened during the treatment. SLIT with Dermatophagoides farinae drops is an efficient and safe treatment for children with HDM-induced AR. Its onset of action can be observed as early as 3 months after treatment.

  14. Influence of food on pharmacokinetics of zolpidem from fast dissolving sublingual zolpidem tartrate tablets.

    Science.gov (United States)

    Greenblatt, David J; Harmatz, Jerold S; Singh, Nikhilesh N; Roth, Thomas; Harris, Stephen C; Kapil, Ram P

    2013-11-01

    Ingesting food can impact the pharmacokinetics of sedative-hypnotic drugs. A buffered zolpidem sublingual tablet (ZST) recently became available for the treatment of middle-of-the-night awakening. In this randomized, open-label, single-site study, the pharmacokinetic profile of ZST was evaluated when administered while fasting and following a standard high-fat meal (fed state). Healthy adults aged 18-64 years received a single morning dose of 3.5 mg ZST in the fed or fasting state. From 20 min to 3 h post-dose, zolpidem plasma levels were lower in the fed state compared to the fasting state. After 4 h post-dose (corresponding to "morning wake time"), higher zolpidem plasma levels were evident in the fed state. Area under the concentration-time curve (AUC) values for the 0-8 h interval were 160 ng/mL h in the fed state and 203 ng/mL h in the fasting state (P fasting states, Cmax was 32.0 ng/mL versus 57.3 ng/mL (P < .001), respectively, and Tmax was 3.0 h versus 0.92 h (P < .001), respectively. Together these data suggest that administration of ZST in the fed state is not optimal for maximizing the likelihood of therapeutic benefit and minimizing the probability of residual sedation. © 2013, The American College of Clinical Pharmacology.

  15. Clinical and immunological responses of dust mite sensitive, atopic dogs to treatment with sublingual immunotherapy (SLIT).

    Science.gov (United States)

    DeBoer, Douglas J; Verbrugge, Maria; Morris, Mary

    2016-04-01

    Sublingual immunotherapy (SLIT) has been reported to be beneficial in people with atopic dermatitis (AD) and dust mite sensitivity. Evaluation of this therapy has not been reported in spontaneous canine AD. The objective of this study was to preliminarily evaluate the effectiveness of an established SLIT protocol, as used in human patients, in dogs with AD. Ten dust mite sensitive dogs with spontaneous AD. Dogs underwent a 6 month open trial of SLIT concurrently with decreasing dose oral methylprednisolone. Clinical evaluations and quantitative serum anti-mite IgE and IgG levels were performed every 2 months. Mean methylprednisolone use from the first 2 months of the study to the final 2 months declined from 10.2 to 4.3 mg/kg/2 months (P test); at 6 months, four dogs required no oral corticosteroid administration. Over the course of the study, median Canine Atopic Dermatitis Extent and Severity Index (CADESI)-03 scores declined from 76.5 to 59; median pruritus scores declined from 65 to 37 (P Wilcoxon signed-rank test). Pre- and post-SLIT intradermal test scores for mite allergen were not significantly different over time. Median Dermatophagoides farinae (DF)-specific IgE levels declined significantly from 150.2 × 10(3) AU/mL to 3.6 × 10(3) AU/mL (P Wilcoxon signed-rank tests). SLIT treatment produced clinical improvement in dogs with dust mite-associated AD and was associated with serological changes supporting this improvement. Further studies in larger numbers of dogs and those with polysensitization are warranted. © 2016 ESVD and ACVD.

  16. Effects of three antagonists on selected pharmacodynamic effects of sublingually administered detomidine in the horse.

    Science.gov (United States)

    Knych, Heather K; Stanley, Scott D

    2014-01-01

    To describe the effects of alpha2 -adrenergic receptor antagonists on the pharmacodynamics of sublingual (SL) detomidine in the horse. Randomized crossover design. Nine healthy adult horses with an average age of 7.6 ± 6.5 years. Four treatment groups were studied: 1) 0.04 mg kg(-1) detomidine SL; 2) 0.04 mg kg(-1) detomidine SL followed 1 hour later by 0.075 mg kg(-1) yohimbine intravenously (IV); 3) 0.04 mg kg(-1) detomidine SL followed 1 hour later by 4 mg kg(-1) tolazoline IV; and 4) 0.04 mg kg(-1) detomidine SL followed 1 hour later by 0.12 mg kg(-1) atipamezole IV. Each horse received all treatments with a minimum of 1 week between treatments. Blood samples were obtained and plasma analyzed for yohimbine, atipamezole and tolazoline concentrations by liquid chromatography-mass spectrometry. Behavioral effects, heart rate and rhythm, glucose, packed cell volume (PCV) and plasma proteins were monitored. Chin-to-ground distance increased following administration of the antagonists, however, this effect was transient, with a return to pre-reversal values as early as 1 hour. Detomidine induced bradycardia and increased incidence of atrioventricular blocks were either transiently or incompletely antagonized by all antagonists. PCV and glucose concentrations increased with tolazoline administration, and atipamezole subjectively increased urination frequency but not volume. At the doses administered in this study, the alpha2 -adrenergic antagonistic effects of tolazoline, yohimbine and atipamezole on cardiac and behavioral effects elicited by SL administration of detomidine are transient and incomplete. © 2013 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia.

  17. Real-life compliance and persistence among users of subcutaneous and sublingual allergen immunotherapy.

    Science.gov (United States)

    Kiel, Menno A; Röder, Esther; Gerth van Wijk, Roy; Al, Maiwenn J; Hop, Wim C J; Rutten-van Mölken, Maureen P M H

    2013-08-01

    Subcutaneous allergen immunotherapy (SCIT) and sublingual allergen immunotherapy (SLIT) are safe and effective treatments of allergic rhinitis, but high levels of compliance and persistence are crucial to achieving the desired clinical effects. Our objective was to assess levels and predictors of compliance and persistence among grass pollen, tree pollen, and house dust mite immunotherapy users in real life and to estimate the costs of premature discontinuation. We performed a retrospective analysis of a community pharmacy database from The Netherlands containing data from 6486 patients starting immunotherapy for 1 or more of the allergens of interest between 1994 and 2009. Two thousand seven hundred ninety-six patients received SCIT, and 3690 received SLIT. Time to treatment discontinuation was analyzed and included Cox proportional hazard models with time-dependent covariates, where appropriate. Overall, only 18% of users reached the minimally required duration of treatment of 3 years (SCIT, 23%; SLIT, 7%). Median durations for SCIT and SLIT users were 1.7 and 0.6 years, respectively (P < .001). Other independent predictors of premature discontinuation were prescriber, with patients of general practitioners demonstrating longer persistence than those of allergologists and other medical specialists; single-allergen immunotherapy, lower socioeconomic status; and younger age. Of the persistent patients, 56% were never late in picking up their medication from the pharmacy. Direct medication costs per nonpersistent patient discontinuing in the third year of treatment were €3800, an amount that was largely misspent. Real-life persistence is better in SCIT users than in SLIT users, although it is low overall. There is an urgent need for further identification of potential barriers and measures that will enhance persistence and compliance. Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

  18. Sublingual immunotherapy for peanut allergy: clinical and immunologic evidence of desensitization.

    Science.gov (United States)

    Kim, Edwin H; Bird, J Andrew; Kulis, Michael; Laubach, Susan; Pons, Laurent; Shreffler, Wayne; Steele, Pamela; Kamilaris, Janet; Vickery, Brian; Burks, A Wesley

    2011-03-01

    There are no treatments currently available for peanut allergy. Sublingual immunotherapy (SLIT) is a novel approach to the treatment of peanut allergy. We sought to investigate the safety, clinical effectiveness, and immunologic changes with SLIT in children with peanut allergy. In this double-blind, placebo-controlled study subjects underwent 6 months of dose escalation and 6 months of maintenance dosing followed by a double-blind, placebo-controlled food challenge. Eighteen children aged 1 to 11 years completed 12 months of dosing and the food challenge. Dosing side effects were primarily oropharyngeal and uncommonly required treatment. During the double-blind, placebo-controlled food challenge, the treatment group safely ingested 20 times more peanut protein than the placebo group (median, 1,710 vs 85 mg; P = .011). Mechanistic studies demonstrated a decrease in skin prick test wheal size (P = .020) and decreased basophil responsiveness after stimulation with 10(-2) μg/mL (P = .009) and 10(-3) μg/mL (P = .009) of peanut. Peanut-specific IgE levels increased over the initial 4 months (P = .002) and then steadily decreased over the remaining 8 months (P = .003), whereas peanut-specific IgG4 levels increased during the 12 months (P = .014). Lastly, IL-5 levels decreased after 12 months (P = .015). No statistically significant changes were found in IL-13 levels, the percentage of regulatory T cells, or IL-10 and IFN-γ production. Peanut SLIT is able to safely induce clinical desensitization in children with peanut allergy, with evidence of immunologic changes suggesting a significant change in the allergic response. Further study is required to determine whether continued peanut SLIT is able to induce long-term immune tolerance. Copyright © 2011 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

  19. α-SNAP prevents docking of the acrosome during sperm exocytosis because it sequesters monomeric syntaxin.

    Directory of Open Access Journals (Sweden)

    Facundo Rodríguez

    Full Text Available α-SNAP has an essential role in membrane fusion that consists of bridging cis SNARE complexes to NSF. α-SNAP stimulates NSF, which releases itself, α-SNAP, and individual SNAREs that subsequently re-engage in the trans arrays indispensable for fusion. α-SNAP also binds monomeric syntaxin and NSF disengages the α-SNAP/syntaxin dimer. Here, we examine why recombinant α-SNAP blocks secretion in permeabilized human sperm despite the fact that the endogenous protein is essential for membrane fusion. The only mammalian organism with a genetically modified α-SNAP is the hyh mouse strain, which bears a M105I point mutation; males are subfertile due to defective sperm exocytosis. We report here that recombinant α-SNAP-M105I has greater affinity for the cytosolic portion of immunoprecipitated syntaxin than the wild type protein and in consequence NSF is less efficient in releasing the mutant. α-SNAP-M105I is a more potent sperm exocytosis blocker than the wild type and requires higher concentrations of NSF to rescue its effect. Unlike other fusion scenarios where SNAREs are subjected to an assembly/disassembly cycle, the fusion machinery in sperm is tuned so that SNAREs progress uni-directionally from a cis configuration in resting cells to monomeric and subsequently trans arrays in cells challenged with exocytosis inducers. By means of functional and indirect immunofluorescense assays, we show that recombinant α-SNAPs--wild type and M105I--inhibit exocytosis because they bind monomeric syntaxin and prevent this SNARE from assembling with its cognates in trans. Sequestration of free syntaxin impedes docking of the acrosome to the plasma membrane assessed by transmission electron microscopy. The N-terminal deletion mutant α-SNAP-(160-295, unable to bind syntaxin, affects neither docking nor secretion. The implications of this study are twofold: our findings explain the fertility defect of hyh mice and indicate that assembly of SNAREs in trans

  20. Induction of antibodies against epitopes inaccessible on the HIV type 1 envelope oligomer by immunization with recombinant monomeric glycoprotein 120

    DEFF Research Database (Denmark)

    Schønning, Kristian; Bolmstedt, A; Novotny, J

    1998-01-01

    An N-glycan (N306) at the base of the V3 loop of HIV-BRU gp120 is shielding a linear neutralization epitope at the tip of the V3 loop on oligomeric Env. In contrast, this epitope is readily antigenic on monomeric gp120. Immunization with recombinant monomeric HIV-BRU gp120 may thus be expected...... immunogenic structures inaccessible on the envelope oligomer. The limited ability of recombinant gp120 vaccines to induce neutralizing antibodies against primary isolates may thus not exclusively reflect genetic variation....

  1. Evaluation of Anti-Trichinella spiralis Obtained by Sublingual and Conventional Immunizations with the 45kDa Protein

    Directory of Open Access Journals (Sweden)

    Francisca Chávez Ruvalcaba

    2017-05-01

    Full Text Available Trichinellosis is a cosmopolitan zoonotic disease produced mainly by the consumption of poorly cooked swine meat. Several studies have probed the efficiency of immunotherapy as a method for the treatment of trichinellosis. In this work, a 45 kDa immunodominant antigen was characterized, and the presence of IgA, IgM and IgG anti-Trichinella spiralis antibodies was evaluated during the course of the infection. In addition, the differences between sublingual and parenteral administration of the 45 kDa T. spiralis antigen were determined. Long Evans rats were used both to purify the 45 kDa antigen and to evaluate the immune response produced in six different groups: healthy and infected controls; two groups of immunized murines (sublingually and parenterally with 4 doses of the 45 kDa T. spiralis immunogen administered at days 0, 7, 14 and 21 and challenged with 500 T. spiralis infective larvae (IL 7 days after the last immunization; and finally, two groups of murines infected with 500 IL of T. spiralis, immunized at week 4 post infection by the same two routes. The humoral response was evaluated by indirect immunofluorescence by confocal microscopyin order to determine the presence of IgA, IgM and IgG antibodies.

  2. Sublingual immunotherapy (SLIT – indications, mechanism, and efficacy Position paper prepared by the Section of Immunotherapy, Polish Society of Allergy

    Directory of Open Access Journals (Sweden)

    Marek Jutel

    2015-12-01

    Full Text Available SLIT ( sublingual immunotherapy induces allergen-specific immune tolerance by sublingual administration of a gradually increasing dose of an allergen. The mechanism of SLIT is comparable to those during SCIT (subcutaneous immunotherapy, with the exception of local oral dendritic cells, pre-programmed to elicit tolerance. In the SLIT dose, to achieve the same efficacy as in SCIT, it should be 50–100 times higher with better safety profile. The highest quality evidence supporting the efficacy of SLIT lasting 1 – 3 years has been provided by the large scale double-blind, placebo-controlled (DBPC trials for grass pollen extracts, both in children and adults with allergic rhinitis. Current indications for SLIT are allergic rhinitis (and conjunctivitis in both children and adults sensitized to pollen allergens (trees, grass, Parietaria , house dust mites ( Dermatophagoides pteronyssinus, Dermatophagoides farinae , cat fur, as well as mild to moderate controlled atopic asthma in children sensitized to house dust mites. There are positive findings for both asthma and new sensitization prevention. Severe adverse events, including anaphylaxis, are very rare, and no fatalities have been reported. Local adverse reactions develop in up to 70 – 80% of patients. Risk factors for SLIT adverse events have not been clearly identified. Risk factors of non-adherence to treatment might be dependent on the patient, disease treatment, physician-patient relationship, and variables in the health care system organization.

  3. Comparison of Intravenous Morphine with Sublingual Buprenorphine in Management of Postoperative Pain after Closed Reduction Orthopedic Surgery

    Directory of Open Access Journals (Sweden)

    Ghasem Soltani

    2015-09-01

    Full Text Available Background: Postoperative pain is a common side effect following surgery that can significantly reduce surgical quality and patient’s satisfaction. Treatment options are morphine and buprenorphine. We aimed to compare the efficacy of a single dose of intravenous morphine with sublingual buprenorphine in postoperative pain control following closed reduction surgery. Methods: This triple blind clinical trial was conducted on 90 patients referred for closed reduction orthopedic surgery. They were older than 18 years and in classes I and II of the American Society of Anesthesiologists (ASA with an operation time of 30-90 minutes. Patients were divided into two groups of buprenorphine (4.5μg/kg sublingually and morphine (0.2mg/kg intravenously. Baseline characteristics, vital signs, pain score, level of sedation and pharmacological side effects were recorded in the recovery room (at 0 and 30 minutes, and in the ward (at 3, 6 and 12 hours. SPSS version 19 software was used for data analysis and the significance level was set at P Results: Ninety patients were studied, 60 males and 30 females with a mean age of 37.7±16.2 years. There was no significant difference between the two groups in terms of baseline characteristics.Pain score in the morphine group was significantly higher than the buprenorphine group with an average score of 2.5 (P

  4. Comparison of Intravenous Morphine with Sublingual Buprenorphine in Management of Postoperative Pain after Closed Reduction Orthopedic Surgery

    Directory of Open Access Journals (Sweden)

    Ghasem Soltani

    2015-10-01

    Full Text Available Background: Postoperative pain is a common side effect following surgery that can significantly reduce surgical quality and patient’s satisfaction. Treatment options are morphine and buprenorphine. We aimed to compare the efficacy of a single dose of intravenous morphine with sublingual buprenorphine in postoperative pain control following closed reduction surgery. Methods: This triple blind clinical trial was conducted on 90 patients referred for closed reduction orthopedic surgery. They were older than 18 years and in classes I and II of the American Society of Anesthesiologists (ASA with an operation time of 30-90 minutes. Patients were divided into two groups of buprenorphine (4.5μg/kg sublingually and morphine (0.2mg/kg intravenously. Baseline characteristics, vital signs, pain score, level of sedation and pharmacological side effects were recorded in the recovery room (at 0 and 30 minutes, and in the ward (at 3, 6 and 12 hours. SPSS version 19 software was used for data analysis and the significance level was set at P Results: Ninety patients were studied, 60 males and 30 females with a mean age of 37.7±16.2 years. There was no significant difference between the two groups in terms of baseline characteristics.Pain score in the morphine group was significantly higher than the buprenorphine group with an average score of 2.5 (P

  5. Pharmacokinetics of a Prototype Formulation of Sublingual Testosterone and a Buspirone Tablet, Versus an Advanced Combination Tablet of Testosterone and Buspirone in Healthy Premenopausal Women

    NARCIS (Netherlands)

    Van Rooij, Kim; De Leede, Leo; Frijlink, Henderik W.; Bloemers, Jos; Poels, Saskia; Koppeschaar, Hans; Olivier, Berend; Tuiten, Adriaan

    2014-01-01

    The study aimed to compare the kinetics of two novel combination drug products for Female Sexual Interest/Arousal Disorder (FSIAD). Thirteen women received testosterone via the sublingual route followed 2.5 hours later by a buspirone tablet, versus a single combination tablet swallowed at once. The

  6. Deposition of a model substance, Tc E-HIDA, in the oral cavity after administration of lozenges, chewing gum and sublingual tablets

    DEFF Research Database (Denmark)

    Christrup, Lona Louring; Davis, S.S.; Melia, C.D.

    1990-01-01

    The deposition and clearance of a model substance, Tc E-HIDA, in the oral cavity/upper oesophagus and in the stomach after administration of lozenges, chewing gum and sublingual tablets has been followed by gamma scintigraphy in a group of healthy male volunteers. Following administration...

  7. Method for the isolation of biologically active monomeric immunoglobulin A from a plasma fraction.

    Science.gov (United States)

    Leibl, H; Tomasits, R; Wolf, H M; Eibl, M M; Mannhalter, J W

    1996-04-12

    A purification method for immunoglobulin A (IgA) yielding monomeric IgA with a purity of over 97% has been developed. This procedure uses ethanol-precipitated plasma (Cohn fraction III precipitate) as the starting material and includes heparin-Sepharose adsorption, dextran sulfate and ammonium sulfate precipitation, hydroxyapatite chromatography, batch adsorption by an anion-exchange matrix and gel permeation. Additional protein G Sepharose treatment leads to an IgA preparation of greater than 99% purity. The isolated IgA presented with an IgA subclass distribution, equivalent to IgA in unfractionated plasma, and was biologically active, as was shown by its ability to down-modulate Haemophilus influenzae-b-induced IL-6 secretion of human monocytes.

  8. Preparation and properties of a monomeric Mn(IV)-oxo complex.

    Science.gov (United States)

    Parsell, Trenton H; Behan, Rachel K; Green, Michael T; Hendrich, Michael P; Borovik, A S

    2006-07-12

    Manganese-oxo complexes have long been investigated because of their proposed roles in biological and chemical catalysis. However, there are few examples of monomeric complexes with terminal oxo ligands, especially those with oxomanganese(IV) units. A oxomanganese(IV) complex has been prepared from [MnIIIH3buea(O)]2- ([H3buea]3-, tris[(N'-tert-butylureaylato)-N-ethylene]aminato), a monomeric MnIII-O complex in which the oxo ligand arises from cleavage of dioxygen. Treating [MnIIIH3buea(O)]2- with [Cp2Fe]BF4 in either DMF at -45 degrees C or DMSO at room temperature produces [MnIVH3buea(O)]-: lambdamax = 635 nm; nu(Mn-16O) = 737 cm-1; nu(Mn-18O) = 709 cm-1; g = 5.15, 2.44, 1.63, D = 3.0 cm-1, E/D = 0.26, aMn = 66 G (A = 190 MHz). These spectroscopic properties support the assignment of a mononuclear MnIV-oxo complex with an S = 3/2 ground state. Density functional theory supports this assignment and the Jahn-Teller distortion around the high-spin MnIV center that would alter the molecular structure of [MnIVH3buea(O)]- from trigonal symmetry (as indicated by the highly rhombic EPR signal). [MnIVH3buea(O)]- is relatively unstable in DMSO, converting to [MnIIIH3buea(OH)]- via a proposed X-H bond cleavage. [MnIVH3buea(O)]- reacts with 1,2-diphenylhydrazine to from azobenzene (95% yield) and [MnIIIH3buea(OH)]-. The MnIV-oxo does not react with triphenyl- or tricyclohexylphosphine. However, O-atom transfer is observed with methyldiphenylphosphine and dimethylphenylphosphine, producing the corresponding phosphine oxides. These results illustrate the diverse reactivity of the MnIV-oxo unit.

  9. Hda monomerization by ADP binding promotes replicase clamp-mediated DnaA-ATP hydrolysis.

    Science.gov (United States)

    Su'etsugu, Masayuki; Nakamura, Kenta; Keyamura, Kenji; Kudo, Yuka; Katayama, Tsutomu

    2008-12-26

    ATP-DnaA is the initiator of chromosomal replication in Escherichia coli, and the activity of DnaA is regulated by the regulatory inactivation of the DnaA (RIDA) system. In this system, the Hda protein promotes DnaA-ATP hydrolysis to produce inactive ADP-DnaA in a mechanism that is mediated by the DNA-loaded form of the replicase sliding clamp. In this study, we first revealed that hda translation uses an unusual initiation codon, CUG, located downstream of the annotated initiation codon. The CUG initiation codon could be used for restricting the Hda level, as this initiation codon has a low translation efficiency, and the cellular Hda level is only approximately 100 molecules per cell. Hda translated using the correct reading frame was purified and found to have a high RIDA activity in vitro. Moreover, we found that Hda has a high affinity for ADP but not for other nucleotides, including ATP. ADP-Hda was active in the RIDA system in vitro and stable in a monomeric state, whereas apo-Hda formed inactive homomultimers. Both ADP-Hda and apo-Hda could form complexes with the DNA-loaded clamp; however, only ADP-Hda-DNA-clamp complexes were highly functional in the following interaction with DnaA. Formation of ADP-Hda was also observed in vivo, and mutant analysis suggested that ADP binding is crucial for cellular Hda activity. Thus, we propose that ADP is a crucial Hda ligand that promotes the activated conformation of the protein. ADP-dependent monomerization might enable the arginine finger of the Hda AAA+ domain to be accessible to ATP bound to the DnaA AAA+ domain.

  10. LRP1 Modulates APP Intraneuronal Transport and Processing in Its Monomeric and Dimeric State

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    Claus U. Pietrzik

    2017-04-01

    Full Text Available The low-density lipoprotein receptor-related protein 1, LRP1, interacts with APP and affects its processing. This is assumed to be mostly caused by the impact of LRP1 on APP endocytosis. More recently, also an interaction of APP and LRP1 early in the secretory pathway was reported whereat retention of LRP1 in the ER leads to decreased APP cell surface levels and in turn, to reduced Aβ secretion. Here, we extended the biochemical and immunocytochemical analyses by showing via live cell imaging analyses in primary neurons that LRP1 and APP are transported only partly in common (one third but to a higher degree in distinct fast axonal transport vesicles. Interestingly, co-expression of LRP1 and APP caused a change of APP transport velocities, indicating that LRP1 recruits APP to a specific type of fast axonal transport vesicles. In contrast lowered levels of LRP1 facilitated APP transport. We further show that monomeric and dimeric APP exhibit similar transport characteristics and that both are affected by LRP1 in a similar way, by slowing down APP anterograde transport and increasing its endocytosis rate. In line with this, a knockout of LRP1 in CHO cells and in primary neurons caused an increase of monomeric and dimeric APP surface localization and in turn accelerated shedding by meprin β and ADAM10. Notably, a choroid plexus specific LRP1 knockout caused a much higher secretion of sAPP dimers into the cerebrospinal fluid compared to sAPP monomers. Together, our data show that LRP1 functions as a sorting receptor for APP, regulating its cell surface localization and thereby its processing by ADAM10 and meprin β, with the latter exhibiting a preference for APP in its dimeric state.

  11. Pharmacokinetics and safety of fentanyl sublingual spray and fentanyl citrate intravenous: a single ascending dose study in opioid-naïve healthy volunteers.

    Science.gov (United States)

    Rauck, Richard; Oh, D Alexander; Parikh, Neha; Koch, Christian; Singla, Neil; Yu, Jin; Nalamachu, Srinivas; Vetticaden, Santosh

    2017-11-01

    Fentanyl sublingual spray offers rapid pain relief in opioid-tolerant cancer patients, and may be useful in acute or post-operative pain. Both opioid-naïve and non-tolerant patients are likely to receive opioids in these settings. Understanding the relationship between systemic exposure of fentanyl sublingual spray and effects on respiratory function in opioid-naïve or non-tolerant populations is important to ensure patient safety. This study evaluated single-dose fentanyl sublingual spray in opioid-naïve participants. Participants were randomized to receive single-dose fentanyl sublingual spray (100, 200, 400, 600, 800 mcg) or fentanyl citrate IV in one of five cohorts. Dosing occurred following a 10-h fast, with fasting continuing for 4 h post-dose. Dose proportionality was assessed using analysis of variance and linear regression techniques. PK assessments and safety monitoring were performed through 24 h post-dose. Safety assessments, including adverse event (AE) monitoring, occurred from dosing through Day 7. Fifty participants (19-53 years) received fentanyl sublingual spray or fentanyl citrate IV. Mean maximum plasma concentrations were reached between 0.27-0.60 h post-dose for fentanyl sublingual spray. Peak (C max ) and total (AUC 0- t , AUC 0-∞ ) fentanyl exposures increased in a linear, but more than dose-proportional manner, with higher doses. The most common AEs were somnolence, nausea, and vomiting. All AEs were mild or moderate in severity. Doses at 400, 600, and 800 mcg were associated with nausea and vomiting, requiring pharmacologic intervention. Hypoxia episodes requiring nasal cannula oxygenation were observed with 600mcg and 800mcg doses. Overall, single-dose fentanyl sublingual spray (100-800 mcg) was generally well tolerated, with greater incidences of AEs (e.g. nausea, vomiting, hypoxia) at higher doses. Doses up to 200 mcg may be safely administered to healthy opioid-naïve individuals with routine monitoring; doses

  12. Sublingual versus subcutaneous immunotherapy: patient adherence at a large German allergy center

    Directory of Open Access Journals (Sweden)

    Lemberg M

    2017-01-01

    Full Text Available Marie-Luise Lemberg,1 Till Berk,2 Kija Shah-Hosseini,1 Elena-Manja Kasche,1,3 Ralph Mösges1 1Faculty of Medicine, Institute of Medical Statistics, Informatics and Epidemiology, University of Cologne, Cologne, Germany; 2Department of Trauma Surgery, University Hospital Zurich, Zurich, Switzerland; 3Center for Dermatology, Specific Allergology and Environmental Medicine, Hamburg, Germany Background: Many placebo-controlled studies have demonstrated that allergen immunotherapy (AIT is an effective therapy for treating allergies. Both commonly used routes, subcutaneous (SCIT and sublingual immunotherapy (SLIT, require high patient adherence to be successful. In the literature, numbers describing adherence vary widely; this investigation compares these two routes of therapy directly.Methods: All data were retrieved from the patient data management system of a center for dermatology, specific allergology, and environmental medicine in Germany. All 330 patients (aged 13–89 years included in this study had commenced AIT between 2003 and 2011, thus allowing a full 3-year AIT cycle to be considered for each investigated patient.Results: In this specific center, SCIT was prescribed to 62.7% and SLIT to 37.3% of all included patients. The total dropout rate of the whole patient cohort was 34.8%. Overall, SLIT patients showed a higher dropout rate (39.0% than did SCIT patients (32.4%; however, the difference between these groups was not significant. Also, no significant difference between the overall dropout rates for men and for women was observed. A Kaplan–Meier curve of the patient collective showed a remarkably high dropout rate for the first year of therapy.Conclusion: The analysis presented in this single-center study shows that most patients who discontinue AIT do so during the first year of therapy. Patients seem likely to finish the 3-year therapy cycle if they manage to adhere to treatment throughout the first year. Strategies for preventing

  13. Quantification of the predominant monomeric catechins in baking chocolate standard reference material by LC/APCI-MS.

    Science.gov (United States)

    Nelson, Bryant C; Sharpless, Katherine E

    2003-01-29

    Catechins are polyphenolic plant compounds (flavonoids) that may offer significant health benefits to humans. These benefits stem largely from their anticarcinogenic, antioxidant, and antimutagenic properties. Recent epidemiological studies suggest that the consumption of flavonoid-containing foods is associated with reduced risk of cardiovascular disease. Chocolate is a natural cocoa bean-based product that reportedly contains high levels of monomeric, oligomeric, and polymeric catechins. We have applied solid-liquid extraction and liquid chromatography coupled with atmospheric pressure chemical ionization-mass spectrometry to the identification and determination of the predominant monomeric catechins, (+)-catechin and (-)-epicatechin, in a baking chocolate Standard Reference Material (NIST Standard Reference Material 2384). (+)-Catechin and (-)-epicatechin are detected and quantified in chocolate extracts on the basis of selected-ion monitoring of their protonated [M + H](+) molecular ions. Tryptophan methyl ester is used as an internal standard. The developed method has the capacity to accurately quantify as little as 0.1 microg/mL (0.01 mg of catechin/g of chocolate) of either catechin in chocolate extracts, and the method has additionally been used to certify (+)-catechin and (-)-epicatechin levels in the baking chocolate Standard Reference Material. This is the first reported use of liquid chromatography/mass spectrometry for the quantitative determination of monomeric catechins in chocolate and the only report certifying monomeric catechin levels in a food-based Standard Reference Material.

  14. Principal Component Regression Analysis of the Relation Between CIELAB Color and Monomeric Anthocyanins in Young Cabernet Sauvignon Wines

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    Chang-Qing Duan

    2008-11-01

    Full Text Available Color is one of the key characteristics used to evaluate the sensory quality of red wine, and anthocyanins are the main contributors to color. Monomeric anthocyanins and CIELAB color values were investigated by HPLC-MS and spectrophotometry during fermentation of Cabernet Sauvignon red wine, and principal component regression (PCR, a statistical tool, was used to establish a linkage between the detected anthocyanins and wine coloring. The results showed that 14 monomeric anthocyanins could be identified in wine samples, and all of these anthocyanins were negatively correlated with the L*, b* and H*ab values, but positively correlated with a* and C*ab values. On an equal concentration basis for each detected anthocyanin, cyanidin-3-O-glucoside (Cy3-glu had the most influence on CIELAB color value, while malvidin 3-O-glucoside (Mv3-glu had the least. The color values of various monomeric anthocyanins were influenced by their structures, substituents on the B-ring, acyl groups on the glucoside and the molecular steric structure. This work develops a statistical method for evaluating correlation between wine color and monomeric anthocyanins, and also provides a basis for elucidating the effect of intramolecular copigmentation on wine coloring.

  15. Distinct subcellular trafficking resulting from monomeric vs multimeric targeting to endothelial ICAM-1: implications for drug delivery.

    Science.gov (United States)

    Ghaffarian, Rasa; Muro, Silvia

    2014-12-01

    Ligand-targeted, receptor-mediated endocytosis is commonly exploited for intracellular drug delivery. However, cells-surface receptors may follow distinct endocytic fates when bound by monomeric vs multimeric ligands. Our purpose was to study this paradigm using ICAM-1, an endothelial receptor involved in inflammation, to better understand its regulation and potential for drug delivery. Our procedure involved fluorescence microscopy of human endothelial cells to determine the endocytic behavior of unbound ICAM-1 vs ICAM-1 bound by model ligands: monomeric (anti-ICAM) vs multimeric (anti-ICAM biotin-streptavidin conjugates or anti-ICAM coated onto 100 nm nanocarriers). Our findings suggest that both monomeric and multimeric ligands undergo a similar endocytic pathway sensitive to amiloride (∼50% inhibition), but not inhibitors of clathrin-pits or caveoli. After 30 min, ∼60-70% of both ligands colocalized with Rab11a-compartments. By 3-5 h, ∼65-80% of multimeric anti-ICAM colocalized with perinuclear lysosomes with ∼60-80% degradation, while 70% of monomeric anti-ICAM remained associated with Rab11a at the cell periphery and recycled to and from the cell-surface with minimal (drug delivery.

  16. Stability of human interferon-beta 1: oligomeric human interferon-beta 1 is inactive but is reactivated by monomerization.

    Science.gov (United States)

    Utsumi, J; Yamazaki, S; Kawaguchi, K; Kimura, S; Shimizu, H

    1989-10-05

    Human interferon-beta 1 is extremely stable is a low ionic strength solution of pH 2 such as 10 mM HCl at 37 degrees C. However, the presence of 0.15 M NaCl led to a remarkable loss of antiviral activity. The molecular-sieve high-performance liquid chromatography revealed that, whereas completely active human interferon-beta 1 eluted as a 25 kDa species (monomeric form), the inactivated preparation eluted primarily as a 90 kDa species (oligomeric form). The specific activity (units per mg protein) of the oligomeric form was approx. 10% of that of the monomeric form. This observation shows that oligomeric human interferon-beta 1 is apparently in an inactive form. When the oligomeric eluate was resolved by polyacrylamide gel containing sodium dodecyl sulphate (SDS), it appeared to be monomeric under non-reducing conditions. Monomerization of the oligomeric human interferon-beta 1 by treatment with 1% SDS, fully regenerated its antiviral activity. These results suggest that the inactivation of the human interferon-beta 1 preparation was caused by its oligomerization via hydrophobic interactions without the formation of intermolecular disulphide bonds. These oligomers can be dissociated by SDS to restore biological activity.

  17. Baixa dose de misoprostol sublingual (12,5 µg para indução do parto Low dose of sublingual misoprostol (12.5 µg for labor induction

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    Daniele Sofia de Moraes Barros Gattás

    2012-04-01

    Full Text Available OBJETIVO: Descrever os resultados maternos e perinatais utilizando 12,5 µg de misoprostol sublingual para indução do parto em gestantes com feto vivo a termo. MÉTODOS: Realizou-se um estudo multicêntrico, tipo ensaio clínico, aberto e não randomizado, no período de julho a dezembro de 2009. Foram incluídas 30 gestantes com indicação de indução do parto, a termo, feto vivo, escore de Bishop menor ou igual a seis, apresentação cefálica, peso fetal estimado menor que 4.000 g e índice de líquido amniótico maior que cinco. Foram excluídas mulheres com cicatriz uterina, alteração da vitalidade fetal, anomalias congênitas, gestação múltipla, restrição de crescimento intrauterino, hemorragia genital e contraindicações ao parto vaginal. O comprimido de misoprostol sublingual 12,5 µg foi administrado a cada seis horas, até o início do trabalho de parto, máximo de oito doses. RESULTADOS: O trabalho de parto foi induzido satisfatoriamente em 90% das gestantes. As médias dos intervalos entre a primeira dose e o início das contrações uterinas e o parto foram de 14,3±11,7 horas e 25,4±13 horas, respectivamente. A frequência de parto vaginal foi de 60%. A taquissistolia ocorreu em duas gestantes, sendo revertida em ambos os casos sem necessitar de cesariana. A eliminação de mecônio foi observada em quatro pacientes e o escore de Apgar foi menor que sete no quinto minuto em um recém-nascido. CONCLUSÃO: Os desfechos maternos e perinatais foram favoráveis depois da indução do parto com misoprostol sublingual na dose de 12,5 µg a cada seis horas. No entanto, são necessários ensaios clínicos controlados comparando esse esquema posológico com outras doses e vias de administraçãoPURPOSE: To describe the maternal and perinatal outcomes after the use of 12.5 µg of sublingual misoprostol for labor induction in women with term pregnancy and a live fetus. METHODS: We conducted a multicenter, open and non

  18. Safety of sublingual immunotherapy Timothy grass tablet in subjects with allergic rhinitis with or without conjunctivitis and history of asthma

    DEFF Research Database (Denmark)

    Maloney, J; Durham, S; Skoner, D

    2015-01-01

    BACKGROUND: Patients with asthma may be more susceptible to adverse events (AEs) with sublingual immunotherapy tablet (SLIT-tablet) treatment, such as severe systemic reactions and asthma-related events. Using data from eight trials of grass SLIT-tablet in subjects with allergic rhinitis with....../without conjunctivitis (AR/C), AE frequencies were determined in adults and children with and without reported asthma. METHODS: Data from randomized, double-blind, placebo-controlled trials of Timothy grass SLIT-tablet MK-7243 (2800 BAU/75 000 SQ-T, Merck/ALK-Abelló) were pooled for post hoc analyses. Subjects...... with asthma treated with grass SLIT-tablet versus subjects without asthma in or outside of pollen season. There were 6/120 asthma-related TRAEs assessed as severe with grass SLIT-tablet and 2/60 with placebo, without a consistent trend among subjects with and without asthma (5 and 3 events, respectively...

  19. Holistic versus monomeric strategies for hydrological modelling of human-modified hydrosystems

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    I. Nalbantis

    2011-03-01

    Full Text Available The modelling of human-modified basins that are inadequately measured constitutes a challenge for hydrological science. Often, models for such systems are detailed and hydraulics-based for only one part of the system while for other parts oversimplified models or rough assumptions are used. This is typically a bottom-up approach, which seeks to exploit knowledge of hydrological processes at the micro-scale at some components of the system. Also, it is a monomeric approach in two ways: first, essential interactions among system components may be poorly represented or even omitted; second, differences in the level of detail of process representation can lead to uncontrolled errors. Additionally, the calibration procedure merely accounts for the reproduction of the observed responses using typical fitting criteria. The paper aims to raise some critical issues, regarding the entire modelling approach for such hydrosystems. For this, two alternative modelling strategies are examined that reflect two modelling approaches or philosophies: a dominant bottom-up approach, which is also monomeric and, very often, based on output information, and a top-down and holistic approach based on generalized information. Critical options are examined, which codify the differences between the two strategies: the representation of surface, groundwater and water management processes, the schematization and parameterization concepts and the parameter estimation methodology. The first strategy is based on stand-alone models for surface and groundwater processes and for water management, which are employed sequentially. For each model, a different (detailed or coarse parameterization is used, which is dictated by the hydrosystem schematization. The second strategy involves model integration for all processes, parsimonious parameterization and hybrid manual-automatic parameter optimization based on multiple objectives. A test case is examined in a hydrosystem in Greece

  20. Recombinant DNA derived monomeric insulin analogue: comparison with soluble human insulin in normal subjects.

    Science.gov (United States)

    Vora, J P; Owens, D R; Dolben, J; Atiea, J A; Dean, J D; Kang, S; Burch, A; Brange, J

    1988-11-12

    To compare the rate of absorption from subcutaneous tissue and the resulting hypoglycaemic effect of iodine-125 labelled soluble human insulin and a monomeric insulin analogue derived by recombinant DNA technology. Single blind randomised comparison of equimolar doses of 125I labelled soluble human insulin and insulin analogue. Study in normal people at a diabetes research unit and a university department of medical physics. Seven healthy male volunteers aged 20-39 not receiving any other drugs. After an overnight fast and a basal period of one hour two doses (0.05 and 0.1 U/kg) of 125I labelled soluble human insulin and insulin analogue were injected subcutaneously into the anterior abdominal wall on four separate days. To find a fast acting insulin for meal related requirements in insulin dependent diabetics. MEASUREMENTS and main results--Residual radioactivity at the injection site was measured continuously for the first two hours after injection of the 125I labelled preparations and thereafter for five minutes simultaneously with blood sampling. Frequent venous blood samples were obtained over six hours for determination of plasma immunoreactive insulin, insulin analogue, glucose, and glucagon values. Time to 50% of initial radioactivity at the injection site for the insulin analogue compared with soluble insulin was 61 v 135 minutes (p less than 0.05) with 0.05 U/kg and 67 v 145 minutes (p less than 0.001) with 0.1 U/kg. Concentrations in plasma increased faster after the insulin analogue compared with soluble insulin, resulting in higher plasma concentrations between 10 and 150 minutes (0.001 less than p less than 0.05) after 0.05 U/kg and between 40 and 360 minutes (0.001 less than p less than 0.05) after 0.1 U/kg. The hypoglycaemic response to insulin analogue was a plasma glucose nadir at 60 minutes with both doses compared with 90 and 120 minutes with soluble insulin at 0.5 and 0.1 U/kg respectively. The response of glucagon substantiated the earlier and

  1. Phenotype and cell proliferation activity of duct-like structures in human sublingual glands: a histological and immunohistochemical study

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    Elen de Souza TOLENTINO

    2015-06-01

    Full Text Available There are several age-related microscopic changes in the salivary glands, including the increase in the number of duct-like structures (DLS. However, the true origin and the phenotype of the DLS are not known. Objective To evaluate the phenotype and the cell proliferation index of the DLS of human sublingual glands. Material and Methods Sixty sublingual glands obtained from human cadavers were divided into two groups - 0-30 and 61-90 years old. The phenotype was estimated by immunostaining for cytokeratin 19 (CK 19 and the S-100 protein as well as by the presence of mucin and glycogen. The cell proliferation index was determined by the Ki-67 antibody. The histochemical techniques used periodic acid-Schiff (PAS and Alcian Blue. In each captured microscopic field, the DLS were counted to establish a percentage for the staining profile. The statistical analysis was accomplished using Student's t-test, the Mann-Whitney test and Pearson's correlation coefficient (p<0.05. Results Comparing both groups, only CK 19 showed a statistically significant difference (p=0.033, with the strongest expression in the elderly group. There was no significant difference between PAS and Alcian Blue (p=0.270. In both groups, the immunostaining for CK 19 was stronger than that for S-100 (p=0.004;p<0.001, but there was no correlation between the two immunomarkers (ρ=-0.163; p=0.315. There was no immunostaining for Ki-67. Conclusions DLS demonstrate a ductal phenotypic profile and do not present cell proliferation activity. DLS may represent a regressive process arising from acini or represent the result of metaplasia.

  2. Sublingual misoprostol versus standard surgical care for treatment of incomplete abortion in five sub-Saharan African countries

    Directory of Open Access Journals (Sweden)

    Shochet Tara

    2012-11-01

    Full Text Available Abstract Background In low-resource settings, where abortion is highly restricted and self-induced abortions are common, access to post-abortion care (PAC services, especially treatment of incomplete terminations, is a priority. Standard post-abortion care has involved surgical intervention but can be hard to access in these areas. Misoprostol provides an alternative to surgical intervention that could increase access to abortion care. We sought to gather additional evidence regarding the efficacy of 400 mcg of sublingual misoprostol vs. standard surgical care for treatment of incomplete abortion in the environments where need for economical non-surgical treatments may be most useful. Methods A total of 860 women received either sublingual misoprostol or standard surgical care for treatment of incomplete abortion in a multi-site randomized trial. Women with confirmed incomplete abortion, defined as past or present history of vaginal bleeding during pregnancy and an open cervical os, were eligible to participate. Participants returned for follow-up one week later to confirm clinical status. If abortion was incomplete at that time, women were offered an additional follow-up visit or immediate surgical evacuation. Results Both misoprostol and surgical evacuation are highly effective treatments for incomplete abortion (misoprostol: 94.4%, surgical: 100.0%. Misoprostol treatment resulted in a somewhat lower chance of success than standard surgical practice (RR = 0.90; 95% CI: 0.89-0.92. Both tolerability of side effects and women’s satisfaction were similar in the two study arms. Conclusion Misoprostol, much easier to provide than surgery in low-resource environments, can be used safely, successfully, and satisfactorily for treatment of incomplete abortion. Focus should shift to program implementation, including task-shifting the provision of post-abortion care to mid- and low- level providers, training and assurance of drug availability. Trial

  3. Sublingual immunization with the phosphate-binding-protein (PstS) reduces oral colonization by Streptococcus mutans.

    Science.gov (United States)

    Ferreira, E L; Batista, M T; Cavalcante, R C M; Pegos, V R; Passos, H M; Silva, D A; Balan, A; Ferreira, L C S; Ferreira, R C C

    2016-10-01

    Bacterial ATP-binding cassette (ABC) transporters play a crucial role in the physiology and pathogenicity of different bacterial species. Components of ABC transporters have also been tested as target antigens for the development of vaccines against different bacterial species, such as those belonging to the Streptococcus genus. Streptococcus mutans is the etiological agent of dental caries, and previous studies have demonstrated that deletion of the gene encoding PstS, the substrate-binding component of the phosphate uptake system (Pst), reduced the adherence of the bacteria to abiotic surfaces. In the current study, we generated a recombinant form of the S. mutans PstS protein (rPstS) with preserved structural features, and we evaluated the induction of antibody responses in mice after sublingual mucosal immunization with a formulation containing the recombinant protein and an adjuvant derived from the heat-labile toxin from enterotoxigenic Escherichia coli strains. Mice immunized with rPstS exhibited systemic and secreted antibody responses, measured by the number of immunoglobulin A-secreting cells in draining lymph nodes. Serum antibodies raised in mice immunized with rPstS interfered with the adhesion of bacteria to the oral cavity of naive mice challenged with S. mutans. Similarly, mice actively immunized with rPstS were partially protected from oral colonization after challenge with the S. mutans NG8 strain. Therefore, our results indicate that S. mutans PstS is a potential target antigen capable of inducing specific and protective antibody responses after sublingual administration. Overall, these observations raise interesting perspectives for the development of vaccines to prevent dental caries. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  4. Pharmacokinetics and safety of fentanyl sublingual spray and fentanyl citrate intravenous: a multiple ascending dose study in opioid-naïve healthy volunteers.

    Science.gov (United States)

    Rauck, Richard L; Oh, D Alexander; Singla, Neil; Koch, Christian; Parikh, Neha; Nalamachu, Srinivas; Wilson, Daniel; Yu, Jin; Vetticaden, Santosh

    2017-11-01

    Fentanyl sublingual spray, with its rapid onset for pain relief, may be efficacious in the management of acute or post-operative pain. Because patients in these settings may be opioid-naïve, the study was conducted to determine the safety, tolerability, and pharmacokinetics of multiple dose administration of fentanyl sublingual spray in an opioid-naïve population. Fentanyl sublingual spray (100 mcg, 200 mcg, and 400 mcg) and fentanyl citrate intravenous (IV; 50 mcg) were administered every 0.5, 1.0, 2.0, and 4.0 h for up to three doses per cohort in opioid-naïve subjects (ClinicalTrials.gov identifier: NCT02641340). Eight subjects in each cohort were randomly assigned (six subjects received fentanyl sublingual spray; two subjects received fentanyl citrate IV). Pharmacokinetic and safety-related pharmacodynamic assessments were performed through 24 h post-first dose. Safety assessments were collected through Day 7. Ninety-six opioid-naïve subjects, aged 20-55 years, with a body mass index of 18.7-31.5 kg/m 2 , participated in the study. Multiple doses of fentanyl sublingual spray (100, 200, and 400 mcg) were generally well tolerated. Hypoxia, observed in the 200-mcg and 400-mcg dose groups, increased with increasing doses and higher dosing frequency, but was readily managed by nasal cannula oxygenation. Overall, nausea increased with increasing doses, and ∼52.6% (10 out of 19) cases of nausea that occurred at the highest dose of 400 mcg were treated with concomitant medication. Overall, the reported adverse events were consistent with the known safety profile of fentanyl. Fentanyl sublingual spray (100 mcg, 200 mg, and 400 mcg) administered every 0.5, 1, 2, and 4 h was generally well tolerated in an opioid-naïve population. The results suggest that doses of 200 mcg or lower may be safe for use in an opioid-naïve population.

  5. Hydrogen production from the monomeric sugars hydrolyzed from hemicellulose by Enterobacter aerogenes

    Energy Technology Data Exchange (ETDEWEB)

    Ren, Yunli; Wang, Jianji; Liu, Zhen; Ren, Yunlai; Li, Guozhi [School of Chemical Engineering and Pharmaceutics, Henan University of Science and Technology, Luoyang 471039, Henan (China)

    2009-12-15

    Relatively large percentages of xylose with glucose, arabinose, mannose, galactose and rhamnose constitute the hydrolysis products of hemicellulose. In this paper, hydrogen production performance of facultative anaerobe (Enterobacter aerogenes) has been investigated from these different monomeric sugars except glucose. It was shown that the stereoisomers of mannose and galactose were more effective for hydrogen production than those of xylose and arabinose. The substrate of 5 g/l xylose resulted in a relative high level of hydrogen yield (73.8 mmol/l), hydrogen production efficiency (2.2 mol/mol) and a maximum hydrogen production rate (249 ml/l/h). The hydrogen yield, hydrogen production efficiency and the maximum hydrogen production rate reached 104 mmol/l, 2.35 mol/mol and 290 ml/l/h, respectively, on a substrate of 10 g/l galactose. The hydrogen yields and the maximum hydrogen production rates increased with an increase of mannose concentrations and reached 119 mmol/l and 518 ml/l/h on the culture of 25 g/l mannose. However, rhamnose was a relative poor carbon resource for E. aerogenes to produce hydrogen, from which the hydrogen yield and hydrogen production efficiency were about one half of that from the mannose substrate. E. aerogenes was found to be a promising strain for hydrogen production from hydrolysis products of hemicellulose. (author)

  6. Action of Monomeric/Gemini Surfactants on Free Cells and Biofilm of Asaia lannensis

    Directory of Open Access Journals (Sweden)

    Anna Koziróg

    2017-11-01

    Full Text Available We investigated the biological activity of surfactants based on quaternary ammonium compounds: gemini surfactant hexamethylene-1,6-bis-(N,N-dimethyl-N-dodecylammonium bromide (C6, synthesized by the reaction of N,N-dimethyl-N-dodecylamine with 1,6-dibromohexane, and its monomeric analogue dodecyltrimethylammonium bromide (DTAB. The experiments were performed with bacteria Asaia lannensis, a common spoilage in the beverage industry. The minimal inhibitory concentration (MIC values were determined using the tube standard two-fold dilution method. The growth and adhesive properties of bacterial cells were studied in different culture media, and the cell viability was evaluated using plate count method. Both of the surfactants were effective against the bacterial strain, but the MIC of gemini compound was significantly lower. Both C6 and DTAB exhibited anti-adhesive abilities. Treatment with surfactants at or below MIC value decreased the number of bacterial cells that were able to form biofilm, however, the gemini surfactant was more effective. The used surfactants were also found to be able to eradicate mature biofilms. After 4 h of treatment with C6 surfactant at concentration 10 MIC, the number of bacterial cells was reduced by 91.8%. The results of this study suggest that the antibacterial activity of the gemini compound could make it an effective microbiocide against the spoilage bacteria Asaia sp. in both planktonic and biofilm stages.

  7. Action of Monomeric/Gemini Surfactants on Free Cells and Biofilm of Asaia lannensis.

    Science.gov (United States)

    Koziróg, Anna; Kręgiel, Dorota; Brycki, Bogumił

    2017-11-22

    We investigated the biological activity of surfactants based on quaternary ammonium compounds: gemini surfactant hexamethylene-1,6-bis-( N,N -dimethyl- N -dodecylammonium bromide) (C6), synthesized by the reaction of N,N -dimethyl- N- dodecylamine with 1,6-dibromohexane, and its monomeric analogue dodecyltrimethylammonium bromide (DTAB). The experiments were performed with bacteria Asaia lannensis , a common spoilage in the beverage industry. The minimal inhibitory concentration (MIC) values were determined using the tube standard two-fold dilution method. The growth and adhesive properties of bacterial cells were studied in different culture media, and the cell viability was evaluated using plate count method. Both of the surfactants were effective against the bacterial strain, but the MIC of gemini compound was significantly lower. Both C6 and DTAB exhibited anti-adhesive abilities. Treatment with surfactants at or below MIC value decreased the number of bacterial cells that were able to form biofilm, however, the gemini surfactant was more effective. The used surfactants were also found to be able to eradicate mature biofilms. After 4 h of treatment with C6 surfactant at concentration 10 MIC, the number of bacterial cells was reduced by 91.8%. The results of this study suggest that the antibacterial activity of the gemini compound could make it an effective microbiocide against the spoilage bacteria Asaia sp. in both planktonic and biofilm stages.

  8. Model of a DNA-protein complex of the architectural monomeric protein MC1 from Euryarchaea.

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    Françoise Paquet

    Full Text Available In Archaea the two major modes of DNA packaging are wrapping by histone proteins or bending by architectural non-histone proteins. To supplement our knowledge about the binding mode of the different DNA-bending proteins observed across the three domains of life, we present here the first model of a complex in which the monomeric Methanogen Chromosomal protein 1 (MC1 from Euryarchaea binds to the concave side of a strongly bent DNA. In laboratory growth conditions MC1 is the most abundant architectural protein present in Methanosarcina thermophila CHTI55. Like most proteins that strongly bend DNA, MC1 is known to bind in the minor groove. Interaction areas for MC1 and DNA were mapped by Nuclear Magnetic Resonance (NMR data. The polarity of protein binding was determined using paramagnetic probes attached to the DNA. The first structural model of the DNA-MC1 complex we propose here was obtained by two complementary docking approaches and is in good agreement with the experimental data previously provided by electron microscopy and biochemistry. Residues essential to DNA-binding and -bending were highlighted and confirmed by site-directed mutagenesis. It was found that the Arg25 side-chain was essential to neutralize the negative charge of two phosphates that come very close in response to a dramatic curvature of the DNA.

  9. Modulation of basophils' degranulation and allergy-related enzymes by monomeric and dimeric naphthoquinones.

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    Brígida R Pinho

    Full Text Available Allergic disorders are characterized by an abnormal immune response towards non-infectious substances, being associated with life quality reduction and potential life-threatening reactions. The increasing prevalence of allergic disorders demands for new and effective anti-allergic treatments. Here we test the anti-allergic potential of monomeric (juglone, menadione, naphthazarin, plumbagin and dimeric (diospyrin and diosquinone naphthoquinones. Inhibition of RBL-2H3 rat basophils' degranulation by naphthoquinones was assessed using two complementary stimuli: IgE/antigen and calcium ionophore A23187. Additionally, we tested for the inhibition of leukotrienes production in IgE/antigen-stimulated cells, and studied hyaluronidase and lipoxidase inhibition by naphthoquinones in cell-free assays. Naphthazarin (0.1 µM decreased degranulation induced by IgE/antigen but not A23187, suggesting a mechanism upstream of the calcium increase, unlike diospyrin (10 µM that reduced degranulation in A23187-stimulated cells. Naphthoquinones were weak hyaluronidase inhibitors, but all inhibited soybean lipoxidase with the most lipophilic diospyrin, diosquinone and menadione being the most potent, thus suggesting a mechanism of competition with natural lipophilic substrates. Menadione was the only naphthoquinone reducing leukotriene C4 production, with a maximal effect at 5 µM. This work expands the current knowledge on the biological properties of naphthoquinones, highlighting naphthazarin, diospyrin and menadione as potential lead compounds for structural modification in the process of improving and developing novel anti-allergic drugs.

  10. Characterization of monomeric DNA-binding protein Histone H1 in Leishmania braziliensis.

    Science.gov (United States)

    Carmelo, Emma; González, Gloria; Cruz, Teresa; Osuna, Antonio; Hernández, Mariano; Valladares, Basilio

    2011-08-01

    Histone H1 in Leishmania presents relevant differences compared to higher eukaryote counterparts, such as the lack of a DNA-binding central globular domain. Despite that, it is apparently fully functional since its differential expression levels have been related to changes in chromatin condensation and infectivity, among other features. The localization and the aggregation state of L. braziliensis H1 has been determined by immunolocalization, mass spectrometry, cross-linking and electrophoretic mobility shift assays. Analysis of H1 sequences from the Leishmania Genome Database revealed that our protein is included in a very divergent group of histones H1 that is present only in L. braziliensis. An antibody raised against recombinant L. braziliensis H1 recognized specifically that protein by immunoblot in L. braziliensis extracts, but not in other Leishmania species, a consequence of the sequence divergences observed among Leishmania species. Mass spectrometry analysis and in vitro DNA-binding experiments have also proven that L. braziliensis H1 is monomeric in solution, but oligomerizes upon binding to DNA. Finally, despite the lack of a globular domain, L. braziliensis H1 is able to form complexes with DNA in vitro, with higher affinity for supercoiled compared to linear DNA.

  11. Comparison of monomeric and polymeric horseradish peroxidase as labels in competitive ELISA for small molecule detection

    International Nuclear Information System (INIS)

    Li, Dongyang; Ying, Yibin; Wu, Jian; Niessner, Reinhard; Knopp, Dietmar

    2013-01-01

    We have developed a simple and sensitive competitive enzyme-linked immunosorbent assay (ELISA) to determine aflatoxin B1 (as a model small analyte) and using streptavidin-polymeric horseradish peroxidase complex (SApolyHRP) as a label for signal amplification. The performance of the assay was evaluated by comparing it with the classical indirect competitive ELISA using HRP labeled anti-mouse IgG as the tracer antibody. The results indicate that the SApolyHRP-based competitive ELISA exhibits a typically 2.4-fold steeper slope of the linear working range of the calibration curve compared to the monomeric HRP based classical ELISA, i.e., the sensitivity was increased. The SApolyHRP conjugate causes a typically 19-fold stronger signal generation in comparison to the traditional HRP labeled anti-mouse IgG at the same concentration (25 ng mL −1 ). Moreover, the SApolyHRP-based assay has a much wider linear range and a 3.8-fold better signal-to-noise ratio. Considering its simplicity, sensitivity and ease of operation, this competitive ELISA is considered to be a promising tool for small molecule immuno detection. (author)

  12. Lipoamino acid-based micelles as promising delivery vehicles for monomeric amphotericin B.

    Science.gov (United States)

    Serafim, Cláudia; Ferreira, Inês; Rijo, Patrícia; Pinheiro, Lídia; Faustino, Célia; Calado, António; Garcia-Rio, Luis

    2016-01-30

    Lipoamino acid-based micelles have been developed as delivery vehicles for the hydrophobic drug amphotericin B (AmB). The micellar solubilisation of AmB by a gemini lipoamino acid (LAA) derived from cysteine and its equimolar mixtures with the bile salts sodium cholate (NaC) and sodium deoxycholate (NaDC), as well as the aggregation sate of the drug in the micellar systems, was studied under biomimetic conditions (phosphate buffered-saline, pH 7.4) using UV-vis spectroscopy. Pure surfactant systems and equimolar mixtures were characterized by tensiometry and important parameters were determined, such as critical micelle concentration (CMC), surface tension at the CMC (γCMC), maximum surface excess concentration (Γmax), and minimum area occupied per molecule at the water/air interface (Amin). Rheological behaviour from viscosity measurements at different shear rates was also addressed. Solubilisation capacity was quantified in terms of molar solubilisation ratio (χ), micelle-water partition coefficient (KM) and Gibbs energy of solubilisation (ΔGs°). Formulations of AmB in micellar media were compared in terms of drug loading, encapsulation efficiency, aggregation state of AmB and in vitro antifungal activity against Candida albicans. The LAA-containing micellar systems solubilise AmB in its monomeric and less toxic form and exhibit in vitro antifungal activity comparable to that of the commercial formulation Fungizone. Copyright © 2015 Elsevier B.V. All rights reserved.

  13. Sulfatide promotes the folding of proinsulin, preserves insulin crystals, and mediates its monomerization.

    Science.gov (United States)

    Osterbye, T; Jørgensen, K H; Fredman, P; Tranum-Jensen, J; Kaas, A; Brange, J; Whittingham, J L; Buschard, K

    2001-06-01

    Sulfatide is a glycolipid that has been associated with insulin-dependent diabetes mellitus. It is present in the islets of Langerhans and follows the same intracellular route as insulin. However, the role of sulfatide in the beta cell has been unclear. Here we present evidence suggesting that sulfatide promotes the folding of reduced proinsulin, indicating that sulfatide possesses molecular chaperone activity. Sulfatide associates with insulin by binding to the insulin domain A8--A10 and most likely by interacting with the hydrophobic side chains of the dimer-forming part of the insulin B-chain. Sulfatide has a dual effect on insulin. It substantially reduces deterioration of insulin hexamer crystals at pH 5.5, conferring stability comparable to those in beta cell granules. Sulfatide also mediates the conversion of insulin hexamers to the biological active monomers at neutral pH, the pH at the beta-cell surface. Finally, we report that inhibition of sulfatide synthesis with chloroquine and fumonisine B1 leads to inhibition of insulin granule formation in vivo. Our observations suggest that sulfatide plays a key role in the folding of proinsulin, in the maintenance of insulin structure, and in the monomerization process.

  14. Comparison of excretory urographic contrast effects of dimeric and monomeric non-ionic iodinated contrast media in dogs

    International Nuclear Information System (INIS)

    Kishimoto, M.; Yamada, K.; Watanabe, A.; Miyamoto, K.; Iwasaki, T.; Miyake, Y.

    2007-01-01

    In excretory urography, the osmolarity of contrast media has rarely been treated as important in veterinary medicine. In this study, the contrast effect of two contrast media (monomeric iohexol and dimeric iodixanol) in the renal cortex and aorta were compared using computed tomography (CT). Five beagle dogs were used and the study employed a cross-over method for each contrast media. The results showed that there was no difference between the media in the aorta, but iodixanol showed higher CT value and a longer contrast effect than iohexol in the renal cortex, in spite of having the same iodine dosage. It is believed that iodixanol, with its low osmolarity, is diluted less by osmotic diuresis than monomeric iohexol. It is important to consider the osmolarity of the contrast media when evaluating the contrast effect, and it is essential to use the same contrast media for each examination, or the renal excretory speed will be under/overestimated

  15. The effect of X-ray irradiation on the function and saliva composition of rat parotid and submandibular/sublingual glands

    International Nuclear Information System (INIS)

    Hashida, Tatsuo; Kamemoto, Hiromasa; Fuchihata, Hajime; Ooshima, Takashi

    1999-01-01

    Radiation therapy to the head and neck area frequently causes severe salivary gland dysfunction and xerostomia. Morphological studies of irradiated salivary glands have suggested that the submandibular/sublingual gland may be less radiosensitive than the parotid gland. The purpose of this study was to evaluate the effect of radiation on major salivary gland functions in rats with radiation-induced xerostomia. The effect of salivary gland irradiation on salivary function was examined in specific pathogen-free Sprague-Dawley rats. The animals were irradiated with a single exposure of either 22 Gy or 32 Gy. Stimulated saliva excretion time was measured for the parotid and submandibular/sublingual glands, and the total protein in saliva was analysed. Our results showed that the saliva flow rate and protein concentration of parotid saliva were significantly reduced in the 32 Gy-irradiated rats. (author)

  16. Metal-free ALS variants of dimeric human Cu,Zn-superoxide dismutase have enhanced populations of monomeric species.

    Directory of Open Access Journals (Sweden)

    Anna-Karin E Svensson

    2010-04-01

    Full Text Available Amino acid replacements at dozens of positions in the dimeric protein human, Cu,Zn superoxide dismutase (SOD1 can cause amyotrophic lateral sclerosis (ALS. Although it has long been hypothesized that these mutations might enhance the populations of marginally-stable aggregation-prone species responsible for cellular toxicity, there has been little quantitative evidence to support this notion. Perturbations of the folding free energy landscapes of metal-free versions of five ALS-inducing variants, A4V, L38V, G93A, L106V and S134N SOD1, were determined with a global analysis of kinetic and thermodynamic folding data for dimeric and stable monomeric versions of these variants. Utilizing this global analysis approach, the perturbations on the global stability in response to mutation can be partitioned between the monomer folding and association steps, and the effects of mutation on the populations of the folded and unfolded monomeric states can be determined. The 2- to 10-fold increase in the population of the folded monomeric state for A4V, L38V and L106V and the 80- to 480-fold increase in the population of the unfolded monomeric states for all but S134N would dramatically increase their propensity for aggregation through high-order nucleation reactions. The wild-type-like populations of these states for the metal-binding region S134N variant suggest that even wild-type SOD1 may also be prone to aggregation in the absence of metals.

  17. Neurodevelopmental Expression Profile of Dimeric and Monomeric Group 1 mGluRs: Relevance to Schizophrenia Pathogenesis and Treatment.

    Science.gov (United States)

    Lum, Jeremy S; Fernandez, Francesca; Matosin, Natalie; Andrews, Jessica L; Huang, Xu-Feng; Ooi, Lezanne; Newell, Kelly A

    2016-10-10

    Group 1 metabotropic glutamate receptors (mGluR1/mGluR5) play an integral role in neurodevelopment and are implicated in psychiatric disorders, such as schizophrenia. mGluR1 and mGluR5 are expressed as homodimers, which is important for their functionality and pharmacology. We examined the protein expression of dimeric and monomeric mGluR1α and mGluR5 in the prefrontal cortex (PFC) and hippocampus throughout development (juvenile/adolescence/adulthood) and in the perinatal phencyclidine (PCP) model of schizophrenia. Under control conditions, mGluR1α dimer expression increased between juvenile and adolescence (209-328%), while monomeric levels remained consistent. Dimeric mGluR5 was steadily expressed across all time points; monomeric mGluR5 was present in juveniles, dramatically declining at adolescence and adulthood (-97-99%). The mGluR regulators, Homer 1b/c and Norbin, significantly increased with age in the PFC and hippocampus. Perinatal PCP treatment significantly increased juvenile dimeric mGluR5 levels in the PFC and hippocampus (37-50%) but decreased hippocampal mGluR1α (-50-56%). Perinatal PCP treatment also reduced mGluR1α dimer levels in the PFC at adulthood (-31%). These results suggest that Group 1 mGluRs have distinct dimeric and monomeric neurodevelopmental patterns, which may impact their pharmacological profiles at specific ages. Perinatal PCP treatment disrupted the early expression of Group 1 mGluRs which may underlie neurodevelopmental alterations observed in this model.

  18. Formulation and Characterization of Fast-Dissolving Sublingual Film of Iloperidone Using Box-Behnken Design for Enhancement of Oral Bioavailability.

    Science.gov (United States)

    Londhe, Vaishali; Shirsat, Rucha

    2018-04-01

    Iloperidone is a second-generation antipsychotic drug which is used for the treatment of schizophrenia and has very low aqueous solubility and bioavailability. This drug also undergoes first-pass metabolism. The aim of this work is to formulate fast-dissolving sublingual films of iloperidone to improve its bioavailability. Sublingual films were prepared by solvent casting method. Hydroxypropyl methyl cellulose E5, propylene glycol 400, and transcutol HP were optimized using Box-Behnken three-level statistical design on the basis of disintegration time and folding endurance of films. Iloperidone:hydroxypropyl-β-cyclodextrin kneaded complex was used in films instead of plain drug due to its low solubility. Optimized film was further evaluated for drug content, pH, dissolution studies, ex vivo permeation studies, and pharmacokinetic studies in rats. The optimized film disintegrated within 30 s. The in vitro dissolution of the film showed 80.3 ± 3.4% drug dissolved within first 5 min. In ex vivo permeation studies using sublingual tissue, flux achieved within first 15 min by film was around 117.1 ± 0.35 (mcg/cm 2 /h) which was ten times more than that of plain drug. This formulation showed excellent uniformity. AUC and C max of film were significantly higher (p films was 148% when compared to the plain drug. Thus, this study showed optimized fast-dissolving sublingual film to improve permeation and bioavailability of iloperidone. Fast-dissolving films will be customer-friendly approach for geadiatric schizophrenic patients.

  19. Discovery of Radioiodinated Monomeric Anthraquinones as a Novel Class of Necrosis Avid Agents for Early Imaging of Necrotic Myocardium.

    Science.gov (United States)

    Wang, Qin; Yang, Shengwei; Jiang, Cuihua; Li, Jindian; Wang, Cong; Chen, Linwei; Jin, Qiaomei; Song, Shaoli; Feng, Yuanbo; Ni, Yicheng; Zhang, Jian; Yin, Zhiqi

    2016-02-16

    Assessment of myocardial viability is deemed necessary to aid in clinical decision making whether to recommend revascularization therapy for patients with myocardial infarction (MI). Dianthraquinones such as hypericin (Hyp) selectively accumulate in necrotic myocardium, but were unsuitable for early imaging after administration to assess myocardial viability. Since dianthraquinones can be composed by coupling two molecules of monomeric anthraquinone and the active center can be found by splitting chemical structure, we propose that monomeric anthraquinones may be effective functional groups for necrosis targetability. In this study, eight radioiodinated monomeric anthraquinones were evaluated as novel necrosis avid agents (NAAs) for imaging of necrotic myocardium. All (131)I-anthraquinones showed high affinity to necrotic tissues and (131)I-rhein emerged as the most promising compound. Infarcts were visualized on SPECT/CT images at 6 h after injection of (131)I-rhein, which was earlier than that with (131)I-Hyp. Moreover, (131)I-rhein showed satisfactory heart-to-blood, heart-to-liver and heart-to-lung ratios for obtaining images of good diagnostic quality. (131)I-rhein was a more promising "hot spot imaging" tracer for earlier visualization of necrotic myocardium than (131)I-Hyp, which supported further development of radiopharmaceuticals based on rhein for SPECT/CT ((123)I and (99m)Tc) or PET/CT imaging ((18)F and (124)I) of myocardial necrosis.

  20. MONOMERIC ß-AMYLOID INTERACTS WITH TYPE-1 INSULIN-LIKE GROWTH FACTOR RECEPTORS TO PROVIDE ENERGY SUPPLY TO NEURONS

    Directory of Open Access Journals (Sweden)

    Maria Laura eGiuffrida

    2015-08-01

    Full Text Available ß-amyloid (Aß1-42 is produced by proteolytic cleavage of the transmembrane type-1 protein, amyloid precursor protein. Under pathological conditions, Aß1-42 self-aggregates into oligomers, which cause synaptic dysfunction and neuronal loss, and are considered the culprit of Alzheimer’s disease (AD. However, Aß1-42 is mainly monomeric at physiological concentrations, and the precise role of monomeric Aß1-42 in neuronal function is largely unknown. We report that the monomer of Aß1-42 activates type-1 insulin-like growth factor receptors and enhances glucose uptake in neurons and peripheral cells by promoting the translocation of the Glut3 glucose transporter from the cytosol to the plasma membrane. In neurons, activity-dependent glucose uptake was blunted after blocking endogenous Aß production, and re-established in the presence of cerebrospinal fluid Aß. APP-null neurons failed to enhance depolarization-stimulated glucose uptake unless exogenous monomeric Aß1-42 was added. These data suggest that Aß1-42 monomers were critical for maintaining neuronal glucose homeostasis. Accordingly, exogenous Aß1-42 monomers were able to rescue the low levels of glucose consumption observed in brain slices from AD mutant mice.

  1. A Case of Sublingual Ranula That Responded Successfully to Localized Injection Treatment with OK-432 after Healing from Drug Induced Hypersensitivity Syndrome

    Directory of Open Access Journals (Sweden)

    Kunio Yoshizawa

    2016-01-01

    Full Text Available A ranula is a mucus retention cyst or pseudocyst caused by leakage of mucus from the sublingual gland and generally occurs in the oral floor. In addition, drug induced hypersensitivity syndrome (DIHS is a rare but well-recognized serious adverse effect characterized by fever, skin rashes, generalized lymphadenopathy, hepatitis, and hepatosplenomegaly and oral stomatitis. This paper presents the first case of successfully treated sublingual ranula with localized injection of OK-432 after healing from drug induced hypersensitivity syndrome, which has previously been unreported in the literature. We present the case of a 38-year-old Japanese woman with sublingual ranula that responded successfully to localized injection treatment with OK-432 after healing from drug induced hypersensitivity syndrome. She was affected with cutaneous myositis and interstitial lung disease when she was 26 years old. At the age 34 years, she received additional oral treatment of diaminodiphenyl-sulfone due to deterioration of the cutaneous myositis, which resulted in drug induced hypersensitivity syndrome (DIHS with severe oral stomatitis. Local injection of OK-432 to the ranula may be a very safe and useful treatment method even if the patient has a history of drug allergy and has connective tissue disease such as cutaneous myositis.

  2. Transdermal buprenorphine, opioid rotation to sublingual buprenorphine, and the avoidance of precipitated withdrawal: a review of the literature and demonstration in three chronic pain patients treated with butrans.

    Science.gov (United States)

    Kornfeld, Howard; Reetz, Heidi

    2015-01-01

    Buprenorphine is an opioid, used in the United States and abroad for both analgesia and addiction, with unique opioid receptor binding properties. There are several pharmacological features of buprenorphine that make it an emerging option for the long-term treatment of chronic pain-its respiratory suppression ceiling effect, its efficacy in neuropathic pain and hyperalgesic states, and its decreased suppression of the immune and endocrine systems compared with other long-acting opioids. Previous studies have shown that high-dose sublingual buprenorphine is an effective treatment of chronic pain patients not responding to other opioids. Guidelines for the introduction of sublingual buprenorphine, termed buprenorphine induction, include an opioid-free "withdrawal" period of 12-48 hours to avoid an anticipated and accelerated opioid withdrawal, a syndrome described in this article as precipitated withdrawal. The requirement of a period of opioid abstinence before buprenorphine use may present a significant barrier to its adoption for chronic pain. We present a case series of a novel method of sublingual buprenorphine introduction without an induction period, using the recently Food and Drug Administration-approved low-dose transdermal buprenorphine (Butrans; Purdue Pharma L.P.) as a bridge medication. In these cases, buprenorphine was started in opioid-dependent chronic noncancer pain patients who had taken short-acting opioid medications within hours of the initiation of the rotation. This method avoids the painful abstinence period and did not result in precipitated withdrawal or other significant adverse effects.

  3. Development and Characterization of an Amorphous Solid Dispersion of Furosemide in the Form of a Sublingual Bioadhesive Film to Enhance Bioavailability.

    Science.gov (United States)

    De Caro, Viviana; Ajovalasit, Alessia; Sutera, Flavia Maria; Murgia, Denise; Sabatino, Maria Antonietta; Dispenza, Clelia

    2017-06-24

    Administered by an oral route, Furosemide (FUR), a diuretic used in several edematous states and hypertension, presents bioavailability problems, reported as a consequence of an erratic gastrointestinal absorption due to various existing polymorphic forms and low and pH-dependent solubility. A mucoadhesive sublingual fast-dissolving FUR based film has been developed and evaluated in order to optimize the bioavailability of FUR by increasing solubility and guaranteeing a good dissolution reproducibility. The Differential Scanning Calorimetry (DSC) analyses confirmed that the film prepared using the solvent casting method entrapped FUR in the amorphous state. As a solid dispersion, FUR increases its solubility up to 28.36 mg/mL. Drug content, thickness, and weight uniformity of film were also evaluated. The measured Young's Modulus, yield strength, and relative elongation of break percentage (EB%) allowed for the classification of the drug-loaded film as an elastomer. Mucoadhesive strength tests showed that the force to detach film from mucosa grew exponentially with increasing contact time up to 7667 N/m². FUR was quickly discharged from the film following a trend well fitted with the Weibull kinetic model. When applied on sublingual mucosa, the new formulation produced a massive drug flux in the systemic compartment. Overall, the proposed sublingual film enhances drug solubility and absorption, allowing for the prediction of a rapid onset of action and reproducible bioavailability in its clinical application.

  4. Structural Analysis of Monomeric RNA-Dependent Polymerases: Evolutionary and Therapeutic Implications.

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    Rodrigo Jácome

    Full Text Available The crystal structures of monomeric RNA-dependent RNA polymerases and reverse transcriptases of more than 20 different viruses are available in the Protein Data Bank. They all share the characteristic right-hand shape of DNA- and RNA polymerases formed by the fingers, palm and thumb subdomains, and, in many cases, "fingertips" that extend from the fingers towards the thumb subdomain, giving the viral enzyme a closed right-hand appearance. Six conserved structural motifs that contain key residues for the proper functioning of the enzyme have been identified in all these RNA-dependent polymerases. These enzymes share a two divalent metal-ion mechanism of polymerization in which two conserved aspartate residues coordinate the interactions with the metal ions to catalyze the nucleotidyl transfer reaction. The recent availability of crystal structures of polymerases of the Orthomyxoviridae and Bunyaviridae families allowed us to make pairwise comparisons of the tertiary structures of polymerases belonging to the four main RNA viral groups, which has led to a phylogenetic tree in which single-stranded negative RNA viral polymerases have been included for the first time. This has also allowed us to use a homology-based structural prediction approach to develop a general three-dimensional model of the Ebola virus RNA-dependent RNA polymerase. Our model includes several of the conserved structural motifs and residues described in other viral RNA-dependent RNA polymerases that define the catalytic and highly conserved palm subdomain, as well as portions of the fingers and thumb subdomains. The results presented here help to understand the current use and apparent success of antivirals, i.e. Brincidofovir, Lamivudine and Favipiravir, originally aimed at other types of polymerases, to counteract the Ebola virus infection.

  5. Monomeric adiponectin increases cell viability in porcine aortic endothelial cells cultured in normal and high glucose conditions: Data on kinases activation

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    Elena Grossini

    2016-09-01

    Full Text Available We found that monomeric adiponectin was able to increase cell viability in porcine aortic endothelial cells (PAE cultured both in normal and high glucose condition. Moreover, in normal glucose condition monomeric adiponectin increased p38MAPK, Akt, ERK1/2 and eNOS phosphorylation in a dose- and time-dependent way. Also in high glucose condition monomeric adiponectin increased eNOS and above kinases phosphorylation with similar patterns but at lower extent. For interpretation of the data presented in this article, please see the research article “Monomeric adiponectin modulates nitric oxide release and calcium movements in porcine aortic endothelial cells in normal/high glucose conditions” (Grossini et al., in press [1].

  6. Fermentation of Arabinoxylan-Oligosaccharides, Oligofructose and their Monomeric Sugars by Hindgut Bacteria from Siberian Sturgeon and African Catfish in Batch Culture in vitro

    NARCIS (Netherlands)

    Geraylou, Z.; Rurangwa, E.; Wiele, van der T.; Courtin, C.M.; Delcour, J.A.; Buyse, J.; Ollevier, F.

    2014-01-01

    The in vitro fermentation of two Non-Digestible Oligosaccharide (NDO) preparations, Arabinoxylan- Oligosaccharides (AXOS) and Oligofructose (OF), and their respective monomeric sugars, xylose and fructose, were investigated by hindgut microbiota of two major aquaculture fish species, Siberian

  7. Role of Combining Peripheral with Sublingual Perfusion on Evaluating Microcirculation and Predicting Prognosis in Patients with Septic Shock.

    Science.gov (United States)

    Pan, Pan; Liu, Da-Wei; Su, Long-Xiang; He, Huai-Wu; Wang, Xiao-Ting; Yu, Chao

    2018-05-20

    Measurement of general microcirculation remains difficult in septic shock patients. The peripheral perfusion index (PI) and sublingual microcirculation monitoring are thought to be possible methods. This study was performed to determine whether assessing microcirculation by PI and a new parameter, proportion of perfusion vessel change rate (△PPV) from sublingual microcirculation monitoring, can be associated with patients' outcome. A prospective observational study was carried out, including 74 patients with septic shock in a mixed intensive care unit. Systemic hemodynamic variables were obtained at T0 and 6 h after (T6). PI and sublingual microcirculation indicators were obtained using a bedside monitor and a sidestream dark-field device, respectively. The t-test, analysis of variance, Mann-Whitney U-test, Kruskal-Wallis test, receiver operating characteristic curve analysis with the Hanley-McNeil test, survival curves using the Kaplan-Meier method, and the log-rank (Mantel-Cox) test were used to statistical analysis. Systemic hemodynamics and microcirculation data were obtained and analyzed. Patients were divided into two groups based on whether the first 6 h lactate clearance (LC) was ≥20%; PI and △PPV were lower at T6 in the LC <20% group compared with LC ≥20% (PI: 1.52 [0.89, 1.98] vs. 0.79 [0.44, 1,81], Z = -2.514, P = 0.012; △PPV: 5.9 ± 15.2 vs. 17.9 ± 20.0, t = -2.914, P = 0.005). The cutoff values of PI and △PPV were 1.41% and 12.1%, respectively. The cutoff value of the combined indicators was 1.379 according to logistic regression. Area under the curve demonstrated 0.709 (P < 0.05), and the sensitivity and specificity of using combined indicators were 0.622 and 0.757, respectively. Based on the PI and △PPV cutoff, all the participants were divided into the following groups: (1) high PI and high △PPV group, (2) high PI and low △PPV group, (3) low PI and high △PPV group, and (4) low PI and low △PPV group. The highest Sequential

  8. Correction of vitamin D deficiency using sublingually administered vitamin D2 in a Crohn's disease patient with mal-absorption and a new ileostomy.

    Science.gov (United States)

    McCullough, Patrick; Heaney, Robert

    2017-10-01

    Vitamin D deficiency has been shown to be associated with many adverse health problems. Studies have shown that patients with Crohn's disease who have low vitamin D levels have a poorer quality of life than those with more adequate levels. It has also been shown that patients with mal-absorption problems have a difficult time achieving normal vitamin D levels in spite of aggressive supplementation, and that exposure to UVB radiation may be the most effective treatment option for these patients. We present a case in which 25-hydroxyvitamin D levels were normalized within 2 weeks in a severely vitamin D deficient patient with Crohn's disease with mal-absorption and a new ileostomy, utilizing sublingually administered vitamin D2. A 58 year-old white female was admitted with a new ileostomy following partial bowel resection due to complications from Crohn's disease. She was found to be severely vitamin D deficient at the time of admission, with a level of 6.1ng/ml on hospital day 3. Her treatment with vitamin D was delayed for a few days. She was initially treated with 5000 units of vitamin D3 orally twice a day for 3days (days 7-10). After discussion with the patient and obtaining her consent, vitamin D3 was stopped, and she was then treated with a total of 8 doses of 50,000 units of vitamin D2 administered sublingually. She was given the first 3 doses on alternating days (days 11, 13, 15), and then 5 more doses on consecutive days (days 17-21). The rise in her 25-hydroxyvitamin D level in response to treatment with sublingual vitamin D2 was significant. On day 10, after receiving 3days of orally administered vitamin D3, her level was 9.8ng/ml. One week later, after receiving 3 sublingual doses of vitamin D2, it rose to 20.3ng/ml. It was then measured on alternating days twice over the next 4days, and it rose to 45.5ng/ml, and then to 47.4ng/ml on the day of discharge to home. The major finding of this study is that sublingual administration of vitamin D2 appears to

  9. Total allowable concentrations of monomeric inorganic aluminum and hydrated aluminum silicates in drinking water.

    Science.gov (United States)

    Willhite, Calvin C; Ball, Gwendolyn L; McLellan, Clifton J

    2012-05-01

    Maximum contaminant levels are used to control potential health hazards posed by chemicals in drinking water, but no primary national or international limits for aluminum (Al) have been adopted. Given the differences in toxicological profiles, the present evaluation derives total allowable concentrations for certain water-soluble inorganic Al compounds (including chloride, hydroxide, oxide, phosphate and sulfate) and for the hydrated Al silicates (including attapulgite, bentonite/montmorillonite, illite, kaolinite) in drinking water. The chemistry, toxicology and clinical experience with Al materials are extensive and depend upon the particular physical and chemical form. In general, the water solubility of the monomeric Al materials depends on pH and their water solubility and gastrointestinal bioavailability are much greater than that of the hydrated Al silicates. Other than Al-containing antacids and buffered aspirin, food is the primary source of Al exposure for most healthy people. Systemic uptake of Al after ingestion of the monomeric salts is somewhat greater from drinking water (0.28%) than from food (0.1%). Once absorbed, Al accumulates in bone, brain, liver and kidney, with bone as the major site for Al deposition in humans. Oral Al hydroxide is used routinely to bind phosphate salts in the gut to control hyperphosphatemia in people with compromised renal function. Signs of chronic Al toxicity in the musculoskeletal system include a vitamin D-resistant osteomalacia (deranged membranous bone formation characterized by accumulation of the osteoid matrix and reduced mineralization, reduced numbers of osteoblasts and osteoclasts, decreased lamellar and osteoid bands with elevated Al concentrations) presenting as bone pain and proximal myopathy. Aluminum-induced bone disease can progress to stress fractures of the ribs, femur, vertebrae, humerus and metatarsals. Serum Al ≥100 µg/L has a 75-88% positive predictive value for Al bone disease. Chronic Al

  10. Use of the quartz crystal microbalance to determine the monomeric friction coefficient of polyimides

    Science.gov (United States)

    Bechtold, Mary M.

    1995-01-01

    When a thin film of polymer is coated on to a quartz crystal microbalance (QCM), the QCM can be used to detect the rate of increase in weight of the polymer film as the volatile penetrant diffuses into the polymer. From this rate information the diffusion coefficient of the penetrant into the polymer can be computed. Calculations requiring this diffusion coefficient lead to values which approximate the monomeric friction coefficient of the polymer. This project has been concerned with the trial of crystal oscillating circuits suitable for driving polymer coated crystals in an atmosphere of penetrant. For these studies done at room temperature, natural rubber was used as an easily applied polymer that is readily penetrated by toluene vapors, qualities anticipated with polyimides when they are tested at T(g) in the presence of toluene. Three quartz crystal oscillator circuits were tested. The simplest circuit used +/- 5 volt dc and had a transistor to transistor logic (TTL) inverter chip that provides a 180 deg phase shift via a feed back loop. This oscillator circuit was stable but would not drive the crystal when the crystal was coated with polymer and subjected to toluene vapors. Removal of a variable resistor from this circuit increased stability but did not otherwise increase performance. Another driver circuit tested contained a two stage differential input, differential output, wide band video amplifier and also contain a feed back loop. The circuit voltage could not be varied and operated at +/- 5 volts dc; this circuit was also stable but failed to oscillate the polymer coated crystal in an atmosphere saturated with toluene vapors. The third oscillator circuit was of similar construction and relied on the same video amplifier but allowed operation with variable voltage. This circuit would drive the crystal when the crystal was submerged in liquid toluene and when the crystal was coated with polymer and immersed in toluene vapors. The frequency readings

  11. Determination of degradation products and process related impurities of asenapine maleate in asenapine sublingual tablets by UPLC

    Science.gov (United States)

    Kumar, Nitin; Sangeetha, D.; Kalyanraman, L.

    2017-11-01

    For determination of process related impurities and degradation products of asenapine maleate in asenapine sublingual Tablets, a reversed phase, stability indicating UPLC method was developed. Acetonitrile, methanol and potassium dihydrogen phosphate buffer with tetra-n- butyl ammonium hydrogen sulphate as ion pair (pH 2.2; 0.01 M) at flow rate of 0.2 ml/min were used in gradient elution mode. Separation was achieved by using acquity BEH Shield RP18 column (1.7 μm, 2.1 mm×100 mm) at 35 ºC. UV detection was performed at 228 nm. Subsequently the liquid chromatography method was validated as per ICH. The drug product was exposed to the stress conditions of acid hydrolysis, base hydrolysis, water hydrolysis, oxidative, thermal, and photolytic. In oxidative stress and thermal stress significant degradation was observed. All the degradation products were well separated from analyte peak and its impurities. Stability indicating nature of the method was proved by demonstrating the peak purity of Asenapine peak in all the stressed samples. The mass balance was found >95% for all the stress conditions. Based on method validation, the method was found specific, linear, accurate, precise, rugged and robust.

  12. MxiN Differentially Regulates Monomeric and Oligomeric Species of the Shigella Type Three Secretion System ATPase Spa47.

    Science.gov (United States)

    Case, Heather B; Dickenson, Nicholas E

    2018-04-17

    Shigella rely entirely on the action of a single type three secretion system (T3SS) to support cellular invasion of colonic epithelial cells and to circumvent host immune responses. The ATPase Spa47 resides at the base of the Shigella needle-like type three secretion apparatus (T3SA), supporting protein secretion through the apparatus and providing a likely means for native virulence regulation by Shigella and a much needed target for non-antibiotic therapeutics to treat Shigella infections. Here, we show that MxiN is a differential regulator of Spa47 and that its regulatory impact is determined by the oligomeric state of the Spa47 ATPase, with which it interacts. In vitro and in vivo characterization shows that interaction of MxiN with Spa47 requires the six N-terminal residues of Spa47 that are also necessary for stable Spa47 oligomer formation and activation. This interaction with MxiN negatively influences the activity of Spa47 oligomers while upregulating the ATPase activity of monomeric Spa47. Detailed kinetic analyses of monomeric and oligomeric Spa47 in the presence and absence of MxiN uncover additional mechanistic insights into the regulation of Spa47 by MxiN, suggesting that the MxiN/Spa47 species resulting from interaction with monomeric and oligomeric Spa47 are functionally distinct and that both could be involved in Shigella T3SS regulation. Uncovering regulation of Spa47 by MxiN addresses an important gap in the current understanding of how Shigella controls T3SA activity and provides the first description of differential T3SS ATPase regulation by a native T3SS protein.

  13. Structure/function analysis of PARP-1 in oxidative and nitrosative stress-induced monomeric ADPR formation.

    Directory of Open Access Journals (Sweden)

    Ben Buelow

    2009-07-01

    Full Text Available Poly adenosine diphosphate-ribose polymerase-1 (PARP-1 is a multifunctional enzyme that is involved in two major cellular responses to oxidative and nitrosative (O/N stress: detection and response to DNA damage via formation of protein-bound poly adenosine diphosphate-ribose (PAR, and formation of the soluble 2(nd messenger monomeric adenosine diphosphate-ribose (mADPR. Previous studies have delineated specific roles for several of PARP-1's structural domains in the context of its involvement in a DNA damage response. However, little is known about the relationship between the mechanisms through which PARP-1 participates in DNA damage detection/response and those involved in the generation of monomeric ADPR. To better understand the relationship between these events, we undertook a structure/function analysis of PARP-1 via reconstitution of PARP-1 deficient DT40 cells with PARP-1 variants deficient in catalysis, DNA binding, auto-PARylation, and PARP-1's BRCT protein interaction domain. Analysis of responses of the respective reconstituted cells to a model O/N stressor indicated that PARP-1 catalytic activity, DNA binding, and auto-PARylation are required for PARP-dependent mADPR formation, but that BRCT-mediated interactions are dispensable. As the BRCT domain is required for PARP-dependent recruitment of XRCC1 to sites of DNA damage, these results suggest that DNA repair and monomeric ADPR 2(nd messenger generation are parallel mechanisms through which PARP-1 modulates cellular responses to O/N stress.

  14. A model of insulin fibrils derived from the x-ray crystal structure of a monomeric insulin (despentapeptide insulin).

    Science.gov (United States)

    Brange, J; Dodson, G G; Edwards, D J; Holden, P H; Whittingham, J L

    1997-04-01

    The crystal structure of despentapeptide insulin, a monomeric insulin, has been refined at 1.3 A spacing and subsequently used to predict and model the organization in the insulin fibril. The model makes use of the contacts in the densely packed despentapeptide insulin crystal, and takes into account other experimental evidence, including binding studies with Congo red. The dimensions of this model fibril correspond well with those measured experimentally, and the monomer-monomer contacts within the fibril are in accordance with the known physical chemistry of insulin fibrils. Using this model, it may be possible to predict mutations in insulin that might alleviate problems associated with fibril formation during insulin therapy.

  15. Creating a monomeric endonuclease TALE-I-SceI with high specificity and low genotoxicity in human cells.

    Science.gov (United States)

    Lin, Jianfei; Chen, He; Luo, Ling; Lai, Yongrong; Xie, Wei; Kee, Kehkooi

    2015-01-01

    To correct a DNA mutation in the human genome for gene therapy, homology-directed repair (HDR) needs to be specific and have the lowest off-target effects to protect the human genome from deleterious mutations. Zinc finger nucleases, transcription activator-like effector nuclease (TALEN) and CRISPR-CAS9 systems have been engineered and used extensively to recognize and modify specific DNA sequences. Although TALEN and CRISPR/CAS9 could induce high levels of HDR in human cells, their genotoxicity was significantly higher. Here, we report the creation of a monomeric endonuclease that can recognize at least 33 bp by fusing the DNA-recognizing domain of TALEN (TALE) to a re-engineered homing endonuclease I-SceI. After sequentially re-engineering I-SceI to recognize 18 bp of the human β-globin sequence, the re-engineered I-SceI induced HDR in human cells. When the re-engineered I-SceI was fused to TALE (TALE-ISVB2), the chimeric endonuclease induced the same HDR rate at the human β-globin gene locus as that induced by TALEN, but significantly reduced genotoxicity. We further demonstrated that TALE-ISVB2 specifically targeted at the β-globin sequence in human hematopoietic stem cells. Therefore, this monomeric endonuclease has the potential to be used in therapeutic gene targeting in human cells. © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.

  16. Interaction of Classical Platinum Agents with the Monomeric and Dimeric Atox1 Proteins: A Molecular Dynamics Simulation Study

    Directory of Open Access Journals (Sweden)

    Xiaolei Wang

    2013-12-01

    Full Text Available We carried out molecular dynamics simulations and free energy calculations for a series of binary and ternary models of the cisplatin, transplatin and oxaliplatin agents binding to a monomeric Atox1 protein and a dimeric Atox1 protein to investigate their interaction mechanisms. All three platinum agents could respectively combine with the monomeric Atox1 protein and the dimeric Atox1 protein to form a stable binary and ternary complex due to the covalent interaction of the platinum center with the Atox1 protein. The results suggested that the extra interaction from the oxaliplatin ligand–Atox1 protein interface increases its affinity only for the OxaliPt + Atox1 model. The binding of the oxaliplatin agent to the Atox1 protein might cause larger deformation of the protein than those of the cisplatin and transplatin agents due to the larger size of the oxaliplatin ligand. However, the extra interactions to facilitate the stabilities of the ternary CisPt + 2Atox1 and OxaliPt + 2Atox1 models come from the α1 helices and α2-β4 loops of the Atox1 protein–Atox1 protein interface due to the cis conformation of the platinum agents. The combinations of two Atox1 proteins in an asymmetric way in the three ternary models were analyzed. These investigations might provide detailed information for understanding the interaction mechanism of the platinum agents binding to the Atox1 protein in the cytoplasm.

  17. The influence of sublingual immunotherapy on several parameters of immunological response in children suffering from atopic asthma and allergic rhinitis depending on asthma features.

    Science.gov (United States)

    Ciepiela, Olga; Zawadzka-Krajewska, Anna; Kotuła, Iwona; Demkow, Urszula

    2014-01-01

    The clinical efficacy of sublingual immunotherapy (SLIT) has already been proven and is known to be high. Its influence on the immunological system of patients suffering from bronchial asthma was also examined. However, it is still unclear how the polysensitisation, coexistence of other atopic disease and asthma treatment step influence the response to treatment with specific immunotherapy. Herein we evaluate the impact of one-year SLIT on selected markers of immunological response depending on different individual and clinical factors of children suffering from atopic asthma and allergic rhinitis. Twenty-five patients aged 8.1 ± 3.1 years (range 5-15 years), 21 boys and 4 girls, suffering from asthma and allergic rhinitis with polysensitisation to seasonal and non-seasonal allergens, shortlisted for SLIT, were included in the study. Th1 cell and Th2 cell percentages, Bcl-2 expression in T cells, and basophil activation after allergen challenge (house dust mite and/or grass pollen antigen in solution used for skin prick tests) in peripheral blood were measured using flow cytometry. The association between clinical features of asthma and the influence of SLIT on immunological parameters was evaluated with exact Fisher test. No association between the influence of one-year sublingual immunotherapy on immunological system and patients' age, polysensitisation, asthma treatment step, or coexistence of any other atopic diseases was observed. However, an increase of the Th1 percentage in children sensitised against more than three allergens was found more often (at the limit of statistical significance) than in the group of children sensitised against three or less allergens. Based on our results, we cannot point to any subgroup isolated in the study, in which the response of the immunological system to sublingual immunotherapy is more satisfactory than any other. Nevertheless, the increase of Th1 cells may be more specific for polysensitised children.

  18. Sequential Treatment Initiation with Timothy Grass and Ragweed Sublingual Immunotherapy Tablets Followed by Simultaneous Treatment Is Well Tolerated.

    Science.gov (United States)

    Maloney, Jennifer; Berman, Gary; Gagnon, Remi; Bernstein, David I; Nelson, Harold S; Kleine-Tebbe, Jörg; Kaur, Amarjot; Li, Qing; Nolte, Hendrik

    2016-01-01

    Dual treatment with grass and ragweed sublingual immunotherapy (SLIT) tablets has not been studied. To characterize the safety and tolerability of dual grass and ragweed SLIT-tablet administration. This open-label, multicenter trial (NCT02256553) enrolled North American adults (N = 102) allergic to grass and ragweed. The trial had 3 periods, each of 2 weeks duration. In period 1, subjects received once-daily timothy grass SLIT tablet (2800 bioequivalent allergen unit; Merck, Inc, Kenilworth, NJ/ALK, Hørsholm, Denmark). In period 2, subjects received a short ragweed SLIT tablet (12 Ambrosia artemisiifolia 1-U; Merck/ALK) every morning and a grass SLIT tablet every evening. In period 3, subjects received once-daily grass and ragweed SLIT tablets within 5 minutes (simultaneous intake). The primary end point was the proportion of subjects with 1 or more local swelling events in each period. Secondary end points were the proportion of subjects with 1 or more local adverse events (AEs), that discontinued the treatment because of AEs, and subjects with 1 or more local AEs requiring treatment. No severe swellings, systemic allergic reactions, asthma attacks, or reactions requiring epinephrine were reported. Most (99%) AEs were graded mild to moderate. The proportions of subjects with 1 or more local swelling events were 14%, 22%, and 15% for periods 1, 2, and 3, respectively. For periods 1, 2, and 3, the proportions of subjects with 1 or more local AEs were 71%, 69%, and 56%, respectively; the proportions discontinuing the treatment because of treatment-related AEs were 5%, 1%, and 2%, and the proportions with 1 or more local AEs requiring treatment were 4%, 4%, and 1%. In this trial, a 4-week sequential SLIT-tablet dosing schedule followed by simultaneous intake of timothy grass and ragweed tablets was well tolerated. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  19. Cine MR enterography grading of small bowel peristalsis: evaluation of the antiperistaltic effectiveness of sublingual hyoscyamine sulfate.

    Science.gov (United States)

    Ghobrial, Peter M; Neuberger, Ilana; Guglielmo, Flavius F; Mitchell, Donald G; Parker, Laurence; O'Kane, Patrick L; Roth, Christopher G; Deshmukh, Sandeep P; Borowski, Allison

    2014-01-01

    To use a cine balanced steady-state free precession magnetic resonance enterography (cine MRE) pulse sequence to assess the effectiveness of a sublingual (SL) antiperistaltic agent, hyoscyamine sulfate. Institutional review board approval was granted with an exemption for informed consent in this Health Insurance Portability and Accountability Act-compliant, retrospective, single-institution study. Of the 288 MRE examinations performed between October 1, 2007 and January 15, 2011, 92 using SL hyoscyamine sulfate for antiperistalsis were included for review, each with cine MRE before and after medication. These 184 cine MRE data sets were randomized, blinded for treatment, and independently reviewed by five attending abdominal radiologists, who rated the degree of whole abdomen bowel motility on each cine MRE data set on a 5-point scale. Pre- and postmedication mean peristalsis ratings, standard deviation, mean difference, and treatment effect sizes were calculated. A repeated measures analysis of variance test was performed using a significance threshold of P = .05. Interobserver reliabilities were also calculated. Mean peristalsis ratings ranged 2.63-3.34 and 2.36-3.03, before and after medication administration, respectively. The mean differences ranged from 0.22 to 0.46, which are treatment effect sizes of 0.20 to 0.37. The decrease in peristalsis observed by the five reviewing radiologists after SL hyoscyamine sulfate administration was significant (df = 1/182, f = 7.35, P cine MRE sequences show decreased bowel peristalsis after the use of SL hyoscyamine sulfate, the small size of the observed treatment effect is likely insufficient to justify its use for MRE. Copyright © 2014 AUR. Published by Elsevier Inc. All rights reserved.

  20. Sublingual Buprenorphine and Methadone Maintenance Treatment: A Three-Year Follow-Up of Quality of Life Assessment

    Directory of Open Access Journals (Sweden)

    Salvatore M. Giacomuzzi

    2005-01-01

    Full Text Available This study was conducted to compare long-term outcome effects on the quality of life (QOL of oral methadone with sublingual buprenorphine maintenance treatment. The QOL status of opioid-dependent patients was assessed using the German version (“Berlin Quality of Life Profile” of the Lancashire Quality of Life Profile. Physical symptoms were measured using the Opiate Withdrawal Scale (OWS. Urine tests were carried out randomly to detect additional consumption. In the first study period, 53 opioid-dependent subjects were enrolled and 25 could be reached after 3 years. The retention rate was 50% for methadone and 45% for buprenorphine (p = 0.786. Baseline values of the total sample (completers and noncompleters QOL and somatic complaints did not show significant differences between the two treatment groups. QOL characteristics at 6 months of treatment of the buprenorphine completer and noncompleter groups differed significantly regarding job (p = 0.013, family, and total score of physical symptoms (p = 0.002, in which the completer group showed the more favorable values. Concerning physical symptoms at 36 months, logistic regression revealed significantly less stomach cramps (p = 0.037 and fatigue and tiredness (p = 0.034 in buprenorphine compared to the methadone. Moreover, the buprenorphine-maintained group showed significantly less additional consumption of benzodiazepines (p = 0.015 compared with methadone participants. It is concluded that opioid addicts improved their QOL and health status when treated with methadone or buprenorphine. In summary, regarding QOL and health status, the present data indicate that buprenorphine is also a useful long-term alternative for maintenance treatment of opioid-dependent patients.

  1. A Domain of Herpes Simplex Virus pUL33 Required To Release Monomeric Viral Genomes from Cleaved Concatemeric DNA.

    Science.gov (United States)

    Yang, Kui; Dang, Xiaoqun; Baines, Joel D

    2017-10-15

    Monomeric herpesvirus DNA is cleaved from concatemers and inserted into preformed capsids through the actions of the viral terminase. The terminase of herpes simplex virus (HSV) is composed of three subunits encoded by U L 15, U L 28, and U L 33. The U L 33-encoded protein (pU L 33) interacts with pU L 28, but its precise role in the DNA cleavage and packaging reaction is unclear. To investigate the function of pU L 33, we generated a panel of recombinant viruses with either deletions or substitutions in the most conserved regions of U L 33 using a bacterial artificial chromosome system. Deletion of 11 amino acids (residues 50 to 60 or residues 110 to 120) precluded viral replication, whereas the truncation of the last 10 amino acids from the pU L 33 C terminus did not affect viral replication or the interaction of pU L 33 with pU L 28. Mutations that replaced the lysine at codon 110 and the arginine at codon 111 with alanine codons failed to replicate, and the pU L 33 mutant interacted with pU L 28 less efficiently. Interestingly, genomic termini of the large (L) and small (S) components were detected readily in cells infected with these mutants, indicating that concatemeric DNA was cleaved efficiently. However, the release of monomeric genomes as assessed by pulsed-field gel electrophoresis was greatly diminished, and DNA-containing capsids were not observed. These results suggest that pU L 33 is necessary for one of the two viral DNA cleavage events required to release individual genomes from concatemeric viral DNA. IMPORTANCE This paper shows a role for pU L 33 in one of the two DNA cleavage events required to release monomeric genomes from concatemeric viral DNA. This is the first time that such a phenotype has been observed and is the first identification of a function of this protein relevant to DNA packaging other than its interaction with other terminase components. Copyright © 2017 Yang et al.

  2. A monomeric G protein-coupled receptor isolated in a high-density lipoprotein particle efficiently activates its G protein

    DEFF Research Database (Denmark)

    Whorton, Matthew R; Bokoch, Michael P; Rasmussen, Søren Gøgsig Faarup

    2007-01-01

    G protein-coupled receptors (GPCRs) respond to a diverse array of ligands, mediating cellular responses to hormones and neurotransmitters, as well as the senses of smell and taste. The structures of the GPCR rhodopsin and several G proteins have been determined by x-ray crystallography, yet...... the organization of the signaling complex between GPCRs and G proteins is poorly understood. The observations that some GPCRs are obligate heterodimers, and that many GPCRs form both homo- and heterodimers, has led to speculation that GPCR dimers may be required for efficient activation of G proteins. However......, technical limitations have precluded a definitive analysis of G protein coupling to monomeric GPCRs in a biochemically defined and membrane-bound system. Here we demonstrate that a prototypical GPCR, the beta2-adrenergic receptor (beta2AR), can be incorporated into a reconstituted high-density lipoprotein...

  3. Development, validation and evaluation of an analytical method for the determination of monomeric and oligomeric procyanidins in apple extracts.

    Science.gov (United States)

    Hollands, Wendy J; Voorspoels, Stefan; Jacobs, Griet; Aaby, Kjersti; Meisland, Ane; Garcia-Villalba, Rocio; Tomas-Barberan, Francisco; Piskula, Mariusz K; Mawson, Deborah; Vovk, Irena; Needs, Paul W; Kroon, Paul A

    2017-04-28

    There is a lack of data for individual oligomeric procyanidins in apples and apple extracts. Our aim was to develop, validate and evaluate an analytical method for the separation, identification and quantification of monomeric and oligomeric flavanols in apple extracts. To achieve this, we prepared two types of flavanol extracts from freeze-dried apples; one was an epicatechin-rich extract containing ∼30% (w/w) monomeric (-)-epicatechin which also contained oligomeric procyanidins (Extract A), the second was an oligomeric procyanidin-rich extract depleted of epicatechin (Extract B). The parameters considered for method optimisation were HPLC columns and conditions, sample heating, mass of extract and dilution volumes. The performance characteristics considered for method validation included standard linearity, method sensitivity, precision and trueness. Eight laboratories participated in the method evaluation. Chromatographic separation of the analytes was best achieved utilizing a Hilic column with a binary mobile phase consisting of acidic acetonitrile and acidic aqueous methanol. The final method showed linearity for epicatechin in the range 5-100μg/mL with a correlation co-efficient >0.999. Intra-day and inter-day precision of the analytes ranged from 2 to 6% and 2 to 13% respectively. Up to dp3, trueness of the method was >95% but decreased with increasing dp. Within laboratory precision showed RSD values <5 and 10% for monomers and oligomers, respectively. Between laboratory precision was 4 and 15% (Extract A) and 7 and 30% (Extract B) for monomers and oligomers, respectively. An analytical method for the separation, identification and quantification of procyanidins in an apple extract was developed, validated and assessed. The results of the inter-laboratory evaluation indicate that the method is reliable and reproducible. Copyright © 2017. Published by Elsevier B.V.

  4. Hda Monomerization by ADP Binding Promotes Replicase Clamp-mediated DnaA-ATP Hydrolysis*S⃞

    Science.gov (United States)

    Su'etsugu, Masayuki; Nakamura, Kenta; Keyamura, Kenji; Kudo, Yuka; Katayama, Tsutomu

    2008-01-01

    ATP-DnaA is the initiator of chromosomal replication in Escherichia coli, and the activity of DnaA is regulated by the regulatory inactivation of the DnaA (RIDA) system. In this system, the Hda protein promotes DnaA-ATP hydrolysis to produce inactive ADP-DnaA in a mechanism that is mediated by the DNA-loaded form of the replicase sliding clamp. In this study, we first revealed that hda translation uses an unusual initiation codon, CUG, located downstream of the annotated initiation codon. The CUG initiation codon could be used for restricting the Hda level, as this initiation codon has a low translation efficiency, and the cellular Hda level is only ∼100 molecules per cell. Hda translated using the correct reading frame was purified and found to have a high RIDA activity in vitro. Moreover, we found that Hda has a high affinity for ADP but not for other nucleotides, including ATP. ADP-Hda was active in the RIDA system in vitro and stable in a monomeric state, whereas apo-Hda formed inactive homomultimers. Both ADP-Hda and apo-Hda could form complexes with the DNA-loaded clamp; however, only ADP-Hda-DNA-clamp complexes were highly functional in the following interaction with DnaA. Formation of ADP-Hda was also observed in vivo, and mutant analysis suggested that ADP binding is crucial for cellular Hda activity. Thus, we propose that ADP is a crucial Hda ligand that promotes the activated conformation of the protein. ADP-dependent monomerization might enable the arginine finger of the Hda AAA+ domain to be accessible to ATP bound to the DnaA AAA+ domain. PMID:18977760

  5. Alpha B- and βA3-crystallins containing d-aspartic acids exist in a monomeric state.

    Science.gov (United States)

    Sakaue, Hiroaki; Takata, Takumi; Fujii, Norihiko; Sasaki, Hiroshi; Fujii, Noriko

    2015-01-01

    Crystallin stability and subunit-subunit interaction are essential for eye lens transparency. There are three types of crystallins in lens, designated as α-, β-, and γ-crystallins. Alpha-crystallin is a hetero-polymer of about 800kDa, consisting of 35-40 subunits of two different αA- and αB-subunits, each of 20kDa. The β/γ-crystallin superfamily comprises oligomeric β-crystallin (2-6 subunits) and monomeric γ-crystallin. Since lens proteins have very long half-lives, they undergo numerous post-translational modifications including racemization, isomerization, deamidation, oxidation, glycation, and truncation, which may decrease crystallin solubility and ultimately cause cataract formation. Racemization and isomerization of aspartyl (Asp) residues have been detected only in polymeric α- and oligomeric β-crystallin, while the situation in monomeric γ-crystallin has not been studied. Here, we investigated the racemization and isomerization of Asp in the γ-crystallin fraction of elderly donors. The results show that Asp residues of γS-, γD- and γC-crystallins were not racemized and isomerized. However, strikingly, we found that a portion of αB-crystallin and βA3-crystallin moved to the lower molecular weight fraction which is the same size of γ-crystallin. In those fractions, Asp-96 of αB-crystallin and Asp-37 of βA3-crystallin were highly inverted, which do not occur in the native lens higher molecular weight fraction. Our results indicate the possibility that the inversion of Asp residues may induce dissociation of αB- and βA3-crystallins from the polymeric and oligomeric states. This is the first report that stereoinversion of amino acids disturbs lens protein assembly in aged human lens. Copyright © 2014 Elsevier B.V. All rights reserved.

  6. Food-specific sublingual immunotherapy is well tolerated and safe in healthy dogs: a blind, randomized, placebo-controlled study.

    Science.gov (United States)

    Maina, E; Pelst, M; Hesta, M; Cox, E

    2017-01-18

    Food allergies are increasing in prevalence but no treatment strategies are currently available to cure dogs with food allergy. Over the past decade, experimental food allergen-specific sublingual immunotherapy (FA-SLIT) has emerged as a potential treatment for food allergies in human medicine. However, FA-SLIT has not been investigated in dogs. Therefore, the objective of this study was to prospectively evaluate the safety, tolerability and dispenser sterility of FA-SLIT in healthy dogs before testing it in food allergic dogs. Eight experimental healthy beagle dogs, never orally exposed to peanut, were randomized in two groups to receive SLIT with peanut or placebo for 4 months. Subjects were monitored daily for local and systemic adverse effects. Blood samples for complete blood count and serum biochemistry, and urine for urinalysis were collected and the dogs' body weight was recorded at day 0, 35 and 119 of the SLIT treatment. Sera for the determination of peanut-specific IgG and IgE were collected at day 0, 35, 49, 70, 91, 105 and 119. Intradermal tests were performed before (day 0) and after (day 119) the experiment. The content of each dispenser used to administer treatment or placebo was tested for sterility after usage. In order to assess the presence or absence of sensitization, dogs were challenged 6 months after the end of the study with 2000 μg of peanut extract daily for 7 to 14 days. All dogs completed the study. The treatment did not provoke either local or systemic side-effects. Peanut-specific IgG significantly increased in treatment group. Even though a significant increase in peanut-specific IgE was also seen, intradermal tests were negative in all dogs before and after the experiment, and the challenge test did not trigger any adverse reactions in the treated dogs, which shows the protocol did not cause sensitization to peanut, but nevertheless primed the immune system as indicated by the humoral immune response. All dispenser solutions

  7. Crystallization and preliminary crystallographic analysis of decameric and monomeric forms of C49S mutant thioredoxin-dependent AhpC from Helicobacter pylori

    International Nuclear Information System (INIS)

    Supangat; Seo, Kyung Hye; Furqoni, Ahmad; Kwon, Young-Chul; Cho, Myung-Je; Rhee, Kwang-Ho; Lee, Sang Yeol; Lee, Kon Ho

    2008-01-01

    Decameric and monomeric forms of recombinant C49S mutant AhpC from H. pylori have been crystallized. Diffraction data were collected to 2.8 and 2.25 Å, respectively. Cys49Ser mutant Helicobacter pylori alkyl hydroperoxide reductase (C49S HpAhpC) was purified under reducing conditions in monomeric and decameric forms. The monomeric form was crystallized by the hanging-drop vapour-diffusion method. The crystals diffracted to 2.25 Å resolution and belonged to space group C2, with unit-cell parameters a = 245.8, b = 140.7, c = 189.5 Å, β = 127°, and contained 20 molecules in the asymmetric unit. A crystal of the decameric form was obtained by the microbatch crystallization method and diffracted to 2.8 Å resolution. It belonged to space group C222, with unit-cell parameters a = 257.5, b = 417.5, c = 95.6 Å. The structure of the monomeric form of C49S HpAhpC has been solved by the molecular-replacement method

  8. Antioxidant effects of phenolic rye (Secale cereale L.) extracts, monomeric hydroxycinnamates, and ferulic acid dehydrodimers on human low-density lipoproteins

    DEFF Research Database (Denmark)

    Andreasen, M.F.; Landbo, Anne-Katrine Regel; Christensen, L.P.

    2001-01-01

    Dietary antioxidants that protect low-density lipoprotein (LDL) from oxidation may help to prevent atherosclerosis and coronary heart disease. The antioxidant activities of purified monomeric and dimeric hydroxycinnamates and of phenolic extracts from rye (whole grain, bran, and flour) were...

  9. Functional alteration of a dimeric insecticidal lectin to a monomeric antifungal protein correlated to its oligomeric status.

    Directory of Open Access Journals (Sweden)

    Nilanjana Banerjee

    Full Text Available BACKGROUND: Allium sativum leaf agglutinin (ASAL is a 25-kDa homodimeric, insecticidal, mannose binding lectin whose subunits are assembled by the C-terminal exchange process. An attempt was made to convert dimeric ASAL into a monomeric form to correlate the relevance of quaternary association of subunits and their functional specificity. Using SWISS-MODEL program a stable monomer was designed by altering five amino acid residues near the C-terminus of ASAL. METHODOLOGY/PRINCIPAL FINDINGS: By introduction of 5 site-specific mutations (-DNSNN-, a β turn was incorporated between the 11(th and 12(th β strands of subunits of ASAL, resulting in a stable monomeric mutant ASAL (mASAL. mASAL was cloned and subsequently purified from a pMAL-c2X system. CD spectroscopic analysis confirmed the conservation of secondary structure in mASAL. Mannose binding assay confirmed that molecular mannose binds efficiently to both mASAL and ASAL. In contrast to ASAL, the hemagglutination activity of purified mASAL against rabbit erythrocytes was lost. An artificial diet bioassay of Lipaphis erysimi with mASAL displayed an insignificant level of insecticidal activity compared to ASAL. Fascinatingly, mASAL exhibited strong antifungal activity against the pathogenic fungi Fusarium oxysporum, Rhizoctonia solani and Alternaria brassicicola in a disc diffusion assay. A propidium iodide uptake assay suggested that the inhibitory activity of mASAL might be associated with the alteration of the membrane permeability of the fungus. Furthermore, a ligand blot assay of the membrane subproteome of R. solani with mASAL detected a glycoprotein receptor having interaction with mASAL. CONCLUSIONS/SIGNIFICANCE: Conversion of ASAL into a stable monomer resulted in antifungal activity. From an evolutionary aspect, these data implied that variable quaternary organization of lectins might be the outcome of defense-related adaptations to diverse situations in plants. Incorporation of m

  10. SQ house dust mite sublingually administered immunotherapy tablet (ALK) improves allergic rhinitis in patients with house dust mite allergic asthma and rhinitis symptoms

    DEFF Research Database (Denmark)

    Mosbech, Holger; Canonica, G Walter; Backer, Vibeke

    2015-01-01

    BACKGROUND: House dust mite (HDM) allergy is associated with persistent allergic rhinitis (AR) and allergic asthma. OBJECTIVE: To investigate the efficacy and safety of a SQ HDM sublingually administered immunotherapy tablet (ALK, Hørsholm, Denmark) in adults and adolescents with HDM respiratory...... allergic disease and report the AR results. METHODS: Six hundred four subjects at least 14 years old with HDM AR and mild to moderate HDM allergic asthma were randomized 1:1:1:1 to double-blinded daily treatment with 1, 3, 6 SQ-HDM or placebo. End-of-treatment rhinoconjunctivitis symptoms and medication...... score were predefined extrapulmonary end points. A subgroup analysis was conducted post hoc in subjects with a total combined rhinitis score (TCRS) > 0 (ie, with AR symptoms and/or AR medication use during the 4-week baseline period). The subgroup was comprised of 498 subjects (82%). RESULTS...

  11. Elucidation of Arctigenin Pharmacokinetics and Tissue Distribution after Intravenous, Oral, Hypodermic and Sublingual Administration in Rats and Beagle Dogs: Integration of In Vitro and In Vivo Findings.

    Science.gov (United States)

    Li, Jie; Li, Xin; Ren, Yu-Shan; Lv, Yuan-Yuan; Zhang, Jun-Sheng; Xu, Xiao-Li; Wang, Xian-Zhen; Yao, Jing-Chun; Zhang, Gui-Min; Liu, Zhong

    2017-01-01

    Although arctigenin ( AG ) has diverse bioactivities, such as anti-oxidant, anti-inflammatory, anti-cancer, immunoregulatory and neuroprotective activities, its pharmacokinetics have not been systematically evaluated. The purpose of this work was to identify the pharmacokinetic properties of AG via various experiments in vivo and in vitro . In this research, rats and beagle dogs were used to investigate the PK (pharmacokinetics, PK) profiles of AG with different drug-delivery manners, including intravenous (i.v), hypodermic injection (i.h), and sublingual (s.l) administration. The data shows that AG exhibited a strong absorption capacity in both rats and beagle dogs (absorption rate 100%), and a strong elimination ability ( t 1/2 beagle dog (25.9 ± 3.24%) > rat (15.7 ± 9%) > monkey (3.69 ± 0.12%). This systematic investigation of pharmacokinetic profiles of arctigenin (AG) in vivo and in vitro is worthy of further exploration.

  12. Fentanyl Sublingual Spray

    Science.gov (United States)

    ... medication, and who are tolerant (used to the effects of the medication) to narcotic pain medications. Fentanyl ... medications for seizures such as carbamazepine (Tegretol, Teril), oxcarbazepine (Trileptal), and phenytoin (Dilantin, Phenytek); modafinil (Provigil); nalbuphine; ...

  13. Effect of artificial accelerated aging on the optical properties and monomeric conversion of composites used after expiration date.

    Science.gov (United States)

    Garcia, Lucas da Fonseca Roberti; Mundim, Fabricio Mariano; Pires-de-Souza, Fernanda de Carvalho Panzeri; Puppin Rontani, Regina Maria; Consani, Simonides

    2013-01-01

    This study sought to evaluate how artificial accelerated aging (AAA) affected color stability (ΔE), opacity (ΔOP), and degree of conversion (DOC) for 3 composite materials (Tetric Ceram, Tetric Ceram HB, and Tetric Flow) used both 180 days before and 180 days after their expiration dates. To evaluate the materials' optical properties, 10 specimens of each composite-5 prior to expiration and 5 after the materials' expiration date-were made in a teflon matrix. After polishing, the specimens were submitted to initial color and opacity readings and submitted to AAA for 384 hours; at that point, new readings were taken to determine ΔE and ΔOP. To evaluate monomeric conversion evaluation, 6 specimens from each composite and expiration date-3 prior to AAA and 3 after-were submitted to DOC analysis. Results of the 2-way ANOVA and Bonferroni's tests (P 0.05). The expired Tetric Flow had the highest DOC values (71.42% ± 4.21) before AAA, significantly different than that of the other composites (P > 0.05). It was concluded that both expiration date and AAA affected the properties of the composites tested.

  14. Gas-phase synthesis and structure of monomeric ZnOH: a model species for metalloenzymes and catalytic surfaces.

    Science.gov (United States)

    Zack, Lindsay N; Sun, Ming; Bucchino, Matthew P; Clouthier, Dennis J; Ziurys, Lucy M

    2012-02-16

    Monomeric ZnOH has been studied for the first time using millimeter and microwave gas-phase spectroscopy. ZnOH is important in surface processes and at the active site of the enzyme carbonic anhydrase. In the millimeter-wave direct-absorption experiments, ZnOH was synthesized by reacting zinc vapor, produced in a Broida-type oven, with water. In the Fourier-transform microwave measurements, ZnOH was produced in a supersonic jet expansion of CH(3)OH and zinc vapor, created by laser ablation. Multiple rotational transitions of six ZnOH isotopologues in their X(2)A' ground states were measured over the frequency range of 22-482 GHz, and splittings due to fine and hyperfine structure were resolved. An asymmetric top pattern was observed in the spectra, showing that ZnOH is bent, indicative of covalent bonding. From these data, spectroscopic constants and an accurate structure were determined. The Zn-O bond length was found to be similar to that in carbonic anhydrase and other model enzyme systems.

  15. Pleiotropic benefit of monomeric and oligomeric flavanols on vascular health--a randomized controlled clinical pilot study.

    Science.gov (United States)

    Weseler, Antje R; Ruijters, Erik J B; Drittij-Reijnders, Marie-José; Reesink, Koen D; Haenen, Guido R M M; Bast, Aalt

    2011-01-01

    Cardiovascular diseases are expanding to a major social-economic burden in the Western World and undermine man's deep desire for healthy ageing. Epidemiological studies suggest that flavanol-rich foods (e.g. grapes, wine, chocolate) sustain cardiovascular health. For an evidenced-based application, however, sound clinical data on their efficacy are strongly demanded. In a double-blind, randomized, placebo-controlled intervention study we supplemented 28 male smokers with 200 mg per day of monomeric and oligomeric flavanols (MOF) from grape seeds. At baseline, after 4 and 8 weeks we measured macro- and microvascular function and a cluster of systemic biomarkers for major pathological processes occurring in the vasculature: disturbances in lipid metabolism and cellular redox balance, and activation of inflammatory cells and platelets. In the MOF group serum total cholesterol and LDL decreased significantly (P ≤ 0.05) by 5% (n = 11) and 7% (n = 9), respectively in volunteers with elevated baseline levels. Additionally, after 8 weeks the ratio of glutathione to glutathione disulphide in erythrocytes rose from baseline by 22% (n = 15, Pbenefit of an 8 weeks supplementation with 200 mg/d MOF in humans. ClinicalTrials.gov NCT00742287.

  16. Resonance Raman assignment and evidence for noncoupling of individual 2- and 4-vinyl vibrational modes in a monomeric cyanomethemoglobin

    International Nuclear Information System (INIS)

    Gersonde, K.; Yu, N.T.; Lin, S.H.; Smith, K.M.; Parish, D.W.

    1989-01-01

    We have investigated the resonance Raman spectra of monomeric insect cyanomethemoglobins (CTT III and CTT IV) reconstituted with (1) protohemes IX selectively deuterated at the 4-vinyl as well as the 2,4-divinyls, (2) monovinyl-truncated hemes such as pemptoheme (2-hydrogen, 4-vinyl) and isopemptoheme (2-vinyl, 4-hydrogen), (3) symmetric hemes such as protoheme III (with 2- and 3-vinyls) and protoheme XIII (with 1- and 4-vinyls), and (4) hemes without 2- and 4-vinyls such as mesoheme IX, deuteroheme IX, 2,4-dimethyldeuteroheme IX, and 2,4-dibromodeuteroheme IX. Evidence is presented that the highly localized vinyl C = C stretching vibrations at the 2- and 4-positions of the heme in these cyanomet CTT hemoglobins are noncoupled and inequivalent; i.e., the 1631- and 1624-cm-1 lines have been assigned to 2-vinyl and 4-vinyl, respectively. The elimination of the 2-vinyl (in pemptoheme) or the 4-vinyl (in isopemptoheme) does not affect the C = C stretching frequency of the remaining vinyl. Furthermore, two low-frequency vinyl bending modes at 412 and 591 cm-1 exhibit greatly different resonance Raman intensities between 2-vinyl and 4-vinyl. The observed intensity at 412 cm-1 is primarily derived from 4-vinyl, whereas the 591-cm-1 line results exclusively from the 2-vinyl. Again, there is no significant coupling between 2-vinyl and 4-vinyl for these two bending modes

  17. Optimized labeling of membrane proteins for applications to super-resolution imaging in confined cellular environments using monomeric streptavidin.

    Science.gov (United States)

    Chamma, Ingrid; Rossier, Olivier; Giannone, Grégory; Thoumine, Olivier; Sainlos, Matthieu

    2017-04-01

    Recent progress in super-resolution imaging (SRI) has created a strong need to improve protein labeling with probes of small size that minimize the target-to-label distance, increase labeling density, and efficiently penetrate thick biological tissues. This protocol describes a method for labeling genetically modified proteins incorporating a small biotin acceptor peptide with a 3-nm fluorescent probe, monomeric streptavidin. We show how to express, purify, and conjugate the probe to organic dyes with different fluorescent properties, and how to label selectively biotinylated membrane proteins for SRI techniques (point accumulation in nanoscale topography (PAINT), stimulated emission depletion (STED), stochastic optical reconstruction microscopy (STORM)). This method is complementary to the previously described anti-GFP-nanobody/SNAP-tag strategies, with the main advantage being that it requires only a short 15-amino-acid tag, and can thus be used with proteins resistant to fusion with large tags and for multicolor imaging. The protocol requires standard molecular biology/biochemistry equipment, making it easily accessible for laboratories with only basic skills in cell biology and biochemistry. The production/purification/conjugation steps take ∼5 d, and labeling takes a few minutes to an hour.

  18. Monomeric, porous type II collagen scaffolds promote chondrogenic differentiation of human bone marrow mesenchymal stem cells in vitro

    Science.gov (United States)

    Tamaddon, M.; Burrows, M.; Ferreira, S. A.; Dazzi, F.; Apperley, J. F.; Bradshaw, A.; Brand, D. D.; Czernuszka, J.; Gentleman, E.

    2017-03-01

    Osteoarthritis (OA) is a common cause of pain and disability and is often associated with the degeneration of articular cartilage. Lesions to the articular surface, which are thought to progress to OA, have the potential to be repaired using tissue engineering strategies; however, it remains challenging to instruct cell differentiation within a scaffold to produce tissue with appropriate structural, chemical and mechanical properties. We aimed to address this by driving progenitor cells to adopt a chondrogenic phenotype through the tailoring of scaffold composition and physical properties. Monomeric type-I and type-II collagen scaffolds, which avoid potential immunogenicity associated with fibrillar collagens, were fabricated with and without chondroitin sulfate (CS) and their ability to stimulate the chondrogenic differentiation of human bone marrow-derived mesenchymal stem cells was assessed. Immunohistochemical analyses showed that cells produced abundant collagen type-II on type-II scaffolds and collagen type-I on type-I scaffolds. Gene expression analyses indicated that the addition of CS - which was released from scaffolds quickly - significantly upregulated expression of type II collagen, compared to type-I and pure type-II scaffolds. We conclude that collagen type-II and CS can be used to promote a more chondrogenic phenotype in the absence of growth factors, potentially providing an eventual therapy to prevent OA.

  19. I222 crystal form of despentapeptide (B26-B30) insulin provides new insights into the properties of monomeric insulin.

    Science.gov (United States)

    Whittingham, Jean L; Youshang, Zhang; Záková, Lenka; Dodson, Eleanor J; Turkenburg, Johan P; Brange, Jens; Dodson, G Guy

    2006-05-01

    Despentapeptide (des-B26-B30) insulin (DPI), an active modified insulin, has been crystallized in the presence of 20% acetic acid pH 2. A crystal structure analysis to 1.8 A spacing (space group I222) revealed that the DPI molecule, which is unable to make beta-strand interactions for physiological dimer formation and is apparently monomeric in solution, formed an alternative lattice-generated dimer. The formation of this dimer involved interactions between surfaces which included the B9-B19 alpha-helices (usually buried by the dimer-dimer contacts within the native hexamer). The two crystallographically independent molecules within the dimer were essentially identical and were similar in conformation to T-state insulin as seen in the T(6) insulin hexamer. An unusual feature of each molecule in the dimer was the presence of two independent conformations at the B-chain C-terminus (residues B20-B25). Both conformations were different from that of native insulin, involving a 3.5 A displacement of the B20-B23 beta-turn and a repositioning of residue PheB25 such that it made close van der Waals contact with the main body of the molecule, appearing to stabilize the B-chain C-terminus.

  20. Antioxidant effects of phenolic rye (Secale cereale L.) extracts, monomeric hydroxycinnamates, and ferulic acid dehydrodimers on human low-density lipoproteins

    DEFF Research Database (Denmark)

    Andreasen, Mette Findal; Landbo, A K; Christensen, L P

    2001-01-01

    Dietary antioxidants that protect low-density lipoprotein (LDL) from oxidation may help to prevent atherosclerosis and coronary heart disease. The antioxidant activities of purified monomeric and dimeric hydroxycinnamates and of phenolic extracts from rye (whole grain, bran, and flour) were...... investigated using an in vitro copper-catalyzed human LDL oxidation assay. The most abundant ferulic acid dehydrodimer (diFA) found in rye, 8-O-4-diFA, was a slightly better antioxidant than ferulic acid and p-coumaric acid. The antioxidant activity of the 8-5-diFA was comparable to that of ferulic acid......, but neither 5-5-diFA nor 8-5-benzofuran-diFA inhibited LDL oxidation when added at 10-40 microM. The antioxidant activity of the monomeric hydroxycinnamates decreased in the following order: caffeic acid > sinapic acid > ferulic acid > p-coumaric acid. The antioxidant activity of rye extracts...

  1. The structure of mAG, a monomeric mutant of the green fluorescent protein Azami-Green, reveals the structural basis of its stable green emission

    International Nuclear Information System (INIS)

    Ebisawa, Tatsuki; Yamamura, Akihiro; Kameda, Yasuhiro; Hayakawa, Kou; Nagata, Koji; Tanokura, Masaru

    2010-01-01

    The crystal structure of a monomeric mutant of Azami-Green (mAG) from G. fascicularis was determined at 2.2 Å resolution. Monomeric Azami-Green (mAG) from the stony coral Galaxea fascicularis is the first known monomeric green-emitting fluorescent protein that is not a variant of Aequorea victoria green fluorescent protein (avGFP). These two green fluorescent proteins are only 27% identical in their amino-acid sequences. mAG is more similar in its amino-acid sequence to four fluorescent proteins: Dendra2 (a green-to-red irreversibly photoconverting fluorescent protein), Dronpa (a bright-and-dark reversibly photoswitchable fluorescent protein), KikG (a tetrameric green-emitting fluorescent protein) and Kaede (another green-to-red irreversibly photoconverting fluorescent protein). To reveal the structural basis of stable green emission by mAG, the 2.2 Å crystal structure of mAG has been determined and compared with the crystal structures of avGFP, Dronpa, Dendra2, Kaede and KikG. The structural comparison revealed that the chromophore formed by Gln62-Tyr63-Gly64 (QYG) and the fixing of the conformation of the imidazole ring of His193 by hydrogen bonds and van der Waals contacts involving His193, Arg66 and Thr69 are likely to be required for the stable green emission of mAG. The crystal structure of mAG will contribute to the design and development of new monomeric fluorescent proteins with faster maturation, brighter fluorescence, improved photostability, new colours and other preferable properties as alternatives to avGFP and its variants

  2. Development of bisphenol A-removing recombinant Escherichia coli by monomeric and dimeric surface display of bisphenol A-binding peptide.

    Science.gov (United States)

    Maruthamuthu, Murali Kannan; Hong, Jiyeon; Arulsamy, Kulandaisamy; Somasundaram, Sivachandiran; Hong, SoonHo; Choe, Woo-Seok; Yoo, Ik-Keun

    2018-04-01

    Peptide-displaying Escherichia coli cells were investigated for use in adsorptive removal of bisphenol A (BPA) both in Luria-Bertani medium including BPA or ATM thermal paper eluted wastewater. Two recombinant strains were constructed with monomeric and dimeric repeats of the 7-mer BPA-binding peptide (KSLENSY), respectively. Greater than threefold increased adsorption of BPA [230.4 µmol BPA per g dry cell weight (DCW)] was found in dimeric peptide-displaying cells compared to monomeric strains (63.4 µmol per g DCW) in 15 ppm BPA solution. The selective removal of BPA from a mixture of BPA analogs (bisphenol F and bisphenol S) was verified in both monomeric and dimeric peptide-displaying cells. The binding chemistry of BPA with the peptide was assumed, based on molecular docking analysis, to be the interaction of BPA with serine and asparagine residues within the 7-mer peptide sequence. The peptide-displaying cells also functioned efficiently in thermal paper eluted wastewater containing 14.5 ppm BPA.

  3. Sequence-specific 1H-NMR assignments for the aromatic region of several biologically active, monomeric insulins including native human insulin.

    Science.gov (United States)

    Roy, M; Lee, R W; Kaarsholm, N C; Thøgersen, H; Brange, J; Dunn, M F

    1990-06-12

    The aromatic region of the 1H-FT-NMR spectrum of the biologically fully-potent, monomeric human insulin mutant, B9 Ser----Asp, B27 Thr----Glu has been investigated in D2O. At 1 to 5 mM concentrations, this mutant insulin is monomeric above pH 7.5. Coupling and amino acid classification of all aromatic signals is established via a combination of homonuclear one- and two-dimensional methods, including COSY, multiple quantum filters, selective spin decoupling and pH titrations. By comparisons with other insulin mutants and with chemically modified native insulins, all resonances in the aromatic region are given sequence-specific assignments without any reliance on the various crystal structures reported for insulin. These comparisons also give the sequence-specific assignments of most of the aromatic resonances of the mutant insulins B16 Tyr----Glu, B27 Thr----Glu and B25 Phe----Asp and the chemically modified species des-(B23-B30) insulin and monoiodo-Tyr A14 insulin. Chemical dispersion of the assigned resonances, ring current perturbations and comparisons at high pH have made possible the assignment of the aromatic resonances of human insulin, and these studies indicate that the major structural features of the human insulin monomer (including those critical to biological function) are also present in the monomeric mutant.

  4. Pleiotropic benefit of monomeric and oligomeric flavanols on vascular health--a randomized controlled clinical pilot study.

    Directory of Open Access Journals (Sweden)

    Antje R Weseler

    Full Text Available BACKGROUND: Cardiovascular diseases are expanding to a major social-economic burden in the Western World and undermine man's deep desire for healthy ageing. Epidemiological studies suggest that flavanol-rich foods (e.g. grapes, wine, chocolate sustain cardiovascular health. For an evidenced-based application, however, sound clinical data on their efficacy are strongly demanded. METHODS: In a double-blind, randomized, placebo-controlled intervention study we supplemented 28 male smokers with 200 mg per day of monomeric and oligomeric flavanols (MOF from grape seeds. At baseline, after 4 and 8 weeks we measured macro- and microvascular function and a cluster of systemic biomarkers for major pathological processes occurring in the vasculature: disturbances in lipid metabolism and cellular redox balance, and activation of inflammatory cells and platelets. RESULTS: In the MOF group serum total cholesterol and LDL decreased significantly (P ≤ 0.05 by 5% (n = 11 and 7% (n = 9, respectively in volunteers with elevated baseline levels. Additionally, after 8 weeks the ratio of glutathione to glutathione disulphide in erythrocytes rose from baseline by 22% (n = 15, P<0.05 in MOF supplemented subjects. We also observed that MOF supplementation exerts anti-inflammatory effects in blood towards ex vivo added bacterial endotoxin and significantly reduces expression of inflammatory genes in leukocytes. Conversely, alterations in macro- and microvascular function, platelet aggregation, plasma levels of nitric oxide surrogates, endothelin-1, C-reactive protein, fibrinogen, prostaglandin F2alpha, plasma antioxidant capacity and gene expression levels of antioxidant defense enzymes did not reach statistical significance after 8 weeks MOF supplementation. However, integrating all measured effects into a global, so-called vascular health index revealed a significant improvement of overall vascular health by MOF compared to placebo (P ≤ 0.05. CONCLUSION: Our

  5. Effect of two different sublingual dosages of vitamin B12 on cobalamin nutritional status in vegans and vegetarians with a marginal deficiency: A randomized controlled trial.

    Science.gov (United States)

    Del Bo', Cristian; Riso, Patrizia; Gardana, Claudio; Brusamolino, Antonella; Battezzati, Alberto; Ciappellano, Salvatore

    2018-02-15

    Vegetarians and vegans are more vulnerable to vitamin B 12 deficiency with severe risks of megaloblastic anemia, cognitive decline, neuropathy, and depression. An easy and simple method of supplementation consists of taking one weekly dosage of 2000 μg. However, single large oral doses of vitamin B 12 are poorly absorbed. The present research evaluates the ability of two different sublingual dosages of vitamin B 12 (350 μg/week vs 2000 μg/week) in improving cyanocobalamin (vitamin B 12 ) nutritional status in vegans and vegetarians with a marginal deficiency. A 12-week randomized, double-blind, controlled, parallel intervention trial was performed. Forty subjects with marginal vitamin B 12 deficiency were enrolled and randomly divided into two groups: test group Ld (low dose, 350 μg/week) and control group Hd (high dose, 2000 μg/week) vitamin B 12 supplementation. Blood samples were collected at baseline and after 15, 30, 60, and 90 days from the intervention for the determination of vitamin B 12 , related metabolic markers, and blood cell counts. Two-way analysis of variance showed a significant effect of time (P < 0.0001) and of time × treatment interaction (P = 0.012) on serum concentration of vitamin B 12 that increased after 90-day supplementation (Ld and Hd) compared to baseline. Both the supplements increased (P < 0.0001, time effect) the levels of holotranscobalamin, succinic acid, methionine and wellness parameter, while decreased (P < 0.0001, time effect) the levels of methylmalonic acid, homocysteine and folate compared to baseline. No difference was observed between groups (LdvsHd). No effect was detected for vitamin B 6 and blood cell count. In our experimental conditions, both supplements were able to restore adequate serum concentrations of vitamin B 12 and to improve the levels of related metabolic blood markers in subjects with a marginal deficiency. The results support the use of a sublingual dosage of 50 μg/day (350

  6. Production of Monomeric Aromatic Compounds from Oil Palm Empty Fruit Bunch Fiber Lignin by Chemical and Enzymatic Methods

    Directory of Open Access Journals (Sweden)

    Pei-Ling Tang

    2015-01-01

    Full Text Available In this study, oil palm empty fruit bunch (OPEFBF was pretreated with alkali, and lignin was extracted for further degradation into lower molecular weight phenolic compounds using enzymes and chemical means. Efficiency of monomeric aromatic compounds production from OPEFBF lignin via chemical (nitrobenzene versus oxygen and enzymatic [cutinase versus manganese peroxidase (MnP] approaches was investigated. The effects of sodium hydroxide concentration (2, 5, and 10% wt. and reaction time (30, 90, and 180 minutes on the yield of aromatic compounds were studied. The results obtained indicated that nitrobenzene oxidation produced the highest yield (333.17±49.44 ppm hydroxybenzoic acid, 5.67±0.25 ppm p-hydroxybenzaldehyde, 25.57±1.64 ppm vanillic acid, 168.68±23.23 ppm vanillin, 75.44±6.71 ppm syringic acid, 815.26±41.77 ppm syringaldehyde, 15.21±2.19 ppm p-coumaric acid, and 44.75±3.40 ppm ferulic acid, among the tested methods. High sodium hydroxide concentration (10% wt. was needed to promote efficient nitrobenzene oxidation. However, less severe oxidation condition was preferred to preserve the hydroxycinnamic acids (p-coumaric acid and ferulic acid. Cutinase-catalyzed hydrolysis was found to be more efficient than MnP-catalyzed oxidation in the production of aromatic compounds. By hydrolyzed 8% wt. of lignin with 0.625 mL cutinase g−1 lignin at pH 8 and 55°C for 24 hours, about 642.83±14.45 ppm hydroxybenzoic acid, 70.19±3.31 ppm syringaldehyde, 22.80±1.04 ppm vanillin, 27.06±1.20 ppm p-coumaric acid, and 50.19±2.23 ppm ferulic acid were produced.

  7. Production of rhesus monkey cloned embryos expressing monomeric red fluorescent protein by interspecies somatic cell nuclear transfer

    International Nuclear Information System (INIS)

    Zhu, Hai-Ying; Kang, Jin-Dan; Li, Suo; Jin, Jun-Xue; Hong, Yu; Jin, Long; Guo, Qing; Gao, Qing-Shan; Yan, Chang-Guo; Yin, Xi-Jun

    2014-01-01

    Highlights: • Rhesus monkey cells were electroporated with a plasmid containing mRFP1, and an mRFP1-expressing cell line was generated. • For the first time, mRFP1-expressing rhesus monkey cells were used as donor cells for iSCNT. • The effect of VPA on the development of embryos cloned using iSCNT was determined. - Abstract: Interspecies somatic cell nuclear transfer (iSCNT) is a promising method to clone endangered animals from which oocytes are difficult to obtain. Monomeric red fluorescent protein 1 (mRFP1) is an excellent selection marker for transgenically modified cloned embryos during somatic cell nuclear transfer (SCNT). In this study, mRFP-expressing rhesus monkey cells or porcine cells were transferred into enucleated porcine oocytes to generate iSCNT and SCNT embryos, respectively. The development of these embryos was studied in vitro. The percentage of embryos that underwent cleavage did not significantly differ between iSCNT and SCNT embryos (P > 0.05; 71.53% vs. 80.30%). However, significantly fewer iSCNT embryos than SCNT embryos reached the blastocyst stage (2.04% vs. 10.19%, P < 0.05). Valproic acid was used in an attempt to increase the percentage of iSCNT embryos that developed to the blastocyst stage. However, the percentages of embryos that underwent cleavage and reached the blastocyst stage were similar between untreated iSCNT embryos and iSCNT embryos treated with 2 mM valproic acid for 24 h (72.12% vs. 70.83% and 2.67% vs. 2.35%, respectively). These data suggest that porcine-rhesus monkey interspecies embryos can be generated that efficiently express mRFP1. However, a significantly lower proportion of iSCNT embryos than SCNT embryos reach the blastocyst stage. Valproic acid does not increase the percentage of porcine-rhesus monkey iSCNT embryos that reach the blastocyst stage. The mechanisms underling nuclear reprogramming and epigenetic modifications in iSCNT need to be investigated further

  8. Production of rhesus monkey cloned embryos expressing monomeric red fluorescent protein by interspecies somatic cell nuclear transfer

    Energy Technology Data Exchange (ETDEWEB)

    Zhu, Hai-Ying; Kang, Jin-Dan; Li, Suo; Jin, Jun-Xue; Hong, Yu; Jin, Long; Guo, Qing; Gao, Qing-Shan; Yan, Chang-Guo; Yin, Xi-Jun, E-mail: yinxj33@msn.com

    2014-02-21

    Highlights: • Rhesus monkey cells were electroporated with a plasmid containing mRFP1, and an mRFP1-expressing cell line was generated. • For the first time, mRFP1-expressing rhesus monkey cells were used as donor cells for iSCNT. • The effect of VPA on the development of embryos cloned using iSCNT was determined. - Abstract: Interspecies somatic cell nuclear transfer (iSCNT) is a promising method to clone endangered animals from which oocytes are difficult to obtain. Monomeric red fluorescent protein 1 (mRFP1) is an excellent selection marker for transgenically modified cloned embryos during somatic cell nuclear transfer (SCNT). In this study, mRFP-expressing rhesus monkey cells or porcine cells were transferred into enucleated porcine oocytes to generate iSCNT and SCNT embryos, respectively. The development of these embryos was studied in vitro. The percentage of embryos that underwent cleavage did not significantly differ between iSCNT and SCNT embryos (P > 0.05; 71.53% vs. 80.30%). However, significantly fewer iSCNT embryos than SCNT embryos reached the blastocyst stage (2.04% vs. 10.19%, P < 0.05). Valproic acid was used in an attempt to increase the percentage of iSCNT embryos that developed to the blastocyst stage. However, the percentages of embryos that underwent cleavage and reached the blastocyst stage were similar between untreated iSCNT embryos and iSCNT embryos treated with 2 mM valproic acid for 24 h (72.12% vs. 70.83% and 2.67% vs. 2.35%, respectively). These data suggest that porcine-rhesus monkey interspecies embryos can be generated that efficiently express mRFP1. However, a significantly lower proportion of iSCNT embryos than SCNT embryos reach the blastocyst stage. Valproic acid does not increase the percentage of porcine-rhesus monkey iSCNT embryos that reach the blastocyst stage. The mechanisms underling nuclear reprogramming and epigenetic modifications in iSCNT need to be investigated further.

  9. Sublingual Immunotherapy with a Five-Grass Pollen Tablet in Adult Patients with Allergic Rhinitis: An Open, Prospective, Noninterventional, Multicenter Study

    Directory of Open Access Journals (Sweden)

    Oliver Pfaar

    2015-01-01

    Full Text Available Background. Although the safety and efficacy of sublingual immunotherapy (SLIT with a five-grass pollen tablet have been demonstrated in randomized clinical trials (RCTs, these outcomes must always be evaluated in real-life medical practice. Methods. In a prospective, open-label, noninterventional, “real-life” study in Germany, we evaluated the safety, tolerability, and effectiveness of SLIT with a five-grass pollen tablet in adults with grass-pollen-induced allergic rhinoconjunctivitis. Results. 808 adults were enrolled between September 2008 and December 2009. 35.3% of the participants experienced at least one adverse drug reaction (ADR, the most common of which were mild-to-moderate gastrointestinal and respiratory disorders. Serious ADRs considered causally related to SLIT treatment occurred in four patients. Overall, the five-grass pollen tablet was considered to have good or very good tolerability by most investigators and patients. Treatment was associated with the relief of nasal, ocular, and bronchial symptoms and decreased symptomatic medication use. However, interpretation of clinical improvements was limited by lower atmospheric grass pollen levels during the study season (relative to the preceding season. Conclusions. In a large population of patients treated in real-life medical practice, SLIT with a five-grass pollen tablet was safe and well tolerated. The patient-reported symptom relief suggests that SLIT was associated with clinical benefits.

  10. Monomeric Aβ1–40 and Aβ1–42 Peptides in Solution Adopt Very Similar Ramachandran Map Distributions That Closely Resemble Random Coil

    Science.gov (United States)

    2016-01-01

    The pathogenesis of Alzheimer’s disease is characterized by the aggregation and fibrillation of amyloid peptides Aβ1–40 and Aβ1–42 into amyloid plaques. Despite strong potential therapeutic interest, the structural pathways associated with the conversion of monomeric Aβ peptides into oligomeric species remain largely unknown. In particular, the higher aggregation propensity and associated toxicity of Aβ1–42 compared to that of Aβ1–40 are poorly understood. To explore in detail the structural propensity of the monomeric Aβ1–40 and Aβ1–42 peptides in solution, we recorded a large set of nuclear magnetic resonance (NMR) parameters, including chemical shifts, nuclear Overhauser effects (NOEs), and J couplings. Systematic comparisons show that at neutral pH the Aβ1–40 and Aβ1–42 peptides populate almost indistinguishable coil-like conformations. Nuclear Overhauser effect spectra collected at very high resolution remove assignment ambiguities and show no long-range NOE contacts. Six sets of backbone J couplings (3JHNHα, 3JC′C′, 3JC′Hα, 1JHαCα, 2JNCα, and 1JNCα) recorded for Aβ1–40 were used as input for the recently developed MERA Ramachandran map analysis, yielding residue-specific backbone ϕ/ψ torsion angle distributions that closely resemble random coil distributions, the absence of a significantly elevated propensity for β-conformations in the C-terminal region of the peptide, and a small but distinct propensity for αL at K28. Our results suggest that the self-association of Aβ peptides into toxic oligomers is not driven by elevated propensities of the monomeric species to adopt β-strand-like conformations. Instead, the accelerated disappearance of Aβ NMR signals in D2O over H2O, particularly pronounced for Aβ1–42, suggests that intermolecular interactions between the hydrophobic regions of the peptide dominate the aggregation process. PMID:26780756

  11. Monomeric Aβ(1-40) and Aβ(1-42) Peptides in Solution Adopt Very Similar Ramachandran Map Distributions That Closely Resemble Random Coil.

    Science.gov (United States)

    Roche, Julien; Shen, Yang; Lee, Jung Ho; Ying, Jinfa; Bax, Ad

    2016-02-09

    The pathogenesis of Alzheimer's disease is characterized by the aggregation and fibrillation of amyloid peptides Aβ(1-40) and Aβ(1-42) into amyloid plaques. Despite strong potential therapeutic interest, the structural pathways associated with the conversion of monomeric Aβ peptides into oligomeric species remain largely unknown. In particular, the higher aggregation propensity and associated toxicity of Aβ(1-42) compared to that of Aβ(1-40) are poorly understood. To explore in detail the structural propensity of the monomeric Aβ(1-40) and Aβ(1-42) peptides in solution, we recorded a large set of nuclear magnetic resonance (NMR) parameters, including chemical shifts, nuclear Overhauser effects (NOEs), and J couplings. Systematic comparisons show that at neutral pH the Aβ(1-40) and Aβ(1-42) peptides populate almost indistinguishable coil-like conformations. Nuclear Overhauser effect spectra collected at very high resolution remove assignment ambiguities and show no long-range NOE contacts. Six sets of backbone J couplings ((3)JHNHα, (3)JC'C', (3)JC'Hα, (1)JHαCα, (2)JNCα, and (1)JNCα) recorded for Aβ(1-40) were used as input for the recently developed MERA Ramachandran map analysis, yielding residue-specific backbone ϕ/ψ torsion angle distributions that closely resemble random coil distributions, the absence of a significantly elevated propensity for β-conformations in the C-terminal region of the peptide, and a small but distinct propensity for αL at K28. Our results suggest that the self-association of Aβ peptides into toxic oligomers is not driven by elevated propensities of the monomeric species to adopt β-strand-like conformations. Instead, the accelerated disappearance of Aβ NMR signals in D2O over H2O, particularly pronounced for Aβ(1-42), suggests that intermolecular interactions between the hydrophobic regions of the peptide dominate the aggregation process.

  12. Synthesis and characterization of monomeric and dimeric manganese(II and zinc(II complexes of pyridine-2-carbaldoxime

    Directory of Open Access Journals (Sweden)

    Jørgen Glerup

    2000-12-01

    Full Text Available The syntheses and characterization of two complexes of manganese(II and one complex of zinc(II with the ligand pyridine-2-carbaldoxime, C6H6N2O, are described. The monomeric manganese(II complex cis-[Mn(C6H6N2O 2Cl2] (1 crystallizes in the orthorhombic space group Pbcn with 4 formula units in a cell of dimensions a = 12.479(3 Å, b = 10.348(2 Å, and c = 11. 974(2 Å. The structure has been refined to a final value of the conventional R-factor of 0.0330 based on 1513 observed independent reflections. The analogous zinc(II complex, cis-[Zn(C6H6N2O2Cl2] (2 also crystallizes in the orthorhombic space group Pbcn with 4 formula units in a cell of dimensions a = 12.215(2 Å, b = 10.383(2 Å, and c = 12. 016(2 Å. The structure has been refined to a final value of the conventional R-factor of 0.0377 based on 1117 observed independent reflections. The two complexes are isostructural, with the central metal atom lying on a crystallographic 2-fold axis. Both complexes are approximately octahedral, the coordination being provided by two trans pyridine nitrogen atoms and two cis amine nitrogen atoms from the oxime ligands, and by two cis chlorides. The dimeric manganese(II complex [(C6H6N2O(CH3OHClMnCl2MnCl(CH3OH(C6H6N2O] (3 crystallizes in the monoclinic space group P21/n with 2 formula units in a cell of dimensions a = 7.895(2 Å, b = 11.196(3 Å, and c = 12. 544(2 Å, and b = 98.39(2o. The structure has been refined to a final value of the conventional R-factor of 0.0312 based on 1568 observed independent reflections. There is a crystallographic inversion center in the middle of the dimer relating one manganese center to the other. The geometry at each manganese(II center is again roughly octahedral, coordination being provided by two nitrogen atoms from the oxime ligand, a terminal chloride ion trans to the amine nitrogen, the oxygen atom of the coordinated methanol molecule, and two bridging chlorides that link the two halves of the dimer. The Mn

  13. Pushing the size limit of de novo structure ensemble prediction guided by sparse SDSL-EPR restraints to 200 residues: The monomeric and homodimeric forms of BAX

    Science.gov (United States)

    Fischer, Axel W.; Bordignon, Enrica; Bleicken, Stephanie; García-Sáez, Ana J.; Jeschke, Gunnar; Meiler, Jens

    2016-01-01

    Structure determination remains a challenge for many biologically important proteins. In particular, proteins that adopt multiple conformations often evade crystallization in all biologically relevant states. Although computational de novo protein folding approaches often sample biologically relevant conformations, the selection of the most accurate model for different functional states remains a formidable challenge, in particular, for proteins with more than about 150 residues. Electron paramagnetic resonance (EPR) spectroscopy can obtain limited structural information for proteins in well-defined biological states and thereby assist in selecting biologically relevant conformations. The present study demonstrates that de novo folding methods are able to accurately sample the folds of 192-residue long soluble monomeric Bcl-2-associated X protein (BAX). The tertiary structures of the monomeric and homodimeric forms of BAX were predicted using the primary structure as well as 25 and 11 EPR distance restraints, respectively. The predicted models were subsequently compared to respective NMR/X-ray structures of BAX. EPR restraints improve the protein-size normalized root-mean-square-deviation (RMSD100) of the most accurate models with respect to the NMR/crystal structure from 5.9 Å to 3.9 Å and from 5.7 Å to 3.3 Å, respectively. Additionally, the model discrimination is improved, which is demonstrated by an improvement of the enrichment from 5% to 15% and from 13% to 21%, respectively. PMID:27129417

  14. Resolved single-molecule detection of individual species within a mixture of anti-biotin antibodies using an engineered monomeric nanopore.

    Science.gov (United States)

    Fahie, Monifa; Chisholm, Christina; Chen, Min

    2015-02-24

    Oligomeric protein nanopores with rigid structures have been engineered for the purpose of sensing a wide range of analytes including small molecules and biological species such as proteins and DNA. We chose a monomeric β-barrel porin, OmpG, as the platform from which to derive the nanopore sensor. OmpG is decorated with seven flexible loops that move dynamically to create a distinct gating pattern when ionic current passes through the pore. Biotin was chemically tethered to the most flexible one of these loops. The gating characteristic of the loop's movement in and out of the porin was substantially altered by analyte protein binding. The gating characteristics of the pore with bound targets were remarkably sensitive to molecular identity, even providing the ability to distinguish between homologues within an antibody mixture. A total of five gating parameters were analyzed for each analyte to create a unique fingerprint for each biotin-binding protein. Our exploitation of gating noise as a molecular identifier may allow more sophisticated sensor design, while OmpG's monomeric structure greatly simplifies nanopore production.

  15. Histometría de la glándula sublingual de ratones (Mus musculus machos y hembras infectados con la cepa RAL del parásito de Chagas, Trypanosoma cruzi

    Directory of Open Access Journals (Sweden)

    Sérgio de Albuquerque

    2008-06-01

    Full Text Available Analizamos morfológica e histométricamente la glándula sublingual de ratones infectados con la cepa RAL del Trypanosoma cruzi, en machos y hembras. Usamos ratones albinos (Mus musculus, variedad Swiss, inoculados con 2x104 tripomastigotes sanguíneos de la cepa RAL del T. cruzi.. Sacrificamos los animales en el pico de la parasitemia (12º día y fijamos las glándulas sublinguales en ALFAC. Los cortes histológicos teñidos con HE fueron evaluados histométricamente (cariometría y estereología. La parasitemia fue más elevada en las hembras. Histopatológicamente, los "ácinos" (acini de los animales infectados eran menores, con escasa secreción, y conductos estriados menores. Los núcleos de las "medialunas" eran menores y había nidos de amastigotes en el citoplasma. Cariométricamente, los núcleos de los ácinos, medialunas y conductos estriados eran menores en los ratones infectados. Estereológicamente, los volúmenes relativos ocupados por ácinos y conductos estriados fueron menores e, inversamente, fue mayor el volumen para el tejido conjuntivo de los machos infectados. Las densidades de superficie de ácinos y conductos fueron mayores, y el diámetro y el espesor de la pared menores, en este grupo. Por otro lado, la densidad de ácinos fue menor, y las de los conductos estriados y tejido conjuntivo, fueron mayores en las hembras infectadas. Las densidades de superficie de ácinos y conductos estriados fueron mayores, mientras que el diámetro y espesor de la pared de los ácinos fueron menores (y las de los conductos estriados mayores, en este grupo. La cepa RAL del T. cruzi causó un cuadro general de atrofia general en la glándula sublingual, con numerosos nidos de parásitos.Histometry of the sublingual gland in male and female mice (Mus musculus infected with the RAL strain of the Chagas parasite, Trypanosoma cruzi. The aim of this work was to analyze histologically and histometrically the sublingual gland of mice infected

  16. Quality of life improvement after a three-year course of sublingual immunotherapy in patients with house dust mite and grass pollen induced allergic rhinitis: results from real-life.

    Science.gov (United States)

    Novakova, Silviya Mihaylova; Staevska, Maria Toncheva; Novakova, Plamena Ivanova; Yoncheva, Manuela Dimitrova; Bratoycheva, Maria Stoykova; Musurlieva, Nina Mihaylova; Tzekov, Valeri Dimitrov; Nicolov, Dimitar Georgiev

    2017-09-29

    Along with its high prevalence, the burden of allergic rhinitis rests upon the serious impact on quality of life of patients. Allergic rhinitis is associated with impairments in daily activities, work and school performance, and practical problems. Patients suffer from sleep disorders and emotional problems. Тhe advantages of sublingual immunotherapy on quality of life have only recently begun to emerge. The objective of this prospective real-life study was to evaluate the effect of a three-year course of sublingual immunotherapy with house dust mite (HDM) and grass pollen extracts on quality of life in adults with allergic rhinitis. A total number of 191 adult patients [105 (54,979%) men; mean age 27.3 years (SD-6.14)] with moderate to severe allergic rhinitis and clinically relevant sensitization to house dust mites or grass pollen were prospectively evaluated in the course of management of their disease. Health-related quality of life was assessed by Rhinoconjunctivitis Quality of Life Questionnaire at baseline and after three-year course of sublingual immunotherapy. The mean overall Qol score assessed at baseline and at the end of the third year of treatment decreased significantly in patients treated with HDM extract (from 2.95 to 0.76) as well as with Grass pollen extract (from 2.83 to 1.22) (р life provided evidence that a three-year course of SLIT with HDM extract as well as with grass pollen extract significantly increased QoL in patients with allergic rhinitis.

  17. Efficacy and safety of 4 months of sublingual immunotherapy with recombinant Mal d 1 and Bet v 1 in patients with birch pollen-related apple allergy.

    Science.gov (United States)

    Kinaciyan, Tamar; Nagl, Birgit; Faustmann, Sandra; Frommlet, Florian; Kopp, Stephan; Wolkersdorfer, Martin; Wöhrl, Stefan; Bastl, Katharina; Huber, Hans; Berger, Uwe; Bohle, Barbara

    2018-03-01

    Birch pollen-related apple allergy is among the most prevalent food allergies in adolescent/adult subjects and mainly results from sensitization to the major birch pollen allergen Bet v 1 and subsequent cross-reaction with the apple protein Mal d 1. However, specific immunotherapy with birch pollen has inconsistent effects on apple allergy. We sought to compare the safety and efficacy of sublingual immunotherapy (SLIT) with 2 formulations containing either rMal d 1 or rBet v 1 on birch pollen-related apple allergy. Sixty participants with birch pollen-related apple allergy were randomized to daily sublingual application of placebo (n = 20) or 25 μg of rMal d 1 (n = 20) or rBet v 1 (n = 20) for 16 weeks. Adverse events were regularly recorded. Sublingual challenges with standardized doses of rMal d 1, skin prick tests with recombinant allergens, and measurements of allergen-specific IgE and IgG 4 antibodies were performed before and after treatment. Both formulations caused comparable, mainly local adverse events. No systemic reactions occurred. Compared with the placebo and rBet v 1-treated groups, SLIT with rMal d 1 reduced rMal d 1-induced oral symptoms (P = .001 and P = .038) accompanied by longitudinally reduced rMal d 1-specific cutaneous reactions (P = .022) and enhanced IgG 4 /IgE ratios (P = .012). SLIT with rBet v 1 neither improved the clinical reactivity to rMal d 1 nor enhanced rMal d 1-specific IgG 4 /IgE ratios. Participants receiving placebo showed no allergen-specific changes. Sublingual treatment with a recombinant food allergen was safe and clinically effective, as determined by using standardized challenges. We present a promising approach for the effective treatment of birch pollen-related apple allergy. Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  18. Formulation and Evaluation of Fast-Disintegrating Sublingual Tablets of Atropine Sulfate: the Effect of Tablet Dimensions and Drug Load on Tablet Characteristics.

    Science.gov (United States)

    Aodah, Alhussain; Bafail, Rawan S; Rawas-Qalaji, Mutasem

    2017-07-01

    In this study, we formulated and evaluated the effects of tablet dimensions and drug load on the characteristics of atropine sulfate (AS) fast-disintegrating sublingual tablets (FDSTs). We aim to develop AS FDSTs as an alternative non-invasive and portable dosage form for the emergency treatment of organophosphate (OP) toxicity. AS autoinjector, AtroPen®, is the only self-administered dosage form available as an antidote for-out-of-hospital emergency use, but it is associated with several limitations and drawbacks. Seven FDST formulations of two tablet sizes, 150 mg (A) and 50 mg (B), and of several AS loads, 0 mg (A1, B1), 2 mg (A2, B2), 4 mg (B3), and 8 mg (B4a, B4b), were formulated and manufactured by direct compression. AS FDST characteristics were evaluated using USP and non-USP tests. Results were statistically compared at p < 0.05. All FDSTs passed the USP content uniformity and friability tests, disintegrated and released AS in ≤30 and 60 s. B1 and B2 were significantly harder than A1 and A2. Water uptake of A1 was significantly the highest. However, B1 and B2 had shorter disintegration and wetting times and higher amounts of AS dissolved than did A1 and A2 (p < 0.05). Increasing AS negatively affected FDST tensile strength (p < 0.05 for B4a) and water uptake (p < 0.05 for B3, B4a and B4b), however, without affecting AS dissolution. Formulation of AS up to 16% into smaller FDSTs was successful. Smaller FDSTs were harder and disintegrated more quickly. These AS FDSTS have the potential for further in vivo testing to evaluate their OP antidote potential.

  19. Evaluation of stability of allergen extracts for sublingual immunotherapy during transport under unfavourable temperature conditions with an innovative thermal insulating packaging.

    Science.gov (United States)

    Puccinelli, P; Natoli, V; Dell'albani, I; Scurati, S; Incorvaia, C; Barbieri, S; Masieri, S; Frati, F

    2013-10-01

    Many pharmaceutical and biotechnological products are temperature-sensitive and should normally be kept at a controlled temperature, particularly during transport, in order to prevent the loss of their stability and activity. Therefore, stability studies should be performed for temperature-sensitive products, considering product characteristics, typical environmental conditions, and anticipating environmental extremes that may occur during product transport in a specific country. Staloral products for sublingual immunotherapy are temperature sensitive and are labelled for maintenance under refrigerated conditions (2-8°C). Given the peculiar climatic context of Italy and the great temperature fluctuations that may occur during transport, this study was aimed at evaluating the impact of a new engineered thermal insulating packaging for Staloral. In particular, the purpose was to assess whether the new packaging could create a container condition able to preserve the stability and immunological activity of the product during the transport phase throughout Italy. The results showed that the range of temperatures that can affect the product, in the area surrounding the product packaging, may reach a peak of 63°C during transport under the most unfavourable climatic conditions, i.e. in a non-refrigerated van during the summer season, from the site of production in France to the patient's house in Catania, the city with the highest temperatures in Italy. However, the highest temperature reached inside the vaccine did not exceed 45°C over a period of about 2 h. The ELISA inhibition test on samples subjected to the extreme temperature conditions previously defined (45°C) showed an immunological activity higher than 75% of that initially measured and was comparable to those obtained with samples stored at controlled temperature (5°C). This means that, even in the worst case scenario, the structure of the allergen extracts is not influenced and the vaccine potency is

  20. Efficacy and safety of sublingual ramelteon as an adjunctive therapy in the maintenance treatment of bipolar I disorder in adults: A phase 3, randomized controlled trial.

    Science.gov (United States)

    Mahableshwarkar, Atul R; Calabrese, Joseph R; Macek, Thomas A; Budur, Kumar; Adefuye, Adedeji; Dong, Xinxin; Hanson, Elizabeth; Sachs, Gary S

    2017-10-15

    The optimal long-term management strategy for bipolar I disorder patients is not yet established. Evidence supports the rationale for circadian rhythm regulation to prevent mood episode relapse in bipolar patients. This study evaluated the efficacy and safety of a new sublingual formulation of the melatonin receptor agonist ramelteon (ramelteon SL) as adjunctive therapy in the maintenance treatment of bipolar I patients. In a double-blinded trial in the United States and Latin America, adult bipolar I disorder patients stable for ≥ 8 weeks before baseline and with a mood episode 8 weeks to 9 months before screening, were randomized to once-daily ramelteon SL 0.1mg (n = 164), 0.4mg (n = 160), or 0.8mg (n = 154), or placebo (n = 164), in addition to their existing treatment. The primary endpoint was time from randomization to relapse of symptoms. The prespecified futility criterion in a planned, unblinded, independent interim analysis was the failure of all ramelteon SL doses to achieve a conditional power ≥ 30% compared with placebo. No significant differences between any dose of ramelteon SL and placebo were observed. The study was terminated after meeting the futility criteria. Ramelteon SL was well tolerated, with a safety profile consistent with that for oral ramelteon. A low rate of relapse events precluded detection of any statistically significant difference between groups. The study failed to demonstrate the efficacy of ramelteon SL as adjunctive maintenance therapy for bipolar disorder. Interim analyses for futility in clinical studies are valuable in preventing unnecessary exposure of subjects to interventions. Copyright © 2017. Published by Elsevier B.V.

  1. Elucidation of Arctigenin Pharmacokinetics and Tissue Distribution after Intravenous, Oral, Hypodermic and Sublingual Administration in Rats and Beagle Dogs: Integration of In Vitro and In Vivo Findings

    Directory of Open Access Journals (Sweden)

    Jie Li

    2017-06-01

    Full Text Available Although arctigenin (AG has diverse bioactivities, such as anti-oxidant, anti-inflammatory, anti-cancer, immunoregulatory and neuroprotective activities, its pharmacokinetics have not been systematically evaluated. The purpose of this work was to identify the pharmacokinetic properties of AG via various experiments in vivo and in vitro. In this research, rats and beagle dogs were used to investigate the PK (pharmacokinetics, PK profiles of AG with different drug-delivery manners, including intravenous (i.v, hypodermic injection (i.h, and sublingual (s.l administration. The data shows that AG exhibited a strong absorption capacity in both rats and beagle dogs (absorption rate < 1 h, a high absorption degree (absolute bioavailability > 100%, and a strong elimination ability (t1/2 < 2 h. The tissue distributions of AG at different time points after i.h showed that the distribution of AG in rat tissues is rapid (2.5 h to reach the peak and wide (detectable in almost all tissues and organs. The AG concentration in the intestine was the highest, followed by that in the heart, liver, pancreas, and kidney. In vitro, AG were incubated with human, monkey, beagle dog and rat liver microsomes. The concentrations of AG were detected by UPLC-MS/MS at different time points (from 0 min to 90 min. The percentages of AG remaining in four species’ liver microsomes were human (62 ± 6.36% > beagle dog (25.9 ± 3.24% > rat (15.7 ± 9% > monkey (3.69 ± 0.12%. This systematic investigation of pharmacokinetic profiles of arctigenin (AG in vivo and in vitro is worthy of further exploration.

  2. The influence of house dust mite sublingual immunotherapy on the TSLP-OX40L signaling pathway in patients with allergic rhinitis.

    Science.gov (United States)

    Meng, Qingxiang; Liu, Xiaolong; Li, Peng; He, Long; Xie, Jinghua; Gao, Xionghui; Wu, Xiaozhong; Su, Fang; Liang, Yong

    2016-08-01

    This study aimed to investigate the clinical efficacy of sublingual immunotherapy (SLIT) with house dust mite (HDM) extract and to examine T helper 2 (Th2)-type immune responses mediated by the thymic stromal lymphopoietin (TSLP-OX40L) signaling pathway in patients with moderate to severe allergic rhinitis (AR) after 12-month HDM SLIT. Forty-six cases of HDM-sensitized patients with persistent AR in southern China were enrolled in this study. Clinical efficacy of SLIT was assessed by determining the individual nasal symptom score (INSS) and total nasal symptom score (TNSS) after 12-month HDM SLIT. Moreover, the TSLP-OX40L signaling pathway was investigated through measurements of TSLP by enzyme-labeled immunosorbent assay (ELISA) and OX40L by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and flow cytometry. After 12 months of HDM SLIT, TNSS and INSS were significantly decreased overall compared with baseline values (p < 0.001). By the end of the 12-month HDM SLIT, TNSS had declined by ∼50% compared with baseline, and the corresponding level of TSLP in nasal lavage decreased significantly (p < 0.05). The level of OX40L messenger RNA (mRNA) in blood was markedly decreased significantly after 12-month HDM SLIT compared with baseline (t = 12.300, p < 0.05). Furthermore, significant decreases in OX40L expression on the surface of peripheral blood mononuclear cells (PBMCs) (t = 13.100, p < 0.05) and OX40L expression on the surface of CD11c+CD86+ cells in PBMCs (t = 9.946, p < 0.05) after 12-month HDM SLIT were observed. HDM SLIT downregulated Th2-type immune responses mediated by the TSLP-OX40L signaling pathway in patients with persistent moderate to severe AR. © 2016 ARS-AAOA, LLC.

  3. Urinary tract infections in women with stress urinary incontinence treated with transobturator suburethral tape and benefit gained from the sublingual polibacterial vaccine.

    Science.gov (United States)

    Lorenzo Gómez, María F; Collazos Robles, Rafael E; Virseda Rodríguez, Álvaro J; García Cenador, María B; Mirón Canelo, José A; Padilla Fernández, Bárbara

    2015-08-01

    Stress urinary incontinence (SUI) and recurrent urinary tract infections (RUTIs) are highly prevalent diseases. Our purpose was to investigate the relationship between RUTIs and surgical correction of SUI with transobturator suburethral tape (TOT) and to describe the benefit gained from a sublingual polibacterial preparation on RUTIs developed after TOT. A retrospective study was performed on 420 women who underwent TOT surgery due to SUI between April 2003 and October 2011. Group A: patients without urinary tract infections (UTIs) before TOT (n = 294). Group B: patients with UTIs before TOT (n = 126). age, personal history, number of UTIs/month prior to and after surgery, appearance of urgent urinary incontinence (UUI) with or without UTIs, response to International Consultation on Incontinence Questionnaire Short Form (ICIQ-SF) and Short Form 36 (SF-36) questionnaires. Group A: 85% dry; 5% UUI; 4% de novo UTIs with good response to antibiotics over 6 days. No RUTIs during the follow-up period, 2% with sporadic UTIs. Group B: 47.61% RUTIs; 52.39% sporadic UTIs; greater incidence of diabetes mellitus (p < 0.0025) and smoking (p < 0.0031) than group A. After TOT: 79.36% dry; 10% RUTIs. After treatment with antibiotics for 6 days and bacterial preparation for 3 months, 82% of patients did not have a UTI anymore. Postoperative cystourethrogram revealed 38% of nondiagnosed cystoceles before TOT. No patient had a postvoiding volume greater than 100 cm(3) after TOT. Improvement of ICIQ-SF (p < 0.001) and SF-36 (p < 0.0004) in both groups. After eliminating bias associated with the tape, the technique and the surgeon's skills, SUI correction may decrease the number of UTIs and improve the quality of life. UTIs disappeared in 82% of patients with RUTIs after TOT.

  4. Hydrolyzable tannins of tamaricaceous plants. V. Structures of monomeric-trimeric tannins and cytotoxicity of macrocyclic-type tannins isolated from Tamarix nilotica (1).

    Science.gov (United States)

    Orabi, Mohamed A A; Taniguchi, Shoko; Sakagami, Hiroshi; Yoshimura, Morio; Yoshida, Takashi; Hatano, Tsutomu

    2013-05-24

    Three new ellagitannin monomers, nilotinins M5-M7 (1-3), a dimer, nilotinin D10 (4), and a trimer, nilotinin T1 (5), together with three known dimers, hirtellin D (7) and tamarixinins B (8) and C (9), and a trimer, hirtellin T2 (6), were isolated from Tamarix nilotica dried leaves. The structures of the tannins were elucidated by intensive spectroscopic methods and chemical conversions into known tannins. The new trimer (5) is a unique macrocyclic type whose monomeric units are linked together by an isodehydrodigalloyl and two dehydrodigalloyl moieties. Additionally, dimeric and trimeric macrocyclic-type tannins isolated from T. nilotica in this study were assessed for possible cytotoxic activity against four human tumor cell lines. Tumor-selective cytotoxicities of the tested compounds were higher than those of synthetic and natural potent cytotoxic compounds, including polyphenols, and comparable with those of 5-fluorouracil and melphalan.

  5. Corrosion inhibition of aluminum with a series of aniline monomeric surfactants and their analog polymers in 0.5 M HCl solution

    Directory of Open Access Journals (Sweden)

    M.M. El-Deeb

    2015-07-01

    Full Text Available The inhibition effect of 3-(12-sodiumsulfonate dodecyloxy aniline monomeric surfactant (MC12 and its analog polymer Poly 3-(dodecyloxy sulfonic acid aniline (PC12 on the corrosion of aluminum in 0.5 M HCl solution was investigated using weight loss and potentiodynamic polarization techniques. The presence of these two compounds in 0.5 M HCl inhibits the corrosion of aluminum without modifying the mechanism of corrosion process. It was found that these inhibitors act as mixed-type inhibitors with anodic predominance as well as the inhibition efficiency increases with increasing inhibitor concentration, but decreases with raising temperature. Langmuir and Frumkin adsorption isotherms fit well with the experimental data. Thermodynamic functions for both dissolution and adsorption processes were determined. The obtained results from weight loss and potentiodynamic polarization techniques are in good agreement with contact angle measurements.

  6. Quinoline derivative containing monomeric and polymeric metal carboxylates: Synthesis, crystal structure and gas adsorption study over a 2D layered framework

    Science.gov (United States)

    Gayen, Saikat; Saha, Debraj; Koner, Subratanath

    2018-06-01

    A new supramolecular metal-carboxylate framework [Co(mqc)2]n (1), and another monomeric compound [Zn (mqc)2(H2O)] (2) (mqcH = 4-methoxy 2-quinolinecarboxylic acid) have been synthesized solvothermally and characterized by single crystal X-ray diffraction, elemental analysis, IR spectra, UV-vis spectra, powdered X-ray diffraction (PXRD) and thermogravimetric analysis. Compound 1 is a 2D coordination polymer, extended to a 3D porous supramolecular network having void space in between 2D layers. Compound 1 exhibits gas uptake capacity of N2, H2, CO2 and CH4 like small gas molecules in which moderately high uptake of H2 and CO2 takes place among the 2D MOFs. While the Zn variety, compound 2 features a one-dimensional chain like structure through strong intermolecular hydrogen-bonding.

  7. Prophylactic Sublingual Immunization with Mycobacterium tuberculosis Subunit Vaccine Incorporating the Natural Killer T Cell Agonist Alpha-Galactosylceramide Enhances Protective Immunity to Limit Pulmonary and Extra-Pulmonary Bacterial Burden in Mice

    Directory of Open Access Journals (Sweden)

    Arshad Khan

    2017-12-01

    Full Text Available Infection by Mycobacterium tuberculosis (Mtb remains a major global concern and the available Bacillus Calmette-Guerin (BCG vaccine is poorly efficacious in adults. Therefore, alternative vaccines and delivery strategies focusing on Mtb antigens and appropriate immune stimulating adjuvants are needed to induce protective immunity targeted to the lungs, the primary sites of infections and pathology. We present here evidence in support of mucosal vaccination by the sublingual route in mice using the subunit Mtb antigens Ag85B and ESAT-6 adjuvanted with the glycolipid alpha-galactosylceramide (α-GalCer, a potent natural killer T (NKT cell agonist. Vaccinated animals exhibited strong antigen-specific CD4 and CD8 T cells responses in the spleen, cervical lymph nodes and lungs. In general, inclusion of the α-GalCer adjuvant significantly enhanced these responses that persisted over 50 days. Furthermore, aerosolized Mtb infection of vaccinated mice resulted in a significant reduction of bacterial load of the lungs and spleens as compared to levels seen in naïve controls or those vaccinated with subunit proteins, adjuvant , or BCG alone. The protection induced by the Mtb antigens and-GalCer vaccine through sublingual route correlated with a TH1-type immunity mediated by antigen-specific IFN-γ and IL-2 producing T cells.

  8. Monomeric RC-LH1 core complexes retard LH2 assembly and intracytoplasmic membrane formation in PufX-minus mutants of Rhodobacter sphaeroides.

    Science.gov (United States)

    Adams, Peter G; Mothersole, David J; Ng, Irene W; Olsen, John D; Hunter, C Neil

    2011-09-01

    In the model photosynthetic bacterium Rhodobacter sphaeroides domains of light-harvesting 2 (LH2) complexes surround and interconnect dimeric reaction centre-light-harvesting 1-PufX (RC-LH1-PufX) 'core' complexes, forming extensive networks for energy transfer and trapping. These complexes are housed in spherical intracytoplasmic membranes (ICMs), which are assembled in a stepwise process where biosynthesis of core complexes tends to dominate the early stages of membrane invagination. The kinetics of LH2 assembly were measured in PufX mutants that assemble monomeric core complexes, as a consequence of either a twelve-residue N-terminal truncation of PufX (PufXΔ12) or the complete removal of PufX (PufX(-)). Lower rates of LH2 assembly and retarded maturation of membrane invagination were observed for the larger and less curved ICM from the PufX(-) mutant, consistent with the proposition that local membrane curvature, initiated by arrays of bent RC-LH1-PufX dimers, creates a favourable environment for stable assembly of LH2 complexes. Transmission electron microscopy and high-resolution atomic force microscopy were used to examine ICM morphology and membrane protein organisation in these mutants. Some partitioning of core and LH2 complexes was observed in PufX(-) membranes, resulting in locally ordered clusters of monomeric RC-LH1 complexes. The distribution of core and LH2 complexes in the three types of membrane examined is consistent with previous models of membrane curvature and domain formation (Frese et al., 2008), which demonstrated that a combination of crowding and asymmetries in sizes and shapes of membrane protein complexes drives membrane organisation. 2011 Elsevier B.V. All rights reserved.

  9. Resolution of two native monomeric 90 kDa nitrate reductase active proteins from Shewanella gelidimarina and the sequence of two napA genes

    International Nuclear Information System (INIS)

    Simpson, Philippa J.L.; McKinzie, Audra A.; Codd, Rachel

    2010-01-01

    Research highlights: → Two monomeric 90 kDa nitrate reductase active proteins from Shewanella gelidimarina. → Sequence of napA from napEDABC-type operon and napA from NapDAGHB-type operon. → Isolation of NAP as NapA or NapAB correlated with NapA P47E amino acid substitution. -- Abstract: The reduction of nitrate to nitrite in the bacterial periplasm occurs in the 90 kDa NapA subunit of the periplasmic nitrate reductase (NAP) system. Most Shewanella genomes contain two nap operons: napEDABC and napDAGHB, which is an unusual feature of this genus. Two native, monomeric, 90 kDa nitrate reductase active proteins were resolved by hydrophobic interaction chromatography from aerobic cultures of Shewanella gelidimarina replete with reduced nitrogen compounds. The 90 kDa protein obtained in higher yield was characterized as NapA by electronic absorption and electron paramagnetic resonance spectroscopies and was identified by LC/MS/MS and MALDI-TOF/TOF MS as NapA from the napEDABC-type operon. The other 90 kDa protein, which was unstable and produced in low yields, was posited as NapA from the napDAGHB-type operon. Two napA genes have been sequenced from the napEDABC-type and napDAGHB-type operons of S. gelidimarina. Native NAP from S. putrefaciens was resolved as one NapA monomer and one NapAB heterodimer. Two amino acid substitutions in NapA correlated with the isolation of NAP as a NapA monomer or a NapAB heterodimer. The resolution of native, redox-active NapA isoforms in Shewanella provides new insight into the respiratory versatility of this genus, which has implications in bioremediation and the assembly of microbial fuel cells.

  10. Crystal Structure of a Monomeric Form of Severe Acute Respiratory Syndrome Coronavirus Endonuclease Nsp15 Suggests a Role for Hexamerization As An Allosteric Switch

    Energy Technology Data Exchange (ETDEWEB)

    Joseph, J.S.; Saikatendu, K.S.; Subramanian, V.; Neuman, B.W.; Buchmeier, M.J.; Stevens, R.C.; Kuhn, P.; /Scripps Res. Inst.

    2007-07-09

    Mature nonstructural protein-15 (nsp15) from the severe acute respiratory syndrome coronavirus (SARS-CoV) contains a novel uridylate-specific Mn{sup 2+}-dependent endoribonuclease (NendoU). Structure studies of the full-length form of the obligate hexameric enzyme from two CoVs, SARS-CoV and murine hepatitis virus, and its monomeric homologue, XendoU from Xenopus laevis, combined with mutagenesis studies have implicated several residues in enzymatic activity and the N-terminal domain as the major determinant of hexamerization. However, the tight link between hexamerization and enzyme activity in NendoUs has remained an enigma. Here, we report the structure of a trimmed, monomeric form of SARS-CoV nsp15 (residues 28 to 335) determined to a resolution of 2.9 Angstroms. The catalytic loop (residues 234 to 249) with its two reactive histidines (His 234 and His 249) is dramatically flipped by {approx}120 degrees into the active site cleft. Furthermore, the catalytic nucleophile Lys 289 points in a diametrically opposite direction, a consequence of an outward displacement of the supporting loop (residues 276 to 295). In the full-length hexameric forms, these two loops are packed against each other and are stabilized by intimate intersubunit interactions. Our results support the hypothesis that absence of an adjacent monomer due to deletion of the hexamerization domain is the most likely cause for disruption of the active site, offering a structural basis for why only the hexameric form of this enzyme is active.

  11. The Escherichia coli P and Type 1 Pilus Assembly Chaperones PapD and FimC Are Monomeric in Solution

    Energy Technology Data Exchange (ETDEWEB)

    Sarowar, Samema; Hu, Olivia J.; Werneburg, Glenn T.; Thanassi, David G.; Li, Huilin; Christie, P. J.

    2016-06-27

    ABSTRACT

    The chaperone/usher pathway is used by Gram-negative bacteria to assemble adhesive surface structures known as pili or fimbriae. Uropathogenic strains ofEscherichia coliuse this pathway to assemble P and type 1 pili, which facilitate colonization of the kidney and bladder, respectively. Pilus assembly requires a periplasmic chaperone and outer membrane protein termed the usher. The chaperone allows folding of pilus subunits and escorts the subunits to the usher for polymerization into pili and secretion to the cell surface. Based on previous structures of mutant versions of the P pilus chaperone PapD, it was suggested that the chaperone dimerizes in the periplasm as a self-capping mechanism. Such dimerization is counterintuitive because the chaperone G1 strand, important for chaperone-subunit interaction, is buried at the dimer interface. Here, we show that the wild-type PapD chaperone also forms a dimer in the crystal lattice; however, the dimer interface is different from the previously solved structures. In contrast to the crystal structures, we found that both PapD and the type 1 pilus chaperone, FimC, are monomeric in solution. Our findings indicate that pilus chaperones do not sequester their G1 β-strand by forming a dimer. Instead, the chaperones may expose their G1 strand for facile interaction with pilus subunits. We also found that the type 1 pilus adhesin, FimH, is flexible in solution while in complex with its chaperone, whereas the P pilus adhesin, PapGII, is rigid. Our study clarifies a crucial step in pilus biogenesis and reveals pilus-specific differences that may relate to biological function.

    IMPORTANCEPili are critical virulence factors for many bacterial pathogens. UropathogenicE. colirelies on P and type 1 pili assembled by the chaperone/usher pathway to

  12. Comparação entre nifedipina por via sublingual e clonidina por via venosa no controle de hipertensão arterial peri-operatória em cirurgias de catarata

    Directory of Open Access Journals (Sweden)

    Stocche Renato Mestriner

    2002-01-01

    Full Text Available JUSTIFICATIVA E OBJETIVOS: Estudo recente mostra que a clonidina por via venosa apresenta-se eficaz e segura no tratamento de crises hipertensivas durante cirurgia de catarata. Este estudo visa comparar o uso de nifedipina, droga amplamente utilizada por via sublingual, e clonidina por via venosa no controle da hipertensão arterial em cirurgias de catarata. MÉTODO: Setenta e cinco pacientes submetidos à facectomia foram distribuídos de forma aleatória e encoberta em: Grupo A, que recebeu nifedipina e Grupos C2 e C3, que receberam, respectivamente, 2 e 3 µg.kg-1 de clonidina por via venosa. Todos os pacientes apresentavam hipertensão arterial (PAS > 170 mmHg ou PAD > 110 mmHg. As PAS, PAD e freqüência cardíaca (FC foram medidas e comparadas nos momentos: 0 (antes do tratamento e de 2 em 2 minutos até o final do procedimento. Os eventos adversos foram anotados. RESULTADOS: Após o tratamento ocorreram diminuições da PAS e PAD nos 3 grupos (p <0,001. Houve controle da pressão arterial (<160 mmHg em 32%, 64% e 72% dos pacientes nos grupos A, C2 e C3, respectivamente (p < 0,05. No grupo C3 ocorreu maior incidência de efeitos colaterais que nos grupos C2 e A (p < 0,05. CONCLUSÕES:A clonidina por via venosa é mais eficaz que a nifedipina, por via sublingual, no controle de crises hipertensivas no peri-operatório de cirurgias de catarata. Contudo, a dose de 3 µg.kg-1 pode estar relacionada a efeitos colaterais, devendo-se iniciar o tratamento com 2 µg.kg-1.

  13. Novel DDR Processing of Corn Stover Achieves High Monomeric Sugar Concentrations from Enzymatic Hydrolysis (230 g/L) and High Ethanol Concentration (10% v/v) During Fermentation

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Xiaowen; Jennings, Ed; Shekiro, Joe; Kuhn, Erik M.; O' Brien, Marykate; Wang, Wei; Schell, Daniel J.; Himmel, Mike; Elander, Richard T.; Tucker, Melvin P.

    2015-04-03

    Distilling and purifying ethanol, butanol, and other products from second and later generation lignocellulosic biorefineries adds significant capital and operating cost for biofuels production. The energy costs associated with distillation affects plant gate and life cycle analysis costs. Lower titers in fermentation due to lower sugar concentrations from pretreatment increase both energy and production costs. In addition, higher titers decrease the volumes required for enzymatic hydrolysis and fermentation vessels. Therefore, increasing biofuels titers has been a research focus in renewable biofuels production for several decades. In this work, we achieved over 200 g/L of monomeric sugars after high solids enzymatic hydrolysis using the novel deacetylation and disc refining (DDR) process on corn stover. The high sugar concentrations and low chemical inhibitor concentrations from the DDR process allowed ethanol titers as high as 82 g/L in 22 hours, which translates into approximately 10 vol% ethanol. To our knowledge, this is the first time that 10 vol% ethanol in fermentation derived from corn stover without any sugar concentration or purification steps has been reported. Techno-economic analysis shows the higher titer ethanol achieved from the DDR process could significantly reduce the minimum ethanol selling price from cellulosic biomass.

  14. Stability of monomeric Cro variants: Isoenergetic transformation of a type I' to a type II' beta-hairpin by single amino acid replacements.

    Science.gov (United States)

    Mollah, A K M M; Stennis, Rhonda L; Mossing, Michael C

    2003-05-01

    The thermodynamic stabilities of three monomeric variants of the bacteriophage lambda Cro repressor that differ only in the sequence of two amino acids at the apex of an engineered beta-hairpin have been determined. The sequences of the turns are EVK-XX-EVK, where the two central residues are DG, GG, and GT, respectively. Standard-state unfolding free energies, determined from circular dichroism measurements as a function of urea concentration, range from 2.4 to 2.7 kcal/mole, while those determined from guanidine hydrochloride range from 2.8 to 3.3 kcal/mole for the three proteins. Thermal denaturation yields van't Hoff unfolding enthalpies of 36 to 40 kcal /mole at midpoint temperatures in the range of 53 to 58 degrees C. Extrapolation of the thermal denaturation free energies with heat capacities of 400 to 600 cal/mole deg gives good agreement with the parameters determined in denaturant titrations. As predicted from statistical surveys of amino acid replacements in beta-hairpins, energetic barriers to transformation from a type I' turn (DG) to a type II' turn (GT) can be quite small.

  15. Interaction of chemokine receptor CXCR4 in monomeric and dimeric state with its endogenous ligand CXCL12: coarse-grained simulations identify differences.

    Science.gov (United States)

    Cutolo, Pasquale; Basdevant, Nathalie; Bernadat, Guillaume; Bachelerie, Françoise; Ha-Duong, Tâp

    2017-02-01

    Despite the recent resolutions of the crystal structure of the chemokine receptor CXCR4 in complex with small antagonists or viral chemokine, a description at the molecular level of the interactions between the full-length CXCR4 and its endogenous ligand, the chemokine CXCL12, in relationship with the receptor recognition and activation, is not yet completely elucidated. Moreover, since CXCR4 is able to form dimers, the question of whether the CXCR4-CXCL12 complex has a 1:1 or 2:1 preferential stoichiometry is still an open question. We present here results of coarse-grained protein-protein docking and molecular dynamics simulations of CXCL12 in association with CXCR4 in monomeric and dimeric states. Our proposed models for the 1:1 and 2:1 CXCR4-CXCL12 quaternary structures are consistent with recognition and activation motifs of both partners provided by the available site-directed mutagenesis data. Notably, we observed that in the 2:1 complex, the chemokine N-terminus makes more steady contacts with the receptor residues critical for binding and activation than in the 1:1 structure, suggesting that the 2:1 stoichiometry would favor the receptor signaling activity with respect to the 1:1 association.

  16. The monomeric form of Neisseria DNA mimic protein DMP19 prevents DNA from binding to the histone-like HU protein

    Science.gov (United States)

    Ko, Tzu-Ping; Liao, Yi-Ting; Hsu, Kai-Cheng

    2017-01-01

    DNA mimicry is a direct and effective strategy by which the mimic competes with DNA for the DNA binding sites on other proteins. Until now, only about a dozen proteins have been shown to function via this strategy, including the DNA mimic protein DMP19 from Neisseria meningitides. We have shown previously that DMP19 dimer prevents the operator DNA from binding to the transcription factor NHTF. Here, we provide new evidence that DMP19 monomer can also interact with the Neisseria nucleoid-associated protein HU. Using BS3 crosslinking, gel filtration and isothermal titration calorimetry assays, we found that DMP19 uses its monomeric form to interact with the Neisseria HU dimer. Crosslinking conjugated mass spectrometry was used to investigate the binding mode of DMP19 monomer and HU dimer. Finally, an electrophoretic mobility shift assay (EMSA) confirmed that the DNA binding affinity of HU is affected by DMP19. These results showed that DMP19 is bifunctional in the gene regulation of Neisseria through its variable oligomeric forms. PMID:29220372

  17. The anchorless adhesin Eap (extracellular adherence protein) from Staphylococcus aureus selectively recognizes extracellular matrix aggregates but binds promiscuously to monomeric matrix macromolecules.

    Science.gov (United States)

    Hansen, Uwe; Hussain, Muzaffar; Villone, Daniela; Herrmann, Mathias; Robenek, Horst; Peters, Georg; Sinha, Bhanu; Bruckner, Peter

    2006-05-01

    Besides a number of cell wall-anchored adhesins, the majority of Staphylococcus aureus strains produce anchorless, cell wall-associated proteins, such as Eap (extracellular adherence protein). Eap contains four to six tandem repeat (EAP)-domains. Eap mediates diverse biological functions, including adherence and immunomodulation, thus contributing to S. aureus pathogenesis. Eap binding to host macromolecules is unusually promiscuous and includes matrix or matricellular proteins as well as plasma proteins. The structural basis of this promiscuity is poorly understood. Here, we show that in spite of the preferential location of the binding epitopes within triple helical regions in some collagens there is a striking specificity of Eap binding to different collagen types. Collagen I, but not collagen II, is a binding substrate in monomolecular form. However, collagen I is virtually unrecognized by Eap when incorporated into banded fibrils. By contrast, microfibrils containing collagen VI as well as basement membrane-associated networks containing collagen IV, or aggregates containing fibronectin bound Eap as effectively as the monomeric proteins. Therefore, Eap-binding to extracellular matrix ligands is promiscuous at the molecular level but not indiscriminate with respect to supramolecular structures containing the same macromolecules. In addition, Eap bound to banded fibrils after their partial disintegration by matrix-degrading proteinases, including matrix metalloproteinase 1. Therefore, adherence to matrix suprastructures by S. aureus can be supported by inflammatory reactions.

  18. Analysis of monomeric and oligomeric organophosphorus flame retardants in fish muscle tissues using liquid chromatography–electrospray ionization tandem mass spectrometry: Application to Nile tilapia (Oreochromis niloticus) from an e-waste processing area in northern Vietnam

    OpenAIRE

    Matsukami, Hidenori; Suzuki, Go; Tue, Nguyen Minh; Tuyen, Le Huu; Viet, Pham Hung; Takahashi, Shin; Tanabe, Shinsuke; Takigami, Hidetaka

    2016-01-01

    Using electrospray ionization tandem mass spectrometry combined with liquid chromatography (LC), a novel analytical method was developed to quantify eight monomeric organophosphorus flame retardants (m-PFRs) and three oligomeric organophosphorus flame retardants (o-PFRs) in fish muscle samples. The optimization and validation experiments indicate that the developed method can determine accurately the concentrations of analytes in fish muscle samples. The recoveries of analytes in fish muscle ...

  19. Crystallization and preliminary X-ray analysis of a monomeric mutant of Azami-Green (mAG), an Aequorea victoria green fluorescent protein-like green-emitting fluorescent protein from the stony coral Galaxea fascicularis

    International Nuclear Information System (INIS)

    Ebisawa, Tatsuki; Yamamura, Akihiro; Kameda, Yasuhiro; Hayakawa, Kou; Nagata, Koji; Tanokura, Masaru

    2009-01-01

    A monomeric mutant of Azami-Green from G. fascicularis was expressed, purified and crystallized using the sitting-drop vapour-diffusion method. The crystal belonged to space group P1 and diffracted X-rays to 2.20 Å resolution. Monomeric Azami-Green (mAG) from the stony coral Galaxea fascicularis is the first monomeric green-emitting fluorescent protein that is not a derivative of Aequorea victoria green fluorescent protein (avGFP). mAG and avGFP are 27% identical in amino-acid sequence. Diffraction-quality crystals of recombinant mAG were obtained by the sitting-drop vapour-diffusion method using PEG 3350 as the precipitant. The mAG crystal diffracted X-rays to 2.20 Å resolution on beamline AR-NW12A at the Photon Factory (Tsukuba, Japan). The crystal belonged to space group P1, with unit-cell parameters a = 41.78, b = 51.72, c = 52.89 Å, α = 90.96, β = 103.41, γ = 101.79°. The Matthews coefficient (V M = 2.10 Å 3 Da −1 ) indicated that the crystal contained two mAG molecules per asymmetric unit

  20. Comparative analysis of the heme iron electronic structure and stereochemistry in tetrameric rabbit hemoglobin and monomeric soybean leghemoglobin a using Mössbauer spectroscopy with a high velocity resolution

    Science.gov (United States)

    Alenkina, I. V.; Kumar, A.; Berkovsky, A. L.; Oshtrakh, M. I.

    2018-02-01

    A comparative study of tetrameric rabbit hemoglobin and monomeric soybean leghemoglobin a in the oxy- and deoxy-forms was carried out using 57Fe Mössbauer spectroscopy with a high velocity resolution in order to analyze the heme iron electronic structure and stereochemistry in relation to the Mössbauer hyperfine parameters. The Mössbauer spectra of tetrameric rabbit hemoglobin in both forms were fitted using two quadrupole doublets related to the 57Fe in ɑ- and β-subunits. In contrast, the Mössbauer spectra of monomeric soybean leghemoglobin a were fitted using: (i) two quadrupole doublets for the oxy-form related to two conformational states of the distal His E7 imidazole ring and different hydrogen bonding of oxygen molecule in the oxy-form and (ii) using three quadrupole doublets for deoxy-form related to three conformational states of the proximal His F8 imidazole ring. Small variations of Mössbauer hyperfine parameters related to small differences in the heme iron electronic structure and stereochemistry in tetrameric rabbit hemoglobin and monomeric soybean leghemoglobin a are discussed.

  1. Medication persistence with long-term, specific grass pollen immunotherapy measured by prescription renewal rates.

    Science.gov (United States)

    Sieber, J; De Geest, S; Shah-Hosseini, K; Mösges, R

    2011-04-01

    We assessed medication persistence using prescription renewal rates for grass pollen specific immunotherapy (SIT) in a representative population of patients in Germany to evaluate whether the perception of superior persistence for the subcutaneous route compared to the sublingual route could be confirmed in clinical practice. Individual prescriptions for allergen immunotherapy were extracted from a national prescription database (INSIGHT Health) and followed over 3 years on a per-patient basis. However, patients' medical history and treatment schedules were not available for analysis. Products were identified by the national drug code (PZN number) and grouped to either subcutaneous immunotherapy (SCIT) with natural extract injections, SCIT with modified allergens (allergoids) or sublingual immunotherapy (SLIT) with natural pollen extract solutions. Persistence was defined as at least one prescription of the individual drug in the respective years. A total of 1409 patients started SIT in 2005 (112, 695, and 602 for natural extract SLIT, natural extract SCIT, and allergoid SCIT, respectively). In 2006, 71%, 55%, and 59% of those patients had at least one renewal prescription of natural extract SLIT, natural extract SCIT, and allergoid SCIT, respectively, as well as 51%, 34%, and 39% in 2007. In both years, persistence with natural extract SLIT was significantly higher than with natural extract SCIT (p = 0.0015 for 2006, p = 0.0003 for 2007) and allergoid SCIT (p = 0.0152 for 2006, p = 0.0111 for 2007). There were no significant differences between the two SCIT groups. Medication persistence with grass pollen SIT in a representative sample of patients in Germany was similar to published medication persistence in asthma and COPD patients. The sublingual application route shows significantly better persistency than the subcutaneous route with native allergens or allergoids.

  2. Fascinating transformations of donor-acceptor complexes of group 13 metal (Al, Ga, In) derivatives with nitriles and isonitriles: from monomeric cyanides to rings and cages.

    Science.gov (United States)

    Timoshkin, Alexey Y; Schaefer, Henry F

    2003-08-20

    Formation of the donor-acceptor complexes of group 13 metal derivatives with nitriles and isonitriles X(3)M-D (M = Al,Ga,In; X = H,Cl,CH(3); D = RCN, RNC; R = H,CH(3)) and their subsequent reactions have been theoretically studied at the B3LYP/pVDZ level of theory. Although complexation with MX(3) stabilizes the isocyanide due to the stronger M-C donor-acceptor bond, this stabilization (20 kJ mol(-1) at most) is not sufficient to make the isocyanide form more favorable. Relationships between the dissociation enthalpy DeltaH degrees (298)(diss), charge-transfer q(CT), donor-acceptor bond energy E(DA), and the shift of the vibrational stretching mode of the CN group upon coordination Deltaomega(CN) have been examined. For a given metal center, there is a good correlation between the energy of the donor-acceptor bond and the degree of a charge transfer. Prediction of the DeltaH degrees (298)(diss) on the basis of the shift of CN stretching mode is possible within limited series of cyanide complexes (for the fixed M,R); in contrast, complexes of the isocyanides exhibit very poor Deltaomega(CN) - DeltaH degrees (298)(diss) correlation. Subsequent X ligand transfer and RX elimination reactions yielding monomeric (including donor-acceptor stabilized) and variety of oligomeric cage and ring compounds with [MN]n, [MC]n, [MNC]n cores have been considered and corresponding to thermodynamic characteristics have been obtained for the first time. Monomeric aluminum isocyanides X(2)AlNC are more stable compared to Al-C bonded isomers; for gallium and indium situation is reversed, in qualitative agreement with Pearson's HSAB concept. Substitution of X by CN in MX(3) increases the dissociation enthalpy of the MX(2)CN-NH(3) complex compared to that for MX(3)-NH(3), irrespective of the substituent X. Mechanisms of the initial reaction of the X transfer have been studied for the case X = R = H. The process of hydrogen transfer from the metal to the carbon atom in H(3)M-CNH is

  3. The monomeric GTPase RabA2 is required for progression and maintenance of membrane integrity of infection threads during root nodule symbiosis.

    Science.gov (United States)

    Dalla Via, Virginia; Traubenik, Soledad; Rivero, Claudio; Aguilar, O Mario; Zanetti, María Eugenia; Blanco, Flavio Antonio

    2017-04-01

    Progression of the infection canal that conducts rhizobia to the nodule primordium requires a functional Rab GTPase located in Golgi/trans-Golgi that also participate in root hair polar growth. Common bean (Phaseolus vulgaris) symbiotically associates with its partner Rhizobium etli, resulting in the formation of root nitrogen-fixing nodules. Compatible bacteria can reach cortical cells in a tightly regulated infection process, in which the specific recognition of signal molecules is a key step to select the symbiotic partner. In this work, we show that RabA2, a monomeric GTPase from common bean, is required for the progression of the infection canal, referred to as the infection thread (IT), toward the cortical cells. Expression of miss-regulated mutant variants of RabA2 resulted in an increased number of abortive infection events, including bursting of ITs and a reduction in the number of nodules. Nodules formed in these plants were small and contained infected cells with disrupted symbiosome membranes, indicating either early senescence of these cells or defects in the formation of the symbiosome membrane during bacterial release. RabA2 localized to mobile vesicles around the IT, but mutations that affect GTP hydrolysis or GTP/GDP exchange modified this localization. Colocalization of RabA2 with ArfA1 and a Golgi marker indicates that RabA2 localizes in Golgi stacks and the trans-Golgi network. Our results suggest that RabA2 is part of the vesicle transport events required to maintain the integrity of the membrane during IT progression.

  4. No need to be HAMLET or BAMLET to interact with histones: binding of monomeric alpha-lactalbumin to histones and basic poly-amino acids.

    Science.gov (United States)

    Permyakov, Serge E; Pershikova, Irina V; Khokhlova, Tatyana I; Uversky, Vladimir N; Permyakov, Eugene A

    2004-05-18

    The ability of a specific complex of human alpha-lactalbumin with oleic acid (HAMLET) to induce cell death with selectivity for tumor and undifferentiated cells was shown recently to be mediated by interaction of HAMLET with histone proteins irreversibly disrupting chromatin structure [Duringer, C., et al. (2003) J. Biol. Chem. 278, 42131-42135]. Here we show that monomeric alpha-lactalbumin (alpha-LA) in the absence of fatty acids is also able to bind efficiently to the primary target of HAMLET, histone HIII, regardless of Ca(2+) content. Thus, the modification of alpha-LA by oleic acid is not required for binding to histones. We suggest that interaction of negatively charged alpha-LA with the basic histone stabilizes apo-alpha-LA and destabilizes the Ca(2+)-bound protein due to compensation for excess negative charge of alpha-LA's Ca(2+)-binding loop by positively charged residues of the histone. Spectrofluorimetric curves of titration of alpha-LA by histone H3 were well approximated by a scheme of cooperative binding of four alpha-LA molecules per molecule of histone, with an equilibrium dissociation constant of 1.0 microM. Such a stoichiometry of binding implies that the binding process is not site-specific with respect to histone and likely is driven by just electrostatic interactions. Co-incubation of positively charged poly-amino acids (poly-Lys and poly-Arg) with alpha-LA resulted in effects which were similar to those caused by histone HIII, confirming the electrostatic nature of the alpha-LA-histone interaction. In all cases that were studied, the binding was accompanied by aggregation. The data indicate that alpha-lactalbumin can be used as a basis for the design of antitumor agents, acting through disorganization of chromatin structure due to interaction between alpha-LA and histone proteins.

  5. Action of DTPA on hepatic plutonium. III. Evidence for a direct chelation mechanism for DTPA-induced excretion of monomeric plutonium into rat bile

    International Nuclear Information System (INIS)

    Bhattacharyya, M.H.; Peterson, D.P.

    1979-01-01

    Trisodium calcium diethylenetriaminepenta[2- 14 C]acetic acid ([ 14 C]DTPA, 0.25 nmole/kg, 0.210 mCi/mmole) was administered via the jugular vein to three rats whose bile ducts and urinary bladders were cannulated. Bile and urine were collected for 24 h after injection, and tissues and excreta were then analyzed for 14 C content. [ 14 C]DTPA was identified in the bile samples by cochromatography with unlabeled DTPA on an anion-exchange column system. Data from this experiment demonstrated the existence of a minor excretion pathway for DTPA into rat bile, accounting for 0.12% of the injected dose by 24 h after administration. Bile was collected for 24 h following the administration of unlabeled Na 3 [CaDTPA] (0.25 mmole/kg, iv) to a rat which had received 239 Pu(IV)-citrate (5.7 μCi/kg, iv) 24 h prior to DTPA. Bile samples containing Pu were analyzed using anion-exchange column chromatography. Eighty to ninety percent of the Pu present in bile chromatographed as a single peak in the position of the Pu-DTPA complex. Cochromatograhy of the 0- to 6-h bile sample with a 239 Pu-[ 14 C]DTPA complex revealed that the Pu appearing in bile following DTPA treatment comigrated with the 239 Pu-[ 14 C]DTPA complex. These data provide strong evidence that, in the rat, DTPA acts to remove hepatic deposits of monomeric Pu by formation of the Pu-DTPA complex followed by excretion of the complex into bile

  6. ADVERSE REACTIONS TO VACCINES AND WAYS OF ITS PREVENTION

    Directory of Open Access Journals (Sweden)

    Yelyseyeva I. V

    2011-04-01

    Full Text Available The overview concerns allergic reaction on vaccines and possible ways of increasing safety of immunization on basis of use of local specific immunotherapies (SIT experience, particularly the sublingual route. The use of chemically altered allergens, allergoids; alternative routes of administration, particularly the sublingual route; use of novel adjuvants, such as CpG oligonucleotides and mycobacterial vaccines; other approaches, such as allergenic peptides, relevant T-cell epitope peptide immunotherapy; DNA vaccination, recombinant and engineered allergens, chimeric molecules and combined therapy are all approaches that have yielded positive results to increase safety of SIT and improve its efficacy.

  7. Improved detection of fill-in using sublingual nitroglycerin in technetium-99m tetrofosmin exercise/rest single photon emission computed tomography one day protocol for old myocardial infarction

    International Nuclear Information System (INIS)

    Miyanaga, Hajime; Kunieda, Yasufumi; Oguni, Atsuhiko; Kamitani, Tadaaki; Kawasaki, Shingo; Takahashi, Toru

    1999-01-01

    Twenty-one patients with old myocardial infarction underwent repeated 99m Tc-tetrofosmin ( 99m Tc) exercise/rest same day protocols with and without the administration of sublingual nitroglycerin (NTG) 5 min before the second injection of 99m Tc for rest SPECT. Twelve of these patients also underwent ordinary exercise/redistribution 201 Tl SPECT. The control study protocol images showed decreased uptake of 99m Tc on exercise in 157 of 420 segments and the presence of fill-in at rest in 58 segments. Images obtained with administration of NTG showed decreased uptake of 99m Tc on exercise in 163 of 420 segments and fill-in in 74 segments at rest. The frequency of fill-in was greater in the NTG protocol than in the control protocol. The segments were scored as different grades according to 99m Tc uptake between 2 protocols. Fill-in was only present or more remarkable in 31 segments in the NTG protocol than in the control protocol. Fill-in was only present or more remarkable in 10 segments in the control protocol than in the NTG protocol. In the NTG protocol, the mean defect score of the exercise images, calculated from the bull's eye image automatically, was higher than that of the rest images. The mean severity score of the exercise images, also calculated from the bull's eye image automatically, was likewise higher than that of the rest images, whereas the mean severity score of the stress images and rest images in the control protocol was not significantly different. Moreover, the mean defect score and severity score of the rest images from the NTG protocol were significantly lower than those obtained from the control protocol. Sublingual NTG administration before the injection of 99m Tc-tetrofosmin at the rest study in the one day exercise/rest studies enhanced fill-in, so may enhance the detection of viable myocardium, allowing more informed decisions regarding cardiac revascularization in patients with chronic coronary artery disease. (K.H.)

  8. Novel sublingual low-dose zolpidem tablet reduces latency to sleep onset following spontaneous middle-of-the-night awakening in insomnia in a randomized, double-blind, placebo-controlled, outpatient study.

    Science.gov (United States)

    Roth, Thomas; Krystal, Andrew; Steinberg, Frank J; Singh, Nikhilesh N; Moline, Margaret

    2013-02-01

    To evaluate efficacy and safety of 3.5-mg zolpidem tartrate sublingual tablets (ZST) on latency to sleep onset after middle-of-the-night (MOTN) awakenings in patients with insomnia characterized by difficulty returning to sleep after MOTN awakenings. Multicenter randomized, double-blind, placebo-controlled, parallel-group. Outpatient. There were 295 adults (median age 43 y; 68.1% female) with primary insomnia and difficulty returning to sleep after MOTN awakenings (three or more MOTN awakenings/wk during screening). After a 2-wk, single-blind placebo eligibility period, participants were randomized 1:1 to as-needed MOTN dosing with 3.5 mg ZST or placebo for 28 nights. An interactive voice response system determined if the study drug could be taken and recorded sleep/wake efficacy measures. ZST significantly (P Zolpidem Tartrate Tablet in Adult Patients with Insomnia" http://www.clinicaltrials.gov/ct2/show/NCT00466193?spons=%22Transcept+Pharmaceuticals%22&spons_ex=Y&rank=2

  9. [ANALYSIS OF BACKGROUNDS AND LEVEL OF UNDERSTANDING OF TREATMENT OF POOR ADHERENCE AND DROPOUT CASES ON SUBLINGUAL IMMUNOTHERAPY FOR JAPANESE CEDAR POLLINOSIS IN THE FIRST FOLLOW-UP YEAR].

    Science.gov (United States)

    Kikkawa, Sayaka; Kamijo, Atsushi; Nakagome, Kazuyuki; Soma, Tomoyuki; Kobayashi, Takehito; Uchida, Yoshitaka; Morita, Eiji; Nagata, Makoto; Inoue, Tomoe; Kase, Yasuhiro

    We considered the factors of poor adherence to and dropout from sublingual immunotherapy (SLIT) by verifying patient backgrounds 1 year after start of treatment. We recruited 38 patients who began SLIT between November 2014 and September 2015. We analyzed their attributes and level of understanding of the treatment, and conducted a self-reported survey on factors behind dropout cases and poor adherence cases. Four patients dropped out 1 year after start of treatment. Three left for reasons related to anxiety about side effects. There were five cases of poor adherence. There was no significant difference between good adherence, poor adherence, and dropout regarding level of understanding of the treatment (p=0.59). In the comparison between good and poor adherence groups, except four dropout patients, the adherence tended to be poor in patients with short duration of disease, smoking patients, and young patients. Continuous rate of SLIT achieved about 90%, suggesting relatively high level of adherence. It appears possible that anxiety related to side effects could be a factor affecting dropout from SLIT. There was no significant difference regarding level of understanding of the treatment. The adherence tended to be poor in patients with short duration of disease, smoking patients, and young patients.

  10. Hue-shifted monomeric variants of Clavularia cyan fluorescent protein: identification of the molecular determinants of color and applications in fluorescence imaging

    Directory of Open Access Journals (Sweden)

    Davidson Michael W

    2008-03-01

    Full Text Available Abstract Background In the 15 years that have passed since the cloning of Aequorea victoria green fluorescent protein (avGFP, the expanding set of fluorescent protein (FP variants has become entrenched as an indispensable toolkit for cell biology research. One of the latest additions to the toolkit is monomeric teal FP (mTFP1, a bright and photostable FP derived from Clavularia cyan FP. To gain insight into the molecular basis for the blue-shifted fluorescence emission we undertook a mutagenesis-based study of residues in the immediate environment of the chromophore. We also employed site-directed and random mutagenesis in combination with library screening to create new hues of mTFP1-derived variants with wavelength-shifted excitation and emission spectra. Results Our results demonstrate that the protein-chromophore interactions responsible for blue-shifting the absorbance and emission maxima of mTFP1 operate independently of the chromophore structure. This conclusion is supported by the observation that the Tyr67Trp and Tyr67His mutants of mTFP1 retain a blue-shifted fluorescence emission relative to their avGFP counterparts (that is, Tyr66Trp and Tyr66His. Based on previous work with close homologs, His197 and His163 are likely to be the residues with the greatest contribution towards blue-shifting the fluorescence emission. Indeed we have identified the substitutions His163Met and Thr73Ala that abolish or disrupt the interactions of these residues with the chromophore. The mTFP1-Thr73Ala/His163Met double mutant has an emission peak that is 23 nm red-shifted from that of mTFP1 itself. Directed evolution of this double mutant resulted in the development of mWasabi, a new green fluorescing protein that offers certain advantages over enhanced avGFP (EGFP. To assess the usefulness of mTFP1 and mWasabi in live cell imaging applications, we constructed and imaged more than 20 different fusion proteins. Conclusion Based on the results of our

  11. Monomeric, dimeric and multimeric system of RGD peptides radiolabeled with 177Lu for tumors therapy that expressing αβ integrin s

    International Nuclear Information System (INIS)

    Luna G, M. A.

    2014-01-01

    The conjugation of peptides to gold nanoparticles (AuNPs) produces biocompatible and stable multimeric systems with target-specific molecular recognition. Peptides based on the cyclic Arg-Gly-Asp (RGD) sequence have been reported as high affinity agents for the α(v)β(3) and α(v)β(5) integrin. The aim of this research was to prepare a multimeric system of 177 Lu-labeled gold nanoparticles conjugated to c[RGDfK(C)] [cyclo(Arg-Gly-Asp-Phe-Lys(Cys)] peptides and to compare the radiation absorbed dose with that of 177 Lu-labeled monomeric and dimeric RGD peptides to α(v)β(3) integrin-positive U87MG tumors in mice, as well as, evaluate the in vitro potential 177 Lu-AuNP-c[RGDfK(C)] as a plasmonic photothermal therapy and targeted radiotherapy system in MCF7 breast cancer cells. DOTA-GGC (1,4,7,10-tetraaza cyclododecane-N,N,N-tetraacetic-Gly-Gly-Cys) and c[RGDfK(C)] peptides were synthesized and conjugated to AuNPs by the spontaneous reaction of the thiol groups. Tem, UV-Vis, XP S, Raman and Far-IR spectroscopy techniques demonstrated that AuNPs were functionalized with the peptides. To obtain 177 Lu-AuNP-c[RGDfK(C)], the 177 Lu-DOTA-GGC radio peptide was first prepared and added to a solution of AuNPs followed by c[RGDfK(C)] (25 μL, 5 μM) at 18 grades C for 15 min. 177 Lu-DOTA-GGC, 177 Lu- DOTA-cRGDfK and 177 Lu-DOTA-E-c(RGDfK) 2 were prepared by adding 177 LuCl 3 (370 MBq) to 5 μL (1 mg/ml) of the DOTA derivative diluted with 50 μL of 1 M acetate buffer at ph 5. The mixture was incubated at 90 grades C in a block heater for 30 min. Radiochemical purity was determined by ultrafiltration and HPLC analyses. After laser irradiation, the presence of c[RGDfK(C)]-AuNP in cells caused a significant increase in the temperature of the medium (50.5 grades C, compared to 40.3 grades C without AuNPs) resulting in a significant decrease in MCF7 cell viability down to 9 %. After treatment with 177 Lu-AuNP-c[RGDfK(C)], the MCF7 cell proliferation was significantly inhibited

  12. Small-angle X-ray scattering analysis reveals the ATP-bound monomeric state of the ATPase domain from the homodimeric MutL endonuclease, a GHKL phosphotransferase superfamily protein.

    Science.gov (United States)

    Iino, Hitoshi; Hikima, Takaaki; Nishida, Yuya; Yamamoto, Masaki; Kuramitsu, Seiki; Fukui, Kenji

    2015-05-01

    DNA mismatch repair is an excision system that removes mismatched bases chiefly generated by replication errors. In this system, MutL endonucleases direct the excision reaction to the error-containing strand of the duplex by specifically incising the newly synthesized strand. Both bacterial homodimeric and eukaryotic heterodimeric MutL proteins belong to the GHKL ATPase/kinase superfamily that comprises the N-terminal ATPase and C-terminal dimerization regions. Generally, the GHKL proteins show large ATPase cycle-dependent conformational changes, including dimerization-coupled ATP binding of the N-terminal domain. Interestingly, the ATPase domain of human PMS2, a subunit of the MutL heterodimer, binds ATP without dimerization. The monomeric ATP-bound state of the domain has been thought to be characteristic of heterodimeric GHKL proteins. In this study, we characterized the ATP-bound state of the ATPase domain from the Aquifex aeolicus MutL endonuclease, which is a homodimeric GHKL protein unlike the eukaryotic MutL. Gel filtration, dynamic light scattering, and small-angle X-ray scattering analyses clearly showed that the domain binds ATP in a monomeric form despite its homodimeric nature. This indicates that the uncoupling of dimerization and ATP binding is a common feature among bacterial and eukaryotic MutL endonucleases, which we suggest is closely related to the molecular mechanisms underlying mismatch repair.

  13. A comparative immunogenicity study in rabbits of disulfide-stabilized, proteolytically cleaved, soluble trimeric human immunodeficiency virus type 1 gp140, trimeric cleavage-defective gp140 and monomeric gp120

    International Nuclear Information System (INIS)

    Beddows, Simon; Franti, Michael; Dey, Antu K.; Kirschner, Marc; Iyer, Sai Prasad N.; Fisch, Danielle C.; Ketas, Thomas; Yuste, Eloisa; Desrosiers, Ronald C.; Klasse, Per Johan; Maddon, Paul J.; Olson, William C.; Moore, John P.

    2007-01-01

    The human immunodeficiency virus type 1 (HIV-1) surface envelope glycoprotein (Env) complex, a homotrimer containing gp120 surface glycoprotein and gp41 transmembrane glycoprotein subunits, mediates the binding and fusion of the virus with susceptible target cells. The Env complex is the target for neutralizing antibodies (NAbs) and is the basis for vaccines intended to induce NAbs. Early generation vaccines based on monomeric gp120 subunits did not confer protection from infection; one alternative approach is therefore to make and evaluate soluble forms of the trimeric Env complex. We have directly compared the immunogenicity in rabbits of two forms of soluble trimeric Env and monomeric gp120 based on the sequence of HIV-1 JR-FL . Both protein-only and DNA-prime, protein-boost immunization formats were evaluated, DNA-priming having little or no influence on the outcome. One form of trimeric Env was made by disrupting the gp120-gp41 cleavage site by mutagenesis (gp140 UNC ), the other contains an intramolecular disulfide bond to stabilize the cleaved gp120 and gp41 moieties (SOSIP.R6 gp140). Among the three immunogens, SOSIP.R6 gp140 most frequently elicited neutralizing antibodies against the homologous, neutralization-resistant strain, HIV-1 JR-FL . All three proteins induced NAbs against more sensitive strains, but the breadth of activity against heterologous primary isolates was limited. When antibodies able to neutralize HIV-1 JR-FL were detected, antigen depletion studies showed they were not directed at the V3 region but were targeted at other, undefined gp120 and also non-gp120 epitopes

  14. Sterically crowded monomeric neutral bis(benzamidinato) compounds of aluminium, [PhC(NSiMe(3))(2)](2)AlX (X=Cl, H); X-ray crystal structure of [PhC(NSiMe(3))(2)]2AlH

    NARCIS (Netherlands)

    Duchateau, R; Meetsma, A; Teuben, JH

    1996-01-01

    AlCl3 reacts with [PhC(NSiMe(3))(2)]Li(OEt(2)) to afford the bis(N,N'-bis(trimethylsilyl)benzamidinato)aluminium chloro compound which, on treatment with KBEt(3)H, yields the structurally characterized monomeric hydride derivative, [PhC(NSiMe(3))(2)]2AlH, whose reactivity towards unsaturated

  15. [Immune response in therapy with allergens and allergoids].

    Science.gov (United States)

    Kalveram, C M; Kalveram, K J; Kästner, H; Forck, G

    1986-02-01

    We report on the patterns of specific IgE, IgG, and IgA antibodies during different kinds of hyposensitization. Whereas sIgE antibodies may even be influenced by environmental stimulants, the production of sIgG antibodies depends on the amount of antigens injected for therapy. There is some evidence that patients who do not reveal sIgG response have increased sIgA antibody titers, instead.

  16. Characterization of the Sweet Taste Receptor Tas1r2 from an Old World Monkey Species Rhesus Monkey and Species-Dependent Activation of the Monomeric Receptor by an Intense Sweetener Perillartine.

    Directory of Open Access Journals (Sweden)

    Chenggu Cai

    Full Text Available Sweet state is a basic physiological sensation of humans and other mammals which is mediated by the broadly acting sweet taste receptor-the heterodimer of Tas1r2 (taste receptor type 1 member 2 and Tas1r3 (taste receptor type 1 member 3. Various sweeteners interact with either Tas1r2 or Tas1r3 and then activate the receptor. In this study, we cloned, expressed and functionally characterized the taste receptor Tas1r2 from a species of Old World monkeys, the rhesus monkey. Paired with the human TAS1R3, it was shown that the rhesus monkey Tas1r2 could respond to natural sugars, amino acids and their derivates. Furthermore, similar to human TAS1R2, rhesus monkey Tas1r2 could respond to artificial sweeteners and sweet-tasting proteins. However, the responses induced by rhesus monkey Tas1r2 could not be inhibited by the sweet inhibitor amiloride. Moreover, we found a species-dependent activation of the Tas1r2 monomeric receptors of human, rhesus monkey and squirrel monkey but not mouse by an intense sweetener perillartine. Molecular modeling and sequence analysis indicate that the receptor has the conserved domains and ligand-specific interactive residues, which have been identified in the characterized sweet taste receptors up to now. This is the first report of the functional characterization of sweet taste receptors from an Old World monkey species.

  17. Analysis of monomeric and oligomeric organophosphorus flame retardants in fish muscle tissues using liquid chromatography–electrospray ionization tandem mass spectrometry: Application to Nile tilapia (Oreochromis niloticus from an e-waste processing area in northern Vietnam

    Directory of Open Access Journals (Sweden)

    Hidenori Matsukami

    2016-06-01

    Full Text Available Using electrospray ionization tandem mass spectrometry combined with liquid chromatography (LC, a novel analytical method was developed to quantify eight monomeric organophosphorus flame retardants (m-PFRs and three oligomeric organophosphorus flame retardants (o-PFRs in fish muscle samples. The optimization and validation experiments indicate that the developed method can determine accurately the concentrations of analytes in fish muscle samples. The recoveries of analytes in fish muscle samples were in the range of 74–105%. The coefficients of variation of the concentrations of analytes in fish muscle samples were 0.6–8.9%. The concentrations of analytes in procedural blanks were below the limit of quantification (LOQ values. Furthermore, the developed method was applied to the analysis of m-PFRs and o-PFRs in the muscle samples of tilapias collected from an electronic waste (e-waste processing area in northern Vietnam. The concentrations of m-PFRs such as tris(2-chloroethyl phosphate (TCEP, tris(2-chloroisopropyl phosphate (TCIPP, and triphenyl phosphate (TPHP were dominant among the investigated m-PFRs. The respective concentrations of TCEP, TCIPP, and TPHP were up to 160, 300, and 230 ng g−1 lipid weight, respectively, whereas those of o-PFRs were up to 10 ng g−1 lipid weight. The results of this study indicate lower accumulation potential of o-PFRs compared with m-PFRs for the first time.

  18. Characterization of the Sweet Taste Receptor Tas1r2 from an Old World Monkey Species Rhesus Monkey and Species-Dependent Activation of the Monomeric Receptor by an Intense Sweetener Perillartine.

    Science.gov (United States)

    Cai, Chenggu; Jiang, Hua; Li, Lei; Liu, Tianming; Song, Xuejie; Liu, Bo

    2016-01-01

    Sweet state is a basic physiological sensation of humans and other mammals which is mediated by the broadly acting sweet taste receptor-the heterodimer of Tas1r2 (taste receptor type 1 member 2) and Tas1r3 (taste receptor type 1 member 3). Various sweeteners interact with either Tas1r2 or Tas1r3 and then activate the receptor. In this study, we cloned, expressed and functionally characterized the taste receptor Tas1r2 from a species of Old World monkeys, the rhesus monkey. Paired with the human TAS1R3, it was shown that the rhesus monkey Tas1r2 could respond to natural sugars, amino acids and their derivates. Furthermore, similar to human TAS1R2, rhesus monkey Tas1r2 could respond to artificial sweeteners and sweet-tasting proteins. However, the responses induced by rhesus monkey Tas1r2 could not be inhibited by the sweet inhibitor amiloride. Moreover, we found a species-dependent activation of the Tas1r2 monomeric receptors of human, rhesus monkey and squirrel monkey but not mouse by an intense sweetener perillartine. Molecular modeling and sequence analysis indicate that the receptor has the conserved domains and ligand-specific interactive residues, which have been identified in the characterized sweet taste receptors up to now. This is the first report of the functional characterization of sweet taste receptors from an Old World monkey species.

  19. Buprenorphine Sublingual and Buccal (opioid dependence)

    Science.gov (United States)

    ... Treximet), and zolmitriptan (Zomig); mirtazapine (Remeron); muscle relaxants; opiate (narcotic) medications for pain control and cough; rifampin (Rifadin, Rimactane, in Rifater, in Rifamate); medications for seizures such as carbamazepine (Epitol, Tegretol, Teril, others), phenobarbital, ...

  20. Sublingual immunotherapy for the treatment of allergies

    African Journals Online (AJOL)

    2016-05-22

    May 22, 2016 ... and autumn when the level of outdoor allergens, i.e. pollen, is elevated ... Atopic dermatitis has an impact on health-related quality of life,. Abstract .... and SLIT consistently demonstrated benefit when compared to placebo ...

  1. NUT Carcinoma of the Sublingual Gland

    DEFF Research Database (Denmark)

    Andreasen, Simon; French, C A; Josiassen, Michael

    2016-01-01

    NUT carcinoma (NC) is a recently described, rare and extremely aggressive cancer primarily located to supradiaphragmatic structures and affecting young individuals. NC is characterized by translocations involving the NUT gene on 15q14 with the most common translocation partner gene being BRD4 on ...

  2. Sublingual immunotherapy in children with allergic rhinitis

    NARCIS (Netherlands)

    E. Röder (Esther)

    2012-01-01

    textabstractAllergic rhinitis is one of the most prevalent chronic diseases in Europe. Besides nose symptoms such as sneezing and a blocked nose, patients also suffer from general complaints like fatigue, sleeping problems and difficulty concentrating. Allergic rhinitis can have a serious impact on

  3. Influence of osmolarity of contrast medium and saline flush on computed tomography angiography: Comparison of monomeric and dimeric iodinated contrast media with different iodine concentrations at an identical iodine delivery rate

    International Nuclear Information System (INIS)

    Kishimoto, Miori; Doi, Shoko; Shimizu, Junichiro; Lee, Ki-Ja; Iwasaki, Toshiroh; Miyake, Yoh-Ichi; Yamada, Kazutaka

    2010-01-01

    Purpose: To evaluate the influence of osmolarity of iodinated contrast media and saline flush on the contrast effect in thoracic computed tomography angiography (CTA) at an identical iodine delivery rate (IDR). Materials and methods: Seven beagles were used in a cross-over experiment. The contrast media used were iohexol 350 mgI/ml (IOH350; osmolarity 844 mmol/kg) and iodixanol 320 mgI/ml (IDX320; osmolarity 290 mmol/kg). Each contrast medium was administered to groups with and without saline flush at 40.0 mgI/kg/s for all experiments. Dynamic CT scanning was performed at the ninth thoracic vertebra level. The peak value, area under the curve (AUC), and time to peak (TTP) were calculated from the time attenuation curves of the pulmonary artery and aorta. Results: There was no significant difference between IOH350 and IDX320 with or without saline flush in the peak values for the pulmonary artery and aorta. AUC was significantly higher in groups with saline flush for both contrast media and arteries (p < 0.05) with no significant difference between contrast media. TTP was significantly longer in groups with saline flush than without saline flush for both contrast media and arteries (p < 0.05), with no significant difference between contrast media. Conclusions: There were no significant differences in the contrast effects of monomeric IOH350 and dimeric IDX320 in thoracic CTA when used at an identical IDR. Moreover, saline flush prolonged the peak duration at 600 mgI/kg.

  4. Synthesis and characterization of monomeric and dimeric ...

    African Journals Online (AJOL)

    The two complexes are isostructural, with the central metal atom lying on a crystallographic 2-fold axis. Both complexes are approximately octahedral, the coordination being provided by two trans pyridine nitrogen atoms and two cis amine nitrogen atoms from the oxime ligands, and by two cis chlorides. The dimeric ...

  5. Novel polymerizable bent-shaped monomeric molecules

    Czech Academy of Sciences Publication Activity Database

    Kozmik, V.; Kovářová, A.; Kuchař, M.; Svoboda, Jiří; Novotná, Vladimíra; Glogarová, Milada; Kroupa, Jan

    2006-01-01

    Roč. 33, č. 1 (2006), s. 41-56 ISSN 0267-8292 R&D Projects: GA ČR(CZ) GA202/05/0431; GA MŠk(CZ) OC D14.50 Institutional research plan: CEZ:AV0Z10100520 Keywords : mesogens * polymerizable * bent-shaped molecules * liquid crystals * ferroelectricity Subject RIV: BM - Solid Matter Physics ; Magnetism Impact factor: 1.417, year: 2006

  6. Monomeric Ellagitannins in Oaks and Sweetgum

    OpenAIRE

    Lei, Zhentian

    2002-01-01

    Ellagitannins are plant phenolics characterized by biaryl-coupled gallic acid moieties esterified to a D-glucose core. They are widely distributed through higher plants. In the case of oaks, ellagitannin concentrations in heartwood can reach up to 10% (dry wt. basis). These secondary metabolites are not only important physiologically but also influence the economic value and quality of wood products that contain them. Efforts were made to develop and validate the methods used to quantify ...

  7. Towards evidence-based medicine in specific grass pollen immunotherapy.

    Science.gov (United States)

    Calderon, M; Mösges, R; Hellmich, M; Demoly, P

    2010-04-01

    When initiating grass pollen immunotherapy for seasonal allergic rhinoconjunctivitis, specialist physicians in many European countries must choose between modalities of differing pharmaceutical and regulatory status. We applied an evidence-based medicine (EBM) approach to commercially available subcutaneous and sublingual Gramineae grass pollen immunotherapies (SCIT and SLIT) by evaluating study design, populations, pollen seasons, treatment doses and durations, efficacy, quality of life, safety and compliance. After searching MEDLINE, Embase and the Cochrane Library up until January 2009, we identified 33 randomized, double-blind, placebo-controlled trials (including seven paediatric trials) with a total of 440 specific immunotherapy (SIT)-treated subjects in seven trials (0 paediatric) for SCIT with natural pollen extracts, 168 in three trials (0 paediatric) for SCIT with allergoids, 906 in 16 trials (five paediatric) for natural extract SLIT drops, 41 in two trials (one paediatric) for allergoid SLIT tablets and 1605 in five trials (two paediatric) for natural extract SLIT tablets. Trial design and quality varied significantly within and between SIT modalities. The multinational, rigorous trials of natural extract SLIT tablets correspond to a high level of evidence in adult and paediatric populations. The limited amount of published data on allergoids prevented us from judging the level of evidence for this modality.

  8. Mouth floor enlargements related to the sublingual glands in edentulous or partially edentulous patients: a microscopic study Tumefações do soalho bucal relacionadas às glândulas sublinguais em pacientes edêntulos ou parcialmente edêntulos: estudo microscópico

    Directory of Open Access Journals (Sweden)

    Liogi Iwaki Filho

    2006-08-01

    Full Text Available Mouth floor enlargements (MFE are observed in edentulous and partially edentulous patients, impairing denture fitting, and have recently been described in the literature as hyperplasias of the sublingual glands. OBJECTIVE: This study aims at describing the microscopic aspects of MFE that contribute to their final diagnosis. METHODS: Twenty-four specimens were surgically removed from the enlarged mouth floor of 19 patients (15 females and 4 males. Patient age ranged from 48 to 74 years, with a mean of 57 years. The main surgical indication was to permit or improve the fitting of dentures. Six patients were completely edentulous and 13 were partially edentulous. The material was processed for microscopic examination and stained with hematoxylin-eosin, Mallory's trichrome and periodic-acid Schiff (PAS. RESULTS AND CONCLUSIONS: The epithelium of the mouth floor was normal in 17 cases, hyperplastic in 4 and atrophic in 3. Six of the 24 sublingual glands removed were microscopically normal, while the other specimens presented acinar atrophy with hyperplasia of duct-like structures. Interstitial fibrosis was observed in 18 cases and was accompanied by adipose tissue infiltration in 15. Decreased lymphoid tissue was observed in 16 samples and oncocytosis was present in 5 cases. We suggest that MFE in edentulous or partially edentulous patients should be considered as an entity for the text books.Tumefações do soalho bucal (TSB são observadas em pacientes edêntulos ou parcialmente edêntulos, prejudicando a adaptação de próteses, e têm sido descritas recentemente na literatura como hiperplasias das glândulas sublinguais. OBJETIVO: O objetivo desse estudo é descrever os aspectos microscópicos das TSB a fim de contribuir para o seu diagnóstico final. MATERIAL E MÉTODOS: Foram removidos cirurgicamente 24 espécimes de 19 pacientes (15 mulheres e 4 homens que possuíam TSB. A idade variou de 48 a 74 anos, com média de 57 anos. A principal

  9. Sublingual atropine for the treatment of severe and hyoscine ...

    African Journals Online (AJOL)

    Comley C, Galletly C, Ash D. Use of atropine eye drops for clozapine induced hypersalivation. Aust N Z J Psychiatry 2000 ; 34(6):1033-. 1034. 6. Sharma A, Ramaswamy S, Dahl E, Dewan V. Intraoral application of atropine sulphate ophthalmic solution for clozapine-induced sialorrhea. Ann Pharmacother 2004 ; 38(9):1538.

  10. Sublingual Delivery of Frovatriptan: An Indication of Potential Alternative Route

    Science.gov (United States)

    Verma, Surajpal; Prasad, Shyam Baboo

    2014-01-01

    Frovatriptan, a 5-HT1B and 5-HT1D receptor agonist, is used for the treatment of acute migraine attack. This molecule is classified into second line therapy because of its slow onset of action (peak response obtained after 4 hours of administration) and low bioavailability (25%). Moreover, its therapy is the most costly among all triptans. Attempt has been made in present work to suggest a way out to fasten its onset of action and to enhance its bioavailability. Prepared tablets were evaluated by physicochemical tests, in vitro permeation studies, ex vivo permeation studies, and histopathological studies. Suitable mathematical calculations were performed to calculate the minimum amount of bioavailability that could be enhanced. Tablets containing chitosan (5% w/w) were found to give optimum results. Prepared tablets can double the bioavailability of frovatriptan and can initiate its response within 10 minutes of its administration. Suggestive alternative has the potential to increase the efficacy of frovatriptan for treating acute migraine attack. PMID:27433492

  11. Sublingual immunotherapy for the treatment of allergies | Schellack ...

    African Journals Online (AJOL)

    The treatment of allergies often involves pharmacological therapy and recommendations by healthcare workers that the allergen should be avoided. Allergen-specific immunotherapy has emerged as an alternative to effectively decrease the immunoglobulin (Ig) E:IgG4 ratio. Two routes of administration are described, ...

  12. Debut of Gastroesophageal Reflux Concomitant with Administration of Sublingual Immunotherapy

    DEFF Research Database (Denmark)

    Juel, J.

    2017-01-01

    Gastroesophageal reflux disease (GORD) is an often debilitating condition characterised by retrograde flow of content from stomach into the oesophagus, where the low pH of the stomach acid irritates the mucosa of the oesophagus. The most dominant symptoms in GORD are pyrosis, regurgitation...

  13. A novel and well tolerated mite allergoid subcutaneous immunotherapy: evidence of clinical and immunologic efficacy

    Science.gov (United States)

    Roger, Albert; Depreux, Nathalie; Jurgens, Yani; Heath, Matthew D; Garcia, Gloria; Skinner, Murray A

    2014-01-01

    Allergy to house dust mite is one of the most common causes of allergic rhinitis. A novel tyrosine-adsorbed, modified allergen product, Acarovac Plus, developed for the treatment of perennial mite allergy seeks to address the underlying cause of allergic rhinitis in this instance. One of two dosing regimens may be used, either the Conventional Regimen or the Cluster Regimen. We sought to compare the efficacy and safety of a specific immunotherapy, developed for the treatment of perennial mite allergy, administered under a Conventional and Clustered dosing schedule in patients with persistent allergic rhinitis. Thirty adult patients, between 18 and 65 years old, with allergic rhinitis and/or asthma secondary to hypersensitivity to Dermatophagoides pteronyssinus were administered with either conventional or cluster initial regime, with a final visit one week after the last dose administration. The efficacy to the Conventional and Cluster regimens was measured using a Nasal Challenge Test monitoring clinical symptoms and peak nasal inspiratory flow. Total IgE, serum-specific inmunoglobulins (IgE and IgG4) to Dermatophagoides pteronyssinus and relevant cytokines (IFN-γ, IL-4, IL-5, IL-10 and IL-13) were assessed. A Satisfaction Questionnaire (TSQM) was completed after each patient's final visit. The tolerability of the vaccine was assessed monitoring adverse reactions. No adverse events were recorded in either conventional or cluster regime. The specific Nasal Challenge Test led to a decrease in symptom scores and a significant decrease in mean nasal peak inspiratory flow drop was recorded in both dosing regimen groups. A significant increase in IgG4-specific antibody titres was assessed. No significant changes were observed in concentrations of total IgE, specific IgE or cytokines (IFN-γ, IL-4, IL-5, IL-10 and IL-13). Patients declared themselves most satisfied in relation to “Secondary effects”, with high overall satisfaction in both groups. Cluster and conventional specific immunotherapy resulted in no adverse reaction(s) and led to similar improvements in immunological parameters, clinical efficacy (Nasal Challenge Test) and high overall satisfaction. PMID:25400929

  14. Detergent organisation in crystals of monomeric outer membrane phospholipase A

    NARCIS (Netherlands)

    Snijder, HJ; Timmins, PA; Kalk, KH; Dijkstra, BW

    The structure of the detergent in crystals of outer membrane phospholipase A (OMPLA) has been determined using neutron diffraction contrast variation. Large crystals were soaked in stabilising solutions, each containing a different H2O/D2O contrast. From the neutron diffraction at five contrasts,

  15. Synthesis and characterization of monomeric manganese(II) and ...

    African Journals Online (AJOL)

    The geometry at the manganese center is seven-coordinate, and is best described as a capped trigonal pyramid with the water molecule forming the cap and the six nitrogen atoms of the tpen ligand occupying the pyramidal sites. The manganese atom and the water molecule lie on a crystallographic twofold axis.

  16. Structure of the novel monomeric glyoxalase I from Zea mays.

    Science.gov (United States)

    Turra, Gino L; Agostini, Romina B; Fauguel, Carolina M; Presello, Daniel A; Andreo, Carlos S; González, Javier M; Campos-Bermudez, Valeria A

    2015-10-01

    The glyoxalase system is ubiquitous among all forms of life owing to its central role in relieving the cell from the accumulation of methylglyoxal, a toxic metabolic byproduct. In higher plants, this system is upregulated under diverse metabolic stress conditions, such as in the defence response to infection by pathogenic microorganisms. Despite their proven fundamental role in metabolic stresses, plant glyoxalases have been poorly studied. In this work, glyoxalase I from Zea mays has been characterized both biochemically and structurally, thus reporting the first atomic model of a glyoxalase I available from plants. The results indicate that this enzyme comprises a single polypeptide with two structurally similar domains, giving rise to two lateral concavities, one of which harbours a functional nickel(II)-binding active site. The putative function of the remaining cryptic active site remains to be determined.

  17. Clinical characterization of patients with macroprolactinemia and monomeric hyperprolactinemia

    Directory of Open Access Journals (Sweden)

    Murat Can

    2011-05-01

    Full Text Available Macroprolactinemia is often a cause of misdiagnosis, unnecessary expensive investigation, and unsuitable treatment. The aim of the present study was to investigate the clinical findings and the concentrations of macroprolactin in patients with hyperprolactinemia in our region. Eighty-four female hyperprolactinemic patients were screened for macroprolactinemia. Prolactin was measured by chemiluminesans method on an Immulite 2000 analyzer (Siemens Health Diagnostics, Deerfield, IL, USA. Recoveries less than or equal to 40% after polyethylene glycol precipitation were indicative of macroprolactinemia. Clinical features and biochemical values were compared in true hyperprolactinemic and macroprolactinemic patients. Macroprolactinemia was detected in 31 patients (36.9%, with 84 hyperprolactinemic female patients. There was no difference in frequency of galactorrhea and oligomenorrhea/amenorrhea between the two groups. When we evaluated the clinical features of patients according to prolactin levels, no significant difference was found between the groups. In conclusion, our initial data show that no clinical features could reliably differentiate macroprolactinemic from true hyperprolactinemic patients, but at least one of these symptoms was present in most macroprolactinemic patients.

  18. Genetic diversity of the monomeric prolamins and hordein in hulless ...

    African Journals Online (AJOL)

    STORAGESEVER

    2009-05-04

    ALELI/MORA/3/CONDOR-BAR… 10. 22. 3. 15. 8. 9. 39. ICNBF8-653. 6. 24. 3. 2. 9. 2. 40. ZARA/BEREMJO/4/DS4931//GLORIA- … 6. 13. 3. 14. 12. 2. 41. Atahualpa. 5. 24. 7. 11. 8. 10. 42. RABANO/4/DS4931//GLORIA-BAR/ … 20.

  19. Bioinspired chemical synthesis of monomeric and dimeric stephacidin A congeners

    Science.gov (United States)

    Mukai, Ken; de Sant'ana, Danilo Pereira; Hirooka, Yasuo; Mercado-Marin, Eduardo V.; Stephens, David E.; Kou, Kevin G. M.; Richter, Sven C.; Kelley, Naomi; Sarpong, Richmond

    2018-01-01

    Stephacidin A and its congeners are a collection of secondary metabolites that possess intriguing structural motifs. They stem from unusual biosynthetic sequences that lead to the incorporation of a prenyl or reverse-prenyl group into a bicyclo[2.2.2]diazaoctane framework, a chromene unit or the vestige thereof. To complement biosynthetic studies, which normally play a significant role in unveiling the biosynthetic pathways of natural products, here we demonstrate that chemical synthesis can provide important insights into biosynthesis. We identify a short total synthesis of congeners in the reverse-prenylated indole alkaloid family related to stephacidin A by taking advantage of a direct indole C6 halogenation of the related ketopremalbrancheamide. This novel strategic approach has now made possible the syntheses of several natural products, including malbrancheamides B and C, notoamides F, I and R, aspergamide B, and waikialoid A, which is a heterodimer of avrainvillamide and aspergamide B. Our approach to the preparation of these prenylated and reverse-prenylated indole alkaloids is bioinspired, and may also inform the as-yet undetermined biosynthesis of several congeners.

  20. Identification of the monomeric composition of poly(styreneacrylates

    Directory of Open Access Journals (Sweden)

    Yu. A. Yakovleva

    2016-12-01

    Full Text Available The work is devoted to qualitative analysis of poly(styreneacrylates, the definition of the content of styrene in them. The methods of IR, NMR spectroscopy and gas chromatography-mass spectrometry were used for analysis. It was shown that the integrated use of modern spectral methods allows unambiguous to lead identification of the components in the copolymer and to use of spectral data for quantitative determinations.

  1. Monomeric, dimeric and multimeric system of RGD peptides radiolabeled with {sup 177}Lu for tumors therapy that expressing αβ integrin s; Sistema monomerico, dimerico y multimerico de peptidos de RGD radiomarcados con {sup 177}Lu para terapia de tumores que expresan integrinas αβ

    Energy Technology Data Exchange (ETDEWEB)

    Luna G, M. A.

    2014-07-01

    The conjugation of peptides to gold nanoparticles (AuNPs) produces biocompatible and stable multimeric systems with target-specific molecular recognition. Peptides based on the cyclic Arg-Gly-Asp (RGD) sequence have been reported as high affinity agents for the α(v)β(3) and α(v)β(5) integrin. The aim of this research was to prepare a multimeric system of {sup 177}Lu-labeled gold nanoparticles conjugated to c[RGDfK(C)] [cyclo(Arg-Gly-Asp-Phe-Lys(Cys)] peptides and to compare the radiation absorbed dose with that of {sup 177}Lu-labeled monomeric and dimeric RGD peptides to α(v)β(3) integrin-positive U87MG tumors in mice, as well as, evaluate the in vitro potential {sup 177}Lu-AuNP-c[RGDfK(C)] as a plasmonic photothermal therapy and targeted radiotherapy system in MCF7 breast cancer cells. DOTA-GGC (1,4,7,10-tetraaza cyclododecane-N,N,N-tetraacetic-Gly-Gly-Cys) and c[RGDfK(C)] peptides were synthesized and conjugated to AuNPs by the spontaneous reaction of the thiol groups. Tem, UV-Vis, XP S, Raman and Far-IR spectroscopy techniques demonstrated that AuNPs were functionalized with the peptides. To obtain {sup 177}Lu-AuNP-c[RGDfK(C)], the {sup 177}Lu-DOTA-GGC radio peptide was first prepared and added to a solution of AuNPs followed by c[RGDfK(C)] (25 μL, 5 μM) at 18 grades C for 15 min. {sup 177}Lu-DOTA-GGC, {sup 177}Lu- DOTA-cRGDfK and {sup 177}Lu-DOTA-E-c(RGDfK){sub 2} were prepared by adding {sup 177}LuCl{sub 3} (370 MBq) to 5 μL (1 mg/ml) of the DOTA derivative diluted with 50 μL of 1 M acetate buffer at ph 5. The mixture was incubated at 90 grades C in a block heater for 30 min. Radiochemical purity was determined by ultrafiltration and HPLC analyses. After laser irradiation, the presence of c[RGDfK(C)]-AuNP in cells caused a significant increase in the temperature of the medium (50.5 grades C, compared to 40.3 grades C without AuNPs) resulting in a significant decrease in MCF7 cell viability down to 9 %. After treatment with {sup 177}Lu

  2. Allergen immunotherapy in allergic rhinitis: current use and future trends.

    Science.gov (United States)

    Klimek, Ludger; Pfaar, Oliver; Bousquet, Jean; Senti, Gabriela; Kündig, Thomas

    2017-09-01

    Type-1 allergies are among the most chronic common diseases of humans. Allergen immunotherapy (AIT) is the only causative and disease-modifying treatment option besides allergen avoidance. Severe systemic adverse allergic reactions may be induced by every AIT treatment. Different approaches have been used to provide safer AIT preparations to lower or even totally overcome this risk. Areas covered: A structured literature recherche in Medline and Pubmed under inclusion of national and international guidelines and Cochrane meta-analyses has been performed aiming at reviewing clinical use of such approaches in AIT. New allergen preparations may include allergoids, recombinant allergens (recA) and modified recombinant allergens (recA) in subcutaneous as well as in mucosal immunotherapies (application e.g. using bronchial, nasal, oral and sublingual application) with sublingual being the established mucosal application route and new ways of application like intralymphatic and epicutaneous immunotherapy. Expert commentary: Immune-modifying agents like Virus-like particles and CpG-motifs, adjuvants like MPL and aluminum hydroxide are evaluated and found to increase and direct the immunological response toward immunological tolerance. New forms of allergen extracts can improve safety and efficacy of AIT and may change our way of performing allergen immunotherapy in the future.

  3. Current insights in allergen immunotherapy.

    Science.gov (United States)

    Passalacqua, Giovanni; Bagnasco, Diego; Ferrando, Matteo; Heffler, Enrico; Puggioni, Francesca; Canonica, Giorgio Walter

    2018-02-01

    Allergen-specific immunotherapy (AIT) in its subcutaneous and sublingual forms is currently a well-established and experimentally supported treatment for respiratory allergy and hymenoptera venom allergy. There have been advances in its use linked strictly to the advancement in the knowledge of the molecular mechanisms of allergy, the production of well-characterized extracts, and diagnostic techniques. The use of AIT in asthma and the application of new approaches are expanding. We briefly review the advances and concerns in the use of AIT. PubMed and Scopus. The most recent and clinically relevant literature was selected and reviewed. The introduction of high-quality products supported by large dose-finding trials has yielded better defined indications, contraindications, and modalities of use. Some specific products in tablet form have recently been approved in the United States. Sublingual immunotherapy has been found to be effective in asthma, which until recently had been a matter of debate. Another promising therapy is oral and sublingual desensitization for food allergy, for which encouraging results have recently been reported. In the near future, other options will be available, including new routes of administration (intralymphatic and epicutaneous), allergoids, engineered allergens, and peptides. The use of component-resolved diagnosis techniques will further refine and target AIT prescriptions. This condensed and updated review shows that AIT remains a viable treatment option, especially after the introduction of standardized tablets for some allergens. Food allergy and new administration routes represent a promising expansion. Copyright © 2017 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  4. Variations in T cell subsets during hyposensitization of grass-sensitive patients with formaldehyde modified extracts: allergoids.

    Science.gov (United States)

    Anfosso, F; Alcaraz, G; Vervloet, D; Charpin, J

    1982-11-01

    In atopic patients with clinical symptoms of hay fever, changes in T gamma and T mu cells were evaluated during desensitization. A significant increase in T mu and overall in T gamma cells was noted. These results suggested that T cell defect could be restored by desensitization treatment.

  5. The European Survey on Adverse Systemic Reactions in Allergen Immunotherapy (EASSI): A paediatric assessment.

    Science.gov (United States)

    Rodríguez Del Río, Pablo; Vidal, Carmen; Just, Jocelyne; Tabar, Ana I; Sanchez-Machin, Inmaculada; Eberle, Peter; Borja, Jesus; Bubel, Petra; Pfaar, Oliver; Demoly, Pascal; Calderón, Moises A

    2017-02-01

    Safety data on 'real-life' allergen immunotherapy (AIT) in children and adolescents is usually extrapolated from studies in adults. Patients aged 18 or under initiating aeroallergen AIT were evaluated in a prospective European survey. Patient profiles and systemic reactions (SRs) were recorded. Descriptive, univariate and multivariate analyses were used to identify risk factors for SRs. A total of 1563 patients (mean ± SD age: 11.7 ± 3.9 years; rhinitis: 93.7%; asthma: 61.5%; polysensitization: 62.5%) and 1578 courses of AIT were assessed. Single-allergen AIT was administered in 89.5% of cases (n = 1412; mites: 49%; grass pollen: 25.8%; tree pollen: 8.7%; Alternaria: 4.6%; dander: 0.8%; weed pollen: 0.6%). Subcutaneous AIT (SCIT) was used in 71.4% (n = 1127) of the treatments, including 574 (50.9%) with natural extracts. Sublingual AIT (SLIT) was used for the remaining 451 treatments (drops: 73.8%; tablets: 26.2%). The mean ± SD follow-up period was 12.9 ± 3.3 months. The estimated total number of doses was 19,669 for SCIT and 131,550 for SLIT. Twenty-four patients (1.53%) experienced 29 SRs. Respiratory (55.7%) and skin symptoms (37.9%) were most frequent. Anaphylaxis was diagnosed in 3 SRs (10.3%), and adrenaline was administered in 2 of these cases. In a univariate analysis, the risk of SRs was lower in mite-sensitized patients and higher in cases of pollen polysensitization (>3), grass pollen extracts and the use of natural extracts (vs. allergoids). In a real-life paediatric setting, AIT is safe. SRs are infrequent and generally not severe. Pollen polysensitization, grass pollen extracts and natural extracts (vs. allergoids) were risk factors for AIT-associated SRs. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  6. Application of Nuclear Radiation to Textile Materials and Processes. Radiation-induced graft copolymerization of vinyl monomers and fibrous polymers; Applications des rayonnements aux textiles. Formation radiochimique de copolymeres ''greffes'' par l'action de monomeres vinyliques sur des polymeres en fibre; Primenenie yadernogo izlucheniya v tekstil'noj promyshlennosti. Obrazovanie privitykh sopolimerov iz vinilovykh monomerov i voloknistykh polimerov pod dejstviem izlucheniya; Aplicaciones de las radiaciones nucleares a los procesos y materiales textiles. Copolimerizacion por injerto radioinducida de monomeros vinilicos y de polimeros fibrosos

    Energy Technology Data Exchange (ETDEWEB)

    Armstrong, Jr., A. A.; Rutherford, H. A. [University of North Carolina at Raleigh, NC (United States)

    1963-11-15

    materials is not good enough for commercial acceptance. The strength of cellulose acetate yam, as well as the modulus, can be materially increased by the addition of polyacrylonitrile. Other monomers do not behave in this manner. There is some indication that the fibre may be improved with one compound, especially with respect to its behaviour in the wet state. Fibre modification by the procedure described might be practical commercially if techniques that will increase the rate of diffusion of the monomer into the fibre structure can be developed. (author) [French] Les auteurs ont mis au point une methode qui permet de realiser par les rayonnements un greffage homogene de monomeres vinyliques volatils sur des polymeres en fibres. Elle consiste a ajouter le compose organique en phase vapeur; on procede, soit par irradiation de l'ensemble, soit par irradiation prealable des polymeres, aux rayons du cobalt-60. Les auteurs ont etudie des systemes qui accelerent la formation des copolymeres ''greffes''; ils ont constate qu'il est possible d'ajouter des quantites significatives de plusieurs des monomeres sans qu'il en resulte de dommages radioinduits dans le substrat fibreux. Les polymeres en fibres relativement instables en presence des rayonnements sont ceux qui fixent le plus facilement les composes vinyliques. C'est le cas des matieres cellulosiques, des esters de cellulose, des polyamides et du polypropylene. Le monomere s'ajoute au substrat fibreux par un mecanisme de radicaux libres, et, comme on l'a indique plus haut, on peut irradier d'abord les polymeres et ensuite provoquer le greffage par exposition de la matiere irradiee S la vapeur du monomere. On a tente de determiner la duree de vie des radicaux libres; il est difficile de donner des chiffres exacts, mais on a demontre qu'ils peuvent subsister dans certaines fibres 15 a 20 heures apres l'irradiation, meme a la temperature ambiante. Des resultats experimentaux preliminaires donnent egalement a penser que le temps

  7. Efficacy of a House Dust Mite Sublingual Allergen Immunotherapy Tablet in Adults With Allergic Asthma

    DEFF Research Database (Denmark)

    Virchow, Johann Christian; Backer, Vibeke; Kuna, Piotr

    2016-01-01

    moderate or severe asthma exacerbation during the ICS reduction period. Secondary outcomes were deterioration in asthma symptoms, change in allergen-specific immunoglobulin G4 (IgG4), change in asthma control or asthma quality-of-life questionnaires, and adverse events. RESULTS: Among 834 randomized...... in allergen-specific IgG4. However, there was no significant difference for change in asthma control questionnaire or asthma quality-of-life questionnaire for either dose. There were no reports of severe systemic allergic reactions. The most frequent adverse events were mild to moderate oral pruritus (13...... corticosteroid (ICS) reduction period. DESIGN, SETTINGS, AND PARTICIPANTS: Double-blind, randomized, placebo-controlled trial conducted between August 2011 and April 2013 in 109 European trial sites. The trial included 834 adults with HDM allergy-related asthma not well controlled by ICS or combination products...

  8. Serious neonatal airway obstruction with massive congenital sublingual ranula and contralateral occurrence

    Directory of Open Access Journals (Sweden)

    Manish M. George

    2015-06-01

    Conclusions: The prenatal diagnosis of congenital ranulas have been seldom reported, with no reported cases of contralateral occurrence and airway obstruction from an intraoral ranula. This rare case highlights the need for a well considered contingency plan when surgery is required for a neonatal airway at risk.

  9. Ránula sublingual en un recién nacido

    OpenAIRE

    Suárez García, Nuvia; Piloña Ruiz, Sergio Germán

    2015-01-01

    Introducción: la mucocele y ránula son quistes de retención mucosa, localizados en la cavidad oral donde se hallen glándulas salivales menores. Caso clínico: se presenta un recién nacido a término, de buen peso, sexo masculino, segundo gemelar producto de una cesárea. En el examen físico al nacer se observa una tumoración azulada en el piso de la boca que dificultó la alimentación del bebé, pero no ocasionó problemas respiratorios. Según la evolución clínica, a los 5 días de vida, la madre no...

  10. The value of pre- and co-seasonal sublingual immunotherapy in pollen-induced allergic rhinoconjunctivitis

    DEFF Research Database (Denmark)

    Demoly, Pascal; Calderon, Moises A; Casale, Thomas B

    2015-01-01

    Allergen immunotherapy (AIT) is a guidelines-approved, disease-modifying treatment option for respiratory allergies, including allergic rhinitis (AR) induced by pollen. The various AIT regimens employed to date in pollen-induced AR can be classified as continuous (i.e. year-round) or discontinuou...

  11. A prospective study comparing the efficacy and safety of two sublingual birch allergen preparations

    NARCIS (Netherlands)

    Klimek, Ludger; Sperl, Annette; van Twuijver, Esther; van Ree, Ronald; Kleinjans, Huub; Boot, Johan Diderik; Pfaar, Oliver

    2014-01-01

    Background: SUBLIVAC FIX Birch (SUB-B) is a liquid oral preparation of Betula verrucosa pollen extract for the treatment of allergic rhinitis/rhinoconjuctivitis induced by birch pollen. The major allergen content of SUB-B and Staloral Birch (Stal-B) have been shown to be comparable. In order to

  12. Anesthetic concerns in a huge congenital sublingual swelling obscuring airway access

    Directory of Open Access Journals (Sweden)

    Nilesh Kumar

    2015-01-01

    Full Text Available Presence of intraoral pathology poses a great challenge during management of pediatric airway. We report management of big intraoral cystic swelling physically occupying the entire oral cavity restricting access to airway. Preintubation aspiration of swelling was done to decrease its size and make room for airway manipulation, followed by laryngoscopy and intubation in lateral position. Airway patency is at risk in postoperative period also, in this case, though the swelling decreased in size postoperatively but presence of significant edema required placement of tongue stitch and modified nasopharyngeal airway. Case report highlights simple maneuvers to manage a difficult case.

  13. Conjunctival provocation tests: a predictive factor for patients' seasonal allergic rhinoconjunctivitis symptoms.

    Science.gov (United States)

    Kruse, Kristian; Gerwin, Eva; Eichel, Andrea; Shah-Hosseini, Kija; Mösges, Ralph

    2015-01-01

    No parameters currently exist that can reliably predict the impact of preseasonal immunotherapy on the symptoms occurring during the season. The purpose of our studies was to prove a correlation between preseasonal conjunctival allergen challenge and coseasonal primary clinical endpoints using the total combined score, ie, a combination of symptoms and medication score, as the primary outcome parameter. Twelve weeks before both the birch and the grass pollen seasons, 2 separate prospective, double-blind, randomized, controlled studies were conducted followed by posttrial observations for each study during the active season. In the studies, patients who reacted to conjunctival allergen challenge were treated with sublingual immunotherapy tablets that contain either birch and/or alder or grass pollen allergoids. In all, 158 patients were included in the grass and 160 in the tree pollen study; of these, 100 and 109 patients, respectively, took part in the posttrial observations. When comparing patients with and without a positive reaction in the final conjunctival allergen challenge, the results revealed a significant difference in the total combined score (grass: P < .001; birch: P = .025). The same applied to the rescue medication score (P = .005; P = .025). A significant difference regarding the rhinoconjunctivitis symptom score was shown in the grass pollen study (P = .002), and the difference of well days was significant in the tree pollen study (P = .049). When comparing patients based on their reaction to allergen challenge after immunotherapy, each study leads to similarly significant results. Therefore, conjunctival allergen challenge can be used effectively as a parameter to predict allergic rhinoconjunctivitis symptoms during the season in patients treated with preseasonal sublingual immunotherapy tablets. Whether this can be transferred to untreated patients needs to be determined. Copyright © 2015 American Academy of Allergy, Asthma & Immunology

  14. Aggregated and Monomeric Forms of Proteins in Boar Seminal Plasma: Characterization and Binding Properties

    Czech Academy of Sciences Publication Activity Database

    Maňásková, Pavla; Liberda, J.; Tichá, M.; Jonáková, Věra

    2000-01-01

    Roč. 46, č. 4 (2000), s. 143-151 ISSN 0015-5500 R&D Projects: GA ČR GA303/99/0357; GA ČR GV524/96/K162; GA MŠk VS96141 Grant - others:GA UK(XC) 12/1998 Institutional research plan: CEZ:AV0Z5052915 Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 0.351, year: 2000

  15. Membrane Curvature Induced by Aggregates of LH2s and Monomeric LH1s

    OpenAIRE

    Chandler, Danielle E.; Gumbart, James; Stack, John D.; Chipot, Christophe; Schulten, Klaus

    2009-01-01

    The photosynthetic apparatus of purple bacteria is contained within organelles called chromatophores, which form as extensions of the cytoplasmic membrane. The shape of these chromatophores can be spherical (as in Rhodobacter sphaeroides), lamellar (as in Rhodopseudomonas acidophila and Phaeospirillum molischianum), or tubular (as in certain Rb. sphaeroides mutants). Chromatophore shape is thought to be influenced by the integral membrane proteins Light Harvesting Complexes I and II (LH1 and ...

  16. Yeast Mitochondrial ADP/ATP Carriers Are Monomeric in Detergents as Demonstrated by Differential Affinity Purification

    NARCIS (Netherlands)

    Bamber, Lisa; Slotboom, Dirk-Jan; Kunji, Edmund R.S.; Barber, L

    2007-01-01

    Most mitochondrial carriers carry out equimolar exchange of substrates and they are believed widely to exist as homo-dimers. Here we show by differential tagging that the yeast mitochondrial ADP/ATP carrier AAC2 is a monomer in mild detergents. Carriers with and without six-histidine or

  17. Monomeric CH3: A Small, Stable Antibody Domain with Therapeutic Promise | Poster

    Science.gov (United States)

    By Ashley DeVine, Staff Writer Antibody domains are emerging as promising biopharmaceuticals because of their relatively small size compared to full-sized antibodies, which are too large to effectively penetrate tumors and bind to sterically restricted therapeutic targets. In an article published in The Journal of Biological Chemistry, Tianlei Ying, Ph.D., Dimiter Dimitrov,

  18. Spin Equilibria in Monomeric Manganocenes: Solid State Magnetic and EXAFS Studies

    Energy Technology Data Exchange (ETDEWEB)

    Walter, M. D.; Sofield, C. D.; Booth, C. H.; Andersen, R. A.

    2009-02-09

    Magnetic susceptibility measurements and X-ray data confirm that tert-butyl-substituted manganocenes [(Me{sub 3}C){sub n}C{sub 5}H{sub 5?n}]{sub 2}Mn (n = 1, 2) follow the trend previously observed with the methylated manganocenes; that is, electron-donating groups attached to the Cp ring stabilize the low-spin (LS) electronic ground state relative to Cp{sub 2}Mn and exhibit higher spin-crossover (SCO) temperatures. However, introducing three CMe{sub 3} groups on each ring gives a temperature-invariant high-spin (HS) state manganocene. The origin of the high-spin state in [1,2,4-(Me{sub 3}C){sub 3}C{sub 5}H{sub 2}]{sub 2}Mn is due to the significant bulk of the [1,2,4-(Me{sub 3}C){sub 3}C{sub 5}H{sub 2}]{sup -} ligand, which is sufficient to generate severe inter-ring steric strain that prevents the realization of the low-spin state. Interestingly, the spin transition in [1,3-(Me{sub 3}C){sub 2}C{sub 5}H{sub 3}]{sub 2}Mn is accompanied by a phase transition resulting in a significant irreversible hysteresis ({Delta}T{sub c} = 16 K). This structural transition was also observed by extended X-ray absorption fine-structure (EXAFS) measurements. Magnetic susceptibility studies and X-ray diffraction data on SiMe{sub 3}-substituted manganocenes [(Me{sub 3}Si){sub n}C{sub 5}H{sub 5-n}]{sub 2}Mn (n = 1, 2, 3) show high-spin configurations in these cases. Although tetra- and hexasubstituted manganocenes are high-spin at all accessible temperatures, the disubstituted manganocenes exhibit a small low-spin admixture at low temperature. In this respect it behaves similarly to [(Me{sub 3}C)(Me{sub 3}Si)C{sub 5}H{sub 3}]{sub 2}Mn, which has a constant low-spin admixture up to 90 K and then gradually converts to high-spin. Thermal spin-trapping can be observed for [(Me{sub 3}C)(Me{sub 3}Si)C{sub 5}H{sub 3}]{sub 2}Mn on rapid cooling.

  19. Single-dose monomeric HA subunit vaccine generates full protection from influenza challenge

    CSIR Research Space (South Africa)

    Mallajosyula, JK

    2014-03-01

    Full Text Available 50% survival, or 100% survival with adjuvant, compared with 10% survival after vaccination with a commercially available H 1 N 1 vaccine. TMV-HA is an effective dose-sparing influenza vaccine, using a single-step process to rapidly generate large...

  20. Monomeric neutrophil gelatinase associated lipocalin is associated with tubulointerstitial damage in chronic kidney disease

    Science.gov (United States)

    Nickolas, Thomas L.; Forster, Catherine; Sise, Meghan E.; Barasch, Nicholas; Valle, David Solá-Del; Viltard, Melanie; Buchen, Charles; Kupferman, Shlomo; Carnevali, Maria Luisa; Bennett, Michael; Mattei, Silvia; Bovino, Achiropita; Argentiero, Lucia; Magnano, Andrea; Devarajan, Prasad; Mori, Kiyoshi; Erdjument-Bromage, Hediye; Tempst, Paul; Allegri, Landino; Barasch, Jonathan

    2012-01-01

    The rate of progression of chronic kidney disease (CKD) is difficult to predict using single measurements of serum creatinine or proteinuria. On the other hand, documented tubulointerstitial disease presages worsening CKD, but kidney biopsy is not practical for routine use and generally does not sample the tubulointerstitial compartment of the medulla. Perhaps a urine test that correlates with specific histological findings may serve as a surrogate for the kidney biopsy. Here we compared both immunoblot analysis (under non-reducing conditions) and a commercially available monomer immunoassays of Neutrophil Gelatinase Associated Lipocalin (NGAL) with pathological changes found in kidney biopsies, to determine whether specific histological characteristics associated with a specific NGAL species. We found that the urine of patients with advanced CKD contained NGAL monomers as well as higher molecular weight complexes containing NGAL, identified by MALDI-TOF/TOF mass spectroscopy. The NGAL monomer significantly correlated with glomerular filtration rate, interstitial fibrosis and tubular atrophy. Hence, specific assays of the NGAL monomer implicate histology associated with progressive, severe CKD. PMID:22695331

  1. Functional Characterization of Monomeric GTPase Rab1 in the Secretory Pathway of Leishmania*

    Science.gov (United States)

    Bahl, Surbhi; Parashar, Smriti; Malhotra, Himanshu; Raje, Manoj; Mukhopadhyay, Amitabha

    2015-01-01

    Leishmania secretes a large number of its effectors to the extracellular milieu. However, regulation of the secretory pathway in Leishmania is not well characterized. Here, we report the cloning, expression, and characterization of the Rab1 homologue from Leishmania. We have found that LdRab1 localizes in Golgi in Leishmania. To understand the role of LdRab1 in the secretory pathway of Leishmania, we have generated transgenic parasites overexpressing GFP-LdRab1:WT, GFP-LdRab1:Q67L (a GTPase-deficient dominant positive mutant of Rab1), and GFP-LdRab1:S22N (a GDP-locked dominant negative mutant of Rab1). Surprisingly, our results have shown that overexpression of GFP-LdRab1:Q67L or GFP-LdRab1:S22N does not disrupt the trafficking and localization of hemoglobin receptor in Leishmania. To determine whether the Rab1-dependent secretory pathway is conserved in parasites, we have analyzed the role of LdRab1 in the secretion of secretory acid phosphatase and Ldgp63 in Leishmania. Our results have shown that overexpression of GFP-LdRab1:Q67L or GFP-LdRab1:S22N significantly inhibits the secretion of secretory acid phosphatase by Leishmania. We have also found that overexpression of GFP-LdRab1:Q67L or GFP-LdRab1:S22N retains RFP-Ldgp63 in Golgi and blocks the secretion of Ldgp63, whereas the trafficking of RFP-Ldgp63 in GFP-LdRab1:WT-expressing cells is unaltered in comparison with control cells. Taken together, our results have shown that the Rab1-regulated secretory pathway is well conserved, and hemoglobin receptor trafficking follows an Rab1-independent secretory pathway in Leishmania. PMID:26499792

  2. Functional Characterization of Monomeric GTPase Rab1 in the Secretory Pathway of Leishmania.

    Science.gov (United States)

    Bahl, Surbhi; Parashar, Smriti; Malhotra, Himanshu; Raje, Manoj; Mukhopadhyay, Amitabha

    2015-12-11

    Leishmania secretes a large number of its effectors to the extracellular milieu. However, regulation of the secretory pathway in Leishmania is not well characterized. Here, we report the cloning, expression, and characterization of the Rab1 homologue from Leishmania. We have found that LdRab1 localizes in Golgi in Leishmania. To understand the role of LdRab1 in the secretory pathway of Leishmania, we have generated transgenic parasites overexpressing GFP-LdRab1:WT, GFP-LdRab1:Q67L (a GTPase-deficient dominant positive mutant of Rab1), and GFP-LdRab1:S22N (a GDP-locked dominant negative mutant of Rab1). Surprisingly, our results have shown that overexpression of GFP-LdRab1:Q67L or GFP-LdRab1:S22N does not disrupt the trafficking and localization of hemoglobin receptor in Leishmania. To determine whether the Rab1-dependent secretory pathway is conserved in parasites, we have analyzed the role of LdRab1 in the secretion of secretory acid phosphatase and Ldgp63 in Leishmania. Our results have shown that overexpression of GFP-LdRab1:Q67L or GFP-LdRab1:S22N significantly inhibits the secretion of secretory acid phosphatase by Leishmania. We have also found that overexpression of GFP-LdRab1:Q67L or GFP-LdRab1:S22N retains RFP-Ldgp63 in Golgi and blocks the secretion of Ldgp63, whereas the trafficking of RFP-Ldgp63 in GFP-LdRab1:WT-expressing cells is unaltered in comparison with control cells. Taken together, our results have shown that the Rab1-regulated secretory pathway is well conserved, and hemoglobin receptor trafficking follows an Rab1-independent secretory pathway in Leishmania. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  3. Stabilization of a β-hairpin in monomeric Alzheimer's amyloid-β peptide inhibits amyloid formation

    Science.gov (United States)

    Hoyer, Wolfgang; Grönwall, Caroline; Jonsson, Andreas; Ståhl, Stefan; Härd, Torleif

    2008-01-01

    According to the amyloid hypothesis, the pathogenesis of Alzheimer's disease is triggered by the oligomerization and aggregation of the amyloid-β (Aβ) peptide into protein plaques. Formation of the potentially toxic oligomeric and fibrillar Aβ assemblies is accompanied by a conformational change toward a high content of β-structure. Here, we report the solution structure of Aβ(1–40) in complex with the phage-display selected affibody protein ZAβ3, a binding protein of nanomolar affinity. Bound Aβ(1–40) features a β-hairpin comprising residues 17–36, providing the first high-resolution structure of Aβ in β conformation. The positions of the secondary structure elements strongly resemble those observed for fibrillar Aβ. ZAβ3 stabilizes the β-sheet by extending it intermolecularly and by burying both of the mostly nonpolar faces of the Aβ hairpin within a large hydrophobic tunnel-like cavity. Consequently, ZAβ3 acts as a stoichiometric inhibitor of Aβ fibrillation. The selected Aβ conformation allows us to suggest a structural mechanism for amyloid formation based on soluble oligomeric hairpin intermediates. PMID:18375754

  4. Stabilization of a β-hairpin in monomeric Alzheimer's amyloid-β peptide inhibits amyloid formation

    OpenAIRE

    Hoyer, Wolfgang; Grönwall, Caroline; Jonsson, Andreas; Ståhl, Stefan; Härd, Torleif

    2008-01-01

    According to the amyloid hypothesis, the pathogenesis of Alzheimer's disease is triggered by the oligomerization and aggregation of the amyloid-β (Aβ) peptide into protein plaques. Formation of the potentially toxic oligomeric and fibrillar Aβ assemblies is accompanied by a conformational change toward a high content of β-structure. Here, we report the solution structure of Aβ(1–40) in complex with the phage-display selected affibody protein ZAβ3, a binding protein of nanomolar affinity. Boun...

  5. Evolution and thermodynamics of the slow unfolding of hyperstable monomeric proteins

    Directory of Open Access Journals (Sweden)

    Koga Yuichi

    2010-07-01

    Full Text Available Abstract Background The unfolding speed of some hyperthermophilic proteins is dramatically lower than that of their mesostable homologs. Ribonuclease HII from the hyperthermophilic archaeon Thermococcus kodakaraensis (Tk-RNase HII is stabilized by its remarkably slow unfolding rate, whereas RNase HI from the thermophilic bacterium Thermus thermophilus (Tt-RNase HI unfolds rapidly, comparable with to that of RNase HI from Escherichia coli (Ec-RNase HI. Results To clarify whether the difference in the unfolding rate is due to differences in the types of RNase H or differences in proteins from archaea and bacteria, we examined the equilibrium stability and unfolding reaction of RNases HII from the hyperthermophilic bacteria Thermotoga maritima (Tm-RNase HII and Aquifex aeolicus (Aa-RNase HII and RNase HI from the hyperthermophilic archaeon Sulfolobus tokodaii (Sto-RNase HI. These proteins from hyperthermophiles are more stable than Ec-RNase HI over all the temperature ranges examined. The observed unfolding speeds of all hyperstable proteins at the different denaturant concentrations studied are much lower than those of Ec-RNase HI, which is in accordance with the familiar slow unfolding of hyperstable proteins. However, the unfolding rate constants of these RNases H in water are dispersed, and the unfolding rate constant of thermophilic archaeal proteins is lower than that of thermophilic bacterial proteins. Conclusions These results suggest that the nature of slow unfolding of thermophilic proteins is determined by the evolutionary history of the organisms involved. The unfolding rate constants in water are related to the amount of buried hydrophobic residues in the tertiary structure.

  6. Binary Toxin Subunits of Lysinibacillus sphaericus Are Monomeric and Form Heterodimers after In Vitro Activation.

    Directory of Open Access Journals (Sweden)

    Wahyu Surya

    Full Text Available The binary toxin from Lysinibacillus sphaericus has been successfully used for controlling mosquito-transmitted diseases. An activation step shortens both subunits BinA and BinB before their interaction with membranes and internalization in midgut cells, but the precise role of this activation step is unknown. Herein, we show conclusively using three orthogonal biophysical techniques that protoxin subunits form only monomers in aqueous solution. However, in vitro activated toxins readily form heterodimers. This oligomeric state did not change after incubation of these heterodimers with detergent. These results are consistent with the evidence that maximal toxicity in mosquito larvae is achieved when the two subunits, BinA and BinB, are in a 1:1 molar ratio, and directly link proteolytic activation to heterodimerization. Formation of a heterodimer must thus be necessary for subsequent steps, e.g., interaction with membranes, or with a suitable receptor in susceptible mosquito species. Lastly, despite existing similarities between BinB C-terminal domain with domains 3 and 4 of pore-forming aerolysin, no aerolysin-like SDS-resistant heptameric oligomers were observed when the activated Bin subunits were incubated in the presence of detergents or lipidic membranes.

  7. Monomeric GLP-1/GIP/glucagon triagonism corrects obesity, hepatosteatosis, and dyslipidemia in female mice

    Directory of Open Access Journals (Sweden)

    Sigrid Jall

    2017-05-01

    Conclusions: We herein show that a recently developed unimolecular peptide triagonist is equally efficient in both sexes, suggesting that this polypharmaceutical strategy might be a relevant alternative to bariatric surgery for the treatment of obesity and related metabolic disorders.

  8. Ultrafast polarized fluorescence measurements on monomeric and self-associated melittin

    NARCIS (Netherlands)

    Pandit, A.; Larsen, O.F.A.; Stokkum, van I.H.M.; Grondelle, van R.; Kraayenhof, R.; Amerongen, van H.

    2003-01-01

    The anisotropic and magic-angle fluorescence decay of the single tryptophan (Trp) residue of melittin, a bee venom peptide, was investigated by time-resolved fluorescence anisotropy using a streak camera setup. The peptide was dissolved either in distilled water or in Hepes/NaOH buffer containing

  9. A monomeric copper-phosphoramide complex: synthesis, structure, and electronic properties

    Czech Academy of Sciences Publication Activity Database

    Henriques, Margarida Isabel Sousa; Gorbunov, D.I.; Ponomaryov, A.Y.; Saneei, A.; Pourayoubi, M.; Dušek, Michal; Zvyagin, S.; Uhlarz, M.; Wosnitza, J.

    2016-01-01

    Roč. 118, Nov (2016), s. 154-158 ISSN 0277-5387 R&D Projects: GA ČR(CZ) GA14-03276S; GA MŠk LO1603 EU Projects: European Commission(XE) CZ.2.16/3.1.00/24510 Institutional support: RVO:68378271 Keywords : phosphoramide * magnetization * EPR * mononuclear copper complex * crystal structure Subject RIV: BM - Solid Matter Physics ; Magnetism Impact factor: 1.926, year: 2016

  10. Monomeric Amyloid Beta Peptide in Hexafluoroisopropanol Detected by Small Angle Neutron Scattering.

    Directory of Open Access Journals (Sweden)

    Bo Zhang-Haagen

    Full Text Available Small proteins like amyloid beta (Aβ monomers are related to neurodegenerative disorders by aggregation to insoluble fibrils. Small angle neutron scattering (SANS is a nondestructive method to observe the aggregation process in solution. We show that SANS is able to resolve monomers of small molecular weight like Aβ for aggregation studies. We examine Aβ monomers after prolonged storing in d-hexafluoroisopropanol (dHFIP by using SANS and dynamic light scattering (DLS. We determined the radius of gyration from SANS as 1.0±0.1 nm for Aβ1-40 and 1.6±0.1 nm for Aβ1-42 in agreement with 3D NMR structures in similar solvents suggesting a solvent surface layer with 5% increased density. After initial dissolution in dHFIP Aβ aggregates sediment with a major component of pure monomers showing a hydrodynamic radius of 1.8±0.3 nm for Aβ1-40 and 3.2±0.4 nm for Aβ1-42 including a surface layer of dHFIP solvent molecules.

  11. Who is Mr. HAMLET? Interaction of human alpha-lactalbumin with monomeric oleic acid.

    Science.gov (United States)

    Knyazeva, Ekaterina L; Grishchenko, Valery M; Fadeev, Roman S; Akatov, Vladimir S; Permyakov, Sergei E; Permyakov, Eugene A

    2008-12-09

    A specific state of the human milk Ca(2+) binding protein alpha-lactalbumin (hLA) complexed with oleic acid (OA) prepared using an OA-pretreated ion-exchange column (HAMLET) triggers several cell death pathways in various tumor cells. The possibility of preparing a hLA-OA complex with structural and cytotoxic properties similar to those of the HAMLET but under solution conditions has been explored. The complex was formed by titration of hLA by OA at pH 8.3 up to OA critical micelle concentration. We have shown that complex formation strongly depends on calcium, ionic strength, and temperature; the optimal conditions were established. The spectrofluorimetrically estimated number of OA molecules irreversibly bound per hLA molecule (after dialysis of the OA-loaded preparation against water followed by lyophilization) depends upon temperature: 2.9 at 17 degrees C (native apo-hLA; resulting complex referred to as LA-OA-17 state) and 9 at 45 degrees C (thermally unfolded apo-hLA; LA-OA-45). Intrinsic tryptophan fluorescence measurements revealed substantially decreased thermal stability of Ca(2+)-free forms of HAMLET, LA-OA-45, and OA-saturated protein. The irreversibly bound OA does not affect the Ca(2+) association constant of the protein. Phase plot analysis of fluorimetric and CD data indicates that the OA binding process involves several hLA intermediates. The effective pseudoequilibrium OA association constants for Ca(2+)-free hLA were estimated. The far-UV CD spectra of Ca(2+)-free hLA show that all OA-bound forms of the protein are characterized by elevated content of alpha-helical structure. The various hLA-OA complexes possess similar cytotoxic activities against human epidermoid larynx carcinoma cells. Overall, the LA-OA-45 complex possesses physicochemical, structural, and cytotoxic properties closely resembling those of HAMLET. The fact that the HAMLET-like complex can be formed in aqueous solution makes the process of its preparation more transparent and controllable, opening up opportunities for formation of active complexes with specific properties.

  12. A rationally designed monomeric peptide triagonist corrects obesity and diabetes in rodents

    DEFF Research Database (Denmark)

    Finan, Brian; Yang, Bin; Ottaway, Nickki

    2015-01-01

    -in-class monoagonists to reduce body weight, enhance glycemic control and reverse hepatic steatosis in relevant rodent models. Various loss-of-function models, including genetic knockout, pharmacological blockade and selective chemical knockout, confirmed contributions of each constituent activity in vivo. We...

  13. Order-disorder transitions govern kinetic cooperativity and allostery of monomeric human glucokinase.

    Directory of Open Access Journals (Sweden)

    Mioara Larion

    Full Text Available Glucokinase (GCK catalyzes the rate-limiting step of glucose catabolism in the pancreas, where it functions as the body's principal glucose sensor. GCK dysfunction leads to several potentially fatal diseases including maturity-onset diabetes of the young type II (MODY-II and persistent hypoglycemic hyperinsulinemia of infancy (PHHI. GCK maintains glucose homeostasis by displaying a sigmoidal kinetic response to increasing blood glucose levels. This positive cooperativity is unique because the enzyme functions exclusively as a monomer and possesses only a single glucose binding site. Despite nearly a half century of research, the mechanistic basis for GCK's homotropic allostery remains unresolved. Here we explain GCK cooperativity in terms of large-scale, glucose-mediated disorder-order transitions using 17 isotopically labeled isoleucine methyl groups and three tryptophan side chains as sensitive nuclear magnetic resonance (NMR probes. We find that the small domain of unliganded GCK is intrinsically disordered and samples a broad conformational ensemble. We also demonstrate that small-molecule diabetes therapeutic agents and hyperinsulinemia-associated GCK mutations share a strikingly similar activation mechanism, characterized by a population shift toward a more narrow, well-ordered ensemble resembling the glucose-bound conformation. Our results support a model in which GCK generates its cooperative kinetic response at low glucose concentrations by using a millisecond disorder-order cycle of the small domain as a "time-delay loop," which is bypassed at high glucose concentrations, providing a unique mechanism to allosterically regulate the activity of human GCK under physiological conditions.

  14. Antimicrobial monomeric and dimeric diterpenes from the leaves of Helichrysum tenax var tenax.

    Science.gov (United States)

    Drewes, Siegfried E; Mudau, K Esther; van Vuuren, Sandy F; Viljoen, Alvaro M

    2006-04-01

    The hexane extract of fresh air-dried leaves of Helichrysum tenax (Asteraceae) afforded ent-beyer-15-en-19-ol (1), its 4-epimer ent-beyer-15-en-18-ol (2), 15beta,16beta-epoxide-ent-beyeran-19-ol (3), as well as (4) consisting of two units of (1) linked as a diester of malonic acid, and (5), a compound. Its constituents are (1) and (3) also linked as a diester of malonic acid. The leaves of the plant are densely covered in fine glandular trichomes. These are extremely sticky and exude a mixture of the above diterpenes. Antimicrobial tests showed that (1), in particular, was highly active (3.1 and 3.6 microg/ml) against Bacillus cereus and Staphylococcus epidermidis, respectively.

  15. Equilibrium and extraction mechanism from monomeric and polimeric species of zirconium in solution. part. 2

    International Nuclear Information System (INIS)

    Azevedo, H.L.P. de.

    1980-01-01

    The mechanism of extraction and the equilibrium of chemical species from Zirconium solutions was studied. The multiple extraction method was used to show the species envolved in the extraction process and qualitative informations was obtained about the equilibrium between extractable species (monomers) and non-extractable species (polymers) in the aqueous phase. (M.J.C.) [pt

  16. New routes of allergen immunotherapy.

    Science.gov (United States)

    Aricigil, Mitat; Muluk, Nuray Bayar; Sakarya, Engin Umut; Sakalar, Emine Güven; Senturk, Mehmet; Reisacher, William R; Cingi, Cemal

    2016-11-01

    Allergen immunotherapy is the only cure for immunoglobulin E mediated type I respiratory allergies. Subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT) are the most common treatments. In this article, we reviewed new routes of allergen immunotherapy. Data on alternative routes to allow intralymphatic immunotherapy (ILIT), epicutaneous immunotherapy (EPIT), local nasal immunotherapy (LNIT), oral immunotherapy (OIT), and oral mucosal immunotherapy (OMIT) were gathered from the literature and were discussed. ILIT features direct injection of allergens into lymph nodes. ILIT may be clinically effective after only a few injections and induces allergen-specific immunoglobulin G, similarly to SCIT. A limitation of ILIT is that intralymphatic injections are required. EPIT features allergen administration by using patches mounted on the skin. EPIT seeks to target epidermal antigen-presenting Langerhans cells rather than mast cells or the vasculature; this should reduce both local and systemic adverse effects. LNIT involves the spraying of allergen extracts into the nasal cavity. Natural or chemically modified allergens (the latter, termed allergoids, lack immunoglobulin E reactivity) are prepared in a soluble form. OIT involves the regular administration of small amounts of a food allergen by mouth and commences with low oral doses, which are then increased as tolerance develops. OMIT seeks to deliver allergenic proteins to an expanded population of Langerhans cells in the mucosa of the oral cavity. ILIT, EPIT, LNIT, OIT, and OMIT are new routes for allergen immunotherapy. They are safe and effective.

  17. The future of immunotherapy for canine atopic dermatitis: a review.

    Science.gov (United States)

    DeBoer, Douglas J

    2017-02-01

    Allergen specific immunotherapy (ASIT) is a foundation treatment for canine atopic dermatitis (CAD), though few critical studies have documented its effectiveness as a disease-modifying treatment in dogs. The mechanisms by which ASIT works in dogs have not been elucidated, although they are likely to parallel those known for humans. Current ASIT approaches in CAD focus on either subcutaneous or sublingual administration. Greater knowledge of major allergens in dogs, ideal dosage regimes and details of allergen admixture are likely to lead to better efficacy in CAD. Evaluation of biomarkers for successful therapy may also be of benefit. Potentially important advances in human medicine, that have yet to be explored in dogs, include use of modified allergen preparations such as allergoids, recombinant major allergens or allergen peptides; modification with adjuvants; or packaging of the above in virus-like particles. Co-administration of immunomodulators such as CpG oligodeoxynucleotides or specific monoclonal antibodies might direct the immune response in the desired direction while calming the "cytokine storm" of active disease. Initial trials of alternative routes of administration such as intralymphatic immunotherapy have yielded exciting results in humans, and continuing study in dogs is underway. Progress in ASIT of human food allergy may provide clues that will assist with improved diagnosis and patient management of CAD. Importantly, further study must be undertaken to clarify the conditions under which ASIT is a valuable treatment modality for dogs. © 2017 ESVD and ACVD.

  18. Immunotherapy: what lies beyond.

    Science.gov (United States)

    Casale, Thomas B; Stokes, Jeffrey R

    2014-03-01

    Allergen immunotherapy has been used to treat allergic diseases, such as asthma, allergic rhinitis, and venom allergy, since first described over a century ago. The current standard of care in the United States involves subcutaneous administration of clinically relevant allergens for several months, building up to eventual monthly injections for typically 3 to 5 years. Recent advances have improved the safety and efficacy of immunotherapy. The addition of omalizumab or Toll-like receptor agonists to standard subcutaneous immunotherapy has proved beneficial. Altering the extract itself, either through chemical manipulation producing allergoids or directly producing recombinant proteins or significant peptides, has been evaluated with promising results. The use of different administration techniques, such as sublingual immunotherapy, is common in Europe and is on the immediate horizon in the United States. Other methods of administering allergen immunotherapy have been studied, including epicutaneous, intralymphatic, intranasal, and oral immunotherapy. In this review we focus on new types and routes of immunotherapy, exploring recent human clinical trial data. The promise of better immunotherapies appears closer than ever before, but much work is still needed to develop novel immunotherapies that induce immunologic tolerance and enhanced clinical efficacy and safety over that noted for subcutaneous allergen immunotherapy. Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

  19. Investigational new drugs for allergic rhinitis.

    Science.gov (United States)

    Ricketti, Peter A; Alandijani, Sultan; Lin, Chen Hsing; Casale, Thomas B

    2017-03-01

    Allergic rhinitis (AR) is a multifactorial disease characterized by paroxysmal symptoms of sneezing, rhinorrhea, postnasal drip and nasal congestion. For over a century, subcutaneous allergen immunotherapy (SCIT) has been recognized as the most effective therapy to date that may modify the underlying disease course and provide long-term benefits for individuals refractory to pharmacotherapy. However, over the past 25 years, there has been substantial growth in developing alternative therapies to traditional SCIT. Areas covered: This article will review the most current literature focusing on advancements of AR therapies. Novel AR therapies that are currently under investigation include: the addition of omalizumab, an anti-immunoglobulin E (IgE) monoclonal antibody (mAb), to SCIT; altering the method of delivery of allergen immunotherapy (AIT) including sublingual (SLIT), epicutaneous (EIT), intralymphatic (ILIT), intranasal (INIT) and oral mucosal immunotherapy (OMIT); use of capsaicin spray; novel H3 and H4 antihistamines; activation of the innate immune system through Toll-like receptor agonists; and the use of chemically altered allergens, allergoids, recombinant allergens and relevant T-cell epitope peptides to improve the efficacy and safety of AIT. Expert opinion: These promising novel therapies may offer more effective and/or safer treatment options for AR patients, and in some instances, induce immunologic tolerance.

  20. Allergen immunotherapy in people, dogs, cats and horses - differences, similarities and research needs.

    Science.gov (United States)

    Mueller, R S; Jensen-Jarolim, E; Roth-Walter, F; Marti, E; Janda, J; Seida, A A; DeBoer, D

    2018-04-19

    In human patients with seasonal allergic rhinoconjunctivitis sensitized to grass pollen, the first successful allergen immunotherapy (AIT) was reported in 1911. Today, immunotherapy is an accepted treatment for allergic asthma, allergic rhinitis and hypersensitivities to insect venom. AIT is also used for atopic dermatitis and recently for food allergy. Subcutaneous, epicutaneous, intralymphatic, oral and sublingual protocols of AIT exist. In animals, most data are available in dogs where subcutaneous AIT is an accepted treatment for atopic dermatitis. Initiating a regulatory response and a production of "blocking" IgG antibodies with AIT are similar mechanisms in human beings and dogs with allergic diseases. Although subcutaneous immunotherapy is used for atopic dermatitis in cats, data for its efficacy is sparse. There is some evidence for successful treatment of feline asthma with AIT. In horses, most studies evaluate the effect of AIT on insect hypersensitivity with conflicting results though promising pilot studies have demonstrated the prophylaxis of insect hypersensitivity with recombinant antigens of biting midges (Culicoides spp.). Optimising AIT using allergoids, peptide immunotherapy, recombinant allergens and new adjuvants with the different administration types of allergen extracts hopefully will further improve compliance and efficacy of this proven treatment modality. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  1. Does sublingual misoprostol reduce pain and facilitate IUD insertion in women with no previous vaginal delivery? A randomized controlled trial

    Directory of Open Access Journals (Sweden)

    Amr Adel Mansy

    2018-03-01

    Conclusion: Although misoprostol is used in cervical ripening in labour induction and medical evacuation of missed abortion, its use to facilitate IUD insertion in women with tight cervix or in whom vaginal delivery was not experienced, has no role in pain reduction or increase the ease of IUD insertion.

  2. 24-hour human urine and serum profiles of bisphenol A: Evidence against sublingual absorption following ingestion in soup

    Energy Technology Data Exchange (ETDEWEB)

    Teeguarden, Justin G., E-mail: jt@pnl.gov [Health Effects and Exposure Science, Pacific Northwest National Laboratory, Richland, WA 99352 (United States); Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR 93771 (United States); Twaddle, Nathan C., E-mail: nathan.twaddle@fda.hhs.gov [Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079 (United States); Churchwell, Mona I., E-mail: mona.churchwell@fda.hhs.gov [Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079 (United States); Yang, Xiaoxia, E-mail: xiaoxia.yang@fda.hhs.gov [Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079 (United States); Fisher, Jeffrey W., E-mail: jeffrey.fisher@fda.hhs.gov [Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079 (United States); Seryak, Liesel M., E-mail: seryak.2@osu.edu [Division of Epidemiology, College of Public Health, The Ohio State University, Columbus, OH 43210 (United States); Doerge, Daniel R., E-mail: daniel.doerge@fda.hhs.gov [Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079 (United States)

    2015-10-15

    Extensive first-pass metabolism of ingested bisphenol A (BPA) in the gastro-intestinal tract and liver restricts blood concentrations of bioactive BPA to < 1% of total BPA in humans and non-human primates. Absorption of ingested BPA through non-metabolizing tissues of the oral cavity, recently demonstrated in dogs, could lead to the higher serum BPA concentrations reported in some human biomonitoring studies. We hypothesized that the extensive interaction with the oral mucosa by a liquid matrix, like soup, relative to solid food or capsules, might enhance absorption through non-metabolizing oral cavity tissues in humans, producing higher bioavailability and higher serum BPA concentrations. Concurrent serum and urine concentrations of d6-BPA, and its glucuronide and sulfate conjugates, were measured over a 24 hour period in 10 adult male volunteers following ingestion of 30 μg d6-BPA/kg body weight in soup. Absorption of d6-BPA was rapid (t{sub 1/2} = 0.45 h) and elimination of the administered dose was complete 24 h post-ingestion, evidence against any tissue depot for BPA. The maximum serum d6-BPA concentration was 0.43 nM at 1.6 h after administration and represented < 0.3% of total d6-BPA. Pharmacokinetic parameters, pharmacokinetic model simulations, and the significantly faster appearance half-life of d6-BPA-glucuronide compared to d6-BPA (0.29 h vs 0.45 h) were evidence against meaningful absorption of BPA in humans through any non-metabolizing tissue (< 1%). This study confirms that typical exposure to BPA in food produces picomolar to subpicomolar serum BPA concentrations in humans, not nM concentrations reported in some biomonitoring studies.

  3. 24-hour human urine and serum profiles of bisphenol A: Evidence against sublingual absorption following ingestion in soup.

    Science.gov (United States)

    Teeguarden, Justin G; Twaddle, Nathan C; Churchwell, Mona I; Yang, Xiaoxia; Fisher, Jeffrey W; Seryak, Liesel M; Doerge, Daniel R

    2015-10-15

    Extensive first-pass metabolism of ingested bisphenol A (BPA) in the gastro-intestinal tract and liver restricts blood concentrations of bioactive BPA to <1% of total BPA in humans and non-human primates. Absorption of ingested BPA through non-metabolizing tissues of the oral cavity, recently demonstrated in dogs, could lead to the higher serum BPA concentrations reported in some human biomonitoring studies. We hypothesized that the extensive interaction with the oral mucosa by a liquid matrix, like soup, relative to solid food or capsules, might enhance absorption through non-metabolizing oral cavity tissues in humans, producing higher bioavailability and higher serum BPA concentrations. Concurrent serum and urine concentrations of d6-BPA, and its glucuronide and sulfate conjugates, were measured over a 24hour period in 10 adult male volunteers following ingestion of 30μg d6-BPA/kg body weight in soup. Absorption of d6-BPA was rapid (t1/2=0.45h) and elimination of the administered dose was complete 24h post-ingestion, evidence against any tissue depot for BPA. The maximum serum d6-BPA concentration was 0.43nM at 1.6h after administration and represented <0.3% of total d6-BPA. Pharmacokinetic parameters, pharmacokinetic model simulations, and the significantly faster appearance half-life of d6-BPA-glucuronide compared to d6-BPA (0.29h vs 0.45h) were evidence against meaningful absorption of BPA in humans through any non-metabolizing tissue (<1%). This study confirms that typical exposure to BPA in food produces picomolar to subpicomolar serum BPA concentrations in humans, not nM concentrations reported in some biomonitoring studies. Published by Elsevier Inc.

  4. Satisfaction and quality of life of allergic patients following sublingual five-grass pollen tablet immunotherapy in Spain

    Science.gov (United States)

    Antolín-Amerigo, Darío; Tabar, Isabel A; del Mar Fernández-Nieto, Maria; Callejo-Melgosa, Anna M; Muñoz-Bellido, Francisco J; Martínez-Alonso, José C; Méndez-Alcalde, Jorge D; Reche, Marta; Rodríguez-Trabado, Ana; Rosado-Ingelmo, Ana; Alonso-Gómez, Alicia; Blanco-González, Rosa; Alvarez-Fernandez, José A; Botella, Isabel; Valls, Ana; Cimarra, Mercedes; Blanco, Carlos

    2017-01-01

    Background Five-grass pollen tablet is an effective and well-tolerated therapy for patients with allergic rhinoconjunctivitis (ARC). This trial sought to determine the satisfaction and health-related quality of life (HRQoL) of patients undergoing this treatment. Methods This was a cross-sectional, multicentre, observational, naturalistic study, following a discontinuous pre- and co-seasonal five-grass pollen regimen over two seasons in Spain (2012, 2013). The HRQoL of the patients was measured with the specific Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) for adults, adolescent (AdolRQLQ), or paediatric (PRQLQ) patients. Treatment satisfaction was assessed by the Satisfaction Scale for Patients Receiving Allergen Immunotherapy (ESPIA) questionnaire. Patients/investigators were surveyed on beliefs and attitudes towards the five-grass pollen tablet. ARC evolution according to allergic rhinitis and its impact on asthma (ARIA) criteria and treatment adherence were evaluated. Results Among the 591 ARC patients included, the mean (SD) HRQoL scores were 1.40 (1.1) in adults, 1.33 (1.1) in adolescents, and 1.15 (1.1) in children, indicating low levels of impairment (scale 0–6). ESPIA answers showed high levels of satisfaction, with an average score of 69.2 (scale 0–100). According to ARIA criteria, 88.2% of patients reported improvement of ARC. Moreover, this was accompanied by a reduced use of symptomatic medication. Adherence to treatment was estimated at 96.8%. In general, both patients and specialists exhibited a positive attitude towards five-grass pollen tablet treatment. Conclusion ARC patients treated with five-grass pollen tablet showed favourable levels of HRQoL and treatment satisfaction, with concomitant improvements in ARC and symptomatic medication use, which translated into high levels of treatment adherence and a positive attitude towards five-grass pollen tablet. PMID:29225657

  5. Simplifying influenza vaccination during pandemics : sublingual priming and intramuscular boosting of immune responses with heterologous whole inactivated influenza vaccine

    NARCIS (Netherlands)

    Murugappan, Senthil; Patil, Harshad P; Frijlink, Henderik W; Huckriede, Anke; Hinrichs, Wouter L J

    2014-01-01

    The best approach to control the spread of influenza virus during a pandemic is vaccination. Yet, an appropriate vaccine is not available early in the pandemic since vaccine production is time consuming. For influenza strains with a high pandemic potential like H5N1, stockpiling of vaccines has been

  6. 24-hour human urine and serum profiles of bisphenol A: Evidence against sublingual absorption following ingestion in soup

    International Nuclear Information System (INIS)

    Teeguarden, Justin G.; Twaddle, Nathan C.; Churchwell, Mona I.; Yang, Xiaoxia; Fisher, Jeffrey W.; Seryak, Liesel M.; Doerge, Daniel R.

    2015-01-01

    Extensive first-pass metabolism of ingested bisphenol A (BPA) in the gastro-intestinal tract and liver restricts blood concentrations of bioactive BPA to < 1% of total BPA in humans and non-human primates. Absorption of ingested BPA through non-metabolizing tissues of the oral cavity, recently demonstrated in dogs, could lead to the higher serum BPA concentrations reported in some human biomonitoring studies. We hypothesized that the extensive interaction with the oral mucosa by a liquid matrix, like soup, relative to solid food or capsules, might enhance absorption through non-metabolizing oral cavity tissues in humans, producing higher bioavailability and higher serum BPA concentrations. Concurrent serum and urine concentrations of d6-BPA, and its glucuronide and sulfate conjugates, were measured over a 24 hour period in 10 adult male volunteers following ingestion of 30 μg d6-BPA/kg body weight in soup. Absorption of d6-BPA was rapid (t 1/2 = 0.45 h) and elimination of the administered dose was complete 24 h post-ingestion, evidence against any tissue depot for BPA. The maximum serum d6-BPA concentration was 0.43 nM at 1.6 h after administration and represented < 0.3% of total d6-BPA. Pharmacokinetic parameters, pharmacokinetic model simulations, and the significantly faster appearance half-life of d6-BPA-glucuronide compared to d6-BPA (0.29 h vs 0.45 h) were evidence against meaningful absorption of BPA in humans through any non-metabolizing tissue (< 1%). This study confirms that typical exposure to BPA in food produces picomolar to subpicomolar serum BPA concentrations in humans, not nM concentrations reported in some biomonitoring studies.

  7. Chemical modification of Art v 1, a major mugwort pollen allergen, by cis-aconitylation and citraconylation

    Directory of Open Access Journals (Sweden)

    DRAGANA STANIĆ

    2009-04-01

    Full Text Available Art v 1 is the major allergen of mugwort (Artemisia vulgaris pollen, a significant cause of hay fever all over Europe. Specific immunotherapy is the only treatment modality for allergic disease. Application of modified allergens makes the treatment safer and more efficient. In this work, two out of three (citraconic anhydride, cis-aconitic anhydride, 2,3-dimethylmaleic anhydride tested anhydrides were proven to be suitable for chemical modifications of allergens. Art v 1 was modified by cis-aconitylation and citraconylation in order to obtain derivatives of Art v 1 that may be suitable for further immunological testing. Acylation of Art v 1 gave derivatives (caaArt v 1 and citArt v 1 with about 80 % modified amino groups. The derivatives were in the monomeric form and had dramatically reduced pI values. Both derivatives were relatively stable at neutral pH values, while the acyl groups undergo hydrolysis under acidic conditions. Modification of allergens by cis-aconitylation and citraconylation could be a new tool for obtaining allergoids.

  8. Interaction of monomeric Ebola VP40 protein with a plasma membrane: A coarse-grained molecular dynamics (CGMD) simulation study.

    Science.gov (United States)

    Mohamad Yusoff, Mohamad Ariff; Abdul Hamid, Azzmer Azzar; Mohammad Bunori, Noraslinda; Abd Halim, Khairul Bariyyah

    2018-06-01

    Ebola virus is a lipid-enveloped filamentous virus that affects human and non-human primates and consists of several types of protein: nucleoprotein, VP30, VP35, L protein, VP40, VP24, and transmembrane glycoprotein. Among the Ebola virus proteins, its matrix protein VP40 is abundantly expressed during infection and plays a number of critical roles in oligomerization, budding and egress from the host cell. VP40 exists predominantly as a monomer at the inner leaflet of the plasma membrane, and has been suggested to interact with negatively charged lipids such as phosphatidylinositol 4,5-bisphosphate (PIP 2 ) and phosphatidylserine (PS) via its cationic patch. The hydrophobic loop at the C-terminal domain has also been shown to be important in the interaction between the VP40 and the membrane. However, details of the molecular mechanisms underpinning their interactions are not fully understood. This study aimed at investigating the effects of mutation in the cationic patch and hydrophobic loop on the interaction between the VP40 monomer and the plasma membrane using coarse-grained molecular dynamics simulation (CGMD). Our simulations revealed that the interaction between VP40 and the plasma membrane is mediated by the cationic patch residues. This led to the clustering of PIP 2 around the protein in the inner leaflet as a result of interactions between some cationic residues including R52, K127, K221, K224, K225, K256, K270, K274, K275 and K279 and PIP 2 lipids via electrostatic interactions. Mutation of the cationic patch or hydrophobic loop amino acids caused the protein to bind at the inner leaflet of the plasma membrane in a different orientation, where no significant clustering of PIP 2 was observed around the mutated protein. This study provides basic understanding of the interaction of the VP40 monomer and its mutants with the plasma membrane. Copyright © 2018 Elsevier Inc. All rights reserved.

  9. A glycosylated form of the human cardiac hormone pro B-type natriuretic peptide is an intrinsically unstructured monomeric protein.

    Science.gov (United States)

    Crimmins, Dan L; Kao, Jeffrey L-F

    2008-07-01

    The N-terminal fragment of pro B-type natriuretic peptide (NT-proBNP) and proBNP are used as gold standard clinical markers of myocardial dysfunction such as cardiac hypertrophy and left ventricle heart failure. The actual circulating molecular forms of these peptides have been the subject of intense investigation particularly since these analytes are measured in clinical assays. Conflicting data has been reported and no firm consensus on the exact nature of the molecular species exists. Because these clinical assays are immunoassay-based, specific epitopes are detected. It is conceivable then that certain epitopes may be masked and therefore unavailable for antibody binding, thus the importance of determining the nature of the circulating molecular forms of these analytes. This situation is an unavoidable Achilles' heel of immunoassays in general. A recombinant O-linked glycosylated form of proBNP has been show to mimic some of the properties of extracted plasma from a heart failure patient. In particular the recombinant and native material co-migrated as diffuse Western-immunostained bands on SDS-PAGE and each band collapsed to an apparent homogeneous band following deglycosylation. Thus, glycosylated-proBNP may be one such circulating form. Here we provide extensive physiochemical characterization for this O-linked protein and compare these results to other described circulating species, non-glycosylated-proBNP and NT-proBNP. It will be shown that glycosylation has no influence on the secondary and quaternary structure of proBNP. In fact, at moderate concentration in benign physiological neutral pH buffer, all three likely circulating species are essentially devoid of major secondary structure, i.e., are intrinsically unstructured proteins (IUPs). Furthermore, all three proteins exist as monomers in solution. These results may have important implications in the design of NT-proBNP/BNP immunoassays.

  10. Interactions between nitric oxide and ethylene in monomeric G-protein activation in relation to food spoilage

    DEFF Research Database (Denmark)

    Hall, M A; moshkov, moshkov; Novikova, G

    2014-01-01

    Climate change is likely to increase crop stress with negative impacts on yield and quality. Therefore, there is a need to develop our understanding of the key events which govern plant tolerance to stress. Intense research has identified key signalling cascades regulating stress tolerance...... and it is notable that many are dependent on the production of volatile signals or signals which have volatile derivatives. Ethylene (ET) has long been recognized as an important regulator of development, stress responses, senescence and food spoilage. Our work has focused on the gaseous signal nitric oxide (NO......) and how it interacts with established stress signalling pathways and in particular, those regulated by ET. Using laser photoacoustic detection (LPAD) we have established that NO production overlaps with that of ethylene during plant responses to disease. To examine the interaction of NO and ET signalling...

  11. Action of DTPA on hepatic plutonium. II. DTPA-induced removal of monomeric plutonium from mouse liver parenchymal cells

    International Nuclear Information System (INIS)

    Bhattacharyya, M.H.; Peterson, D.P.; Lindenbaum, A.

    1978-01-01

    Liver parenchymal cells were isolated 6 and 24 hr following the administration of diethylenetriaminepentaacetic acid (DTPA, 0.25 mmole/kg) to mice previously injected with 239 Pu-citrate (4.4 μCi/kg). Isolated parenchymal cells contained 440 dpm Pu/10 6 cells at 24 hr after Pu injection, just prior to DTPA administration. The PU content decreased to 330 dpm/10 6 cells at 6 hr and 140 dpm/10 6 cells at 24 hr after DTPA administration. Thus DTPA induced a striking decrease in the Pu content of isolated liver parenchymal cells. Parenchymal cells isolated from control mice not treated with DTPA changed little in Pu content from 24 to 48 hr after Pu injection. By 24 hr after DTPA treatment, the decrease in the Pu content of isolated liver parenchymal cells could account for the DTPA-induced release of Pu from the intact liver. Thus in the liver DTPA appears to act preferentially on the Pu associated with parenchymal cells. Liver parenchymal cells isolated 6 hr after DTPA administration and containing 330 dpm Pu/10 6 cells were incubated in vitro in the absence of added DTPA. After 18 hr of incubation the cells contained 130 dpm Pu/10 6 cells. This level corresponds to the level observed in cells isolated 24 hr after DTPA administration. Cells isolated from untreated mice lost only 15% of their Pu content during a similar in vitro incubation. Thus, by 6 hr after DTPA administration to the mouse, isolated liver parenchymal cells appeared to retain their ability to release Pu in vitro with no need for additional exposure to DTPA. The physiological significance of this finding is discussed

  12. Structure of AadA from Salmonella enterica: a monomeric aminoglycoside (3′′)(9) adenyltransferase

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Yang [Uppsala University, Biomedical Center, Box 596, SE-751 24 Uppsala (Sweden); Näsvall, Joakim [Uppsala University, Biomedical Center, Box 582, SE-751 23 Uppsala (Sweden); Wu, Shiying [Uppsala University, Biomedical Center, Box 596, SE-751 24 Uppsala (Sweden); Andersson, Dan I. [Uppsala University, Biomedical Center, Box 582, SE-751 23 Uppsala (Sweden); Selmer, Maria, E-mail: maria.selmer@icm.uu.se [Uppsala University, Biomedical Center, Box 596, SE-751 24 Uppsala (Sweden)

    2015-10-31

    The crystal structure of the aminoglycoside-adenylating enzyme AadA is reported together with functional experiments providing insights into its oligomeric state, ligand binding and catalysis. Aminoglycoside resistance is commonly conferred by enzymatic modification of drugs by aminoglycoside-modifying enzymes such as aminoglycoside nucleotidyltransferases (ANTs). Here, the first crystal structure of an ANT(3′′)(9) adenyltransferase, AadA from Salmonella enterica, is presented. AadA catalyses the magnesium-dependent transfer of adenosine monophosphate from ATP to the two chemically dissimilar drugs streptomycin and spectinomycin. The structure was solved using selenium SAD phasing and refined to 2.5 Å resolution. AadA consists of a nucleotidyltransferase domain and an α-helical bundle domain. AadA crystallizes as a monomer and is a monomer in solution as confirmed by small-angle X-ray scattering, in contrast to structurally similar homodimeric adenylating enzymes such as kanamycin nucleotidyltransferase. Isothermal titration calorimetry experiments show that ATP binding has to occur before binding of the aminoglycoside substrate, and structure analysis suggests that ATP binding repositions the two domains for aminoglycoside binding in the interdomain cleft. Candidate residues for ligand binding and catalysis were subjected to site-directed mutagenesis. In vivo resistance and in vitro binding assays support the role of Glu87 as the catalytic base in adenylation, while Arg192 and Lys205 are shown to be critical for ATP binding.

  13. Multidetector computed tomography (MDCT) evaluation of myocardial viability: intraindividual comparison of monomeric vs. dimeric contrast media in a rabbit model

    Energy Technology Data Exchange (ETDEWEB)

    Mahnken, Andreas H. [RWTH Aachen University, Department of Diagnostic Radiology, Aachen (Germany)]|[RWTH Aachen University, Applied Medical Engineering, Helmholtz Institute, Aachen (Germany)]|[University Hospital, RWTH Aachen University, Department of Diagnostic Radiology, Aachen (Germany); Jost, Gregor; Sieber, Martin; Seidensticker, Peter R.; Pietsch, Hubertus [Bayer-Schering Pharma AG, Berlin (Germany); Bruners, Philipp [RWTH Aachen University, Department of Diagnostic Radiology, Aachen (Germany)]|[RWTH Aachen University, Applied Medical Engineering, Helmholtz Institute, Aachen (Germany); Guenther, Rolf W. [RWTH Aachen University, Department of Diagnostic Radiology, Aachen (Germany)

    2009-02-15

    To evaluate the influence of different types of iodinated contrast media on the assessment of myocardial viability, acute myocardial infarction (MI) was surgically induced in six rabbits. Over a period of 45 min, contrast-enhanced cardiac MDCT (64 x 0.6 mm, 80 kV, 680mAs{sub eff.}) was repeatedly performed using a contrast medium dose of 600 mg iodine/kg body weight. Animals received randomized iopromide 300 and iodixanol 320, respectively. Attenuation values of healthy and infarcted myocardium were measured. The size of MI was computed and compared with nitroblue tetrazolium (NBT)-stained specimen. The highest attenuation differences between infarcted and healthy myocardium occurred during the arterial phase with 140.0{+-}3.5 HU and 141.0{+-}2.2 HU for iopromide and iodixanol, respectively. For iodixanol the highest attenuation difference on delayed contrast-enhanced images was achieved 3 min post injection (73.5 HU). A slightly higher attenuation difference was observed for iopromide 6 min after contrast medium injection (82.2 HU), although not statistically significant (p=0.6437). Mean infarct volume as measured by NBT staining was 33.5%{+-}13.6%. There was an excellent agreement of infarct sizes among NBT-, iopromide- and iodixanol-enhanced MDCT with concordance-correlation coefficients ranging from {rho}{sub (c)=} 0.9928-0.9982. Iopromide and iodixanol both allow a reliable assessment of MI with delayed contrast-enhanced MDCT. (orig.)

  14. Hda Monomerization by ADP Binding Promotes Replicase Clamp-mediated DnaA-ATP Hydrolysis*S⃞

    OpenAIRE

    Su'etsugu, Masayuki; Nakamura, Kenta; Keyamura, Kenji; Kudo, Yuka; Katayama, Tsutomu

    2008-01-01

    ATP-DnaA is the initiator of chromosomal replication in Escherichia coli, and the activity of DnaA is regulated by the regulatory inactivation of the DnaA (RIDA) system. In this system, the Hda protein promotes DnaA-ATP hydrolysis to produce inactive ADP-DnaA in a mechanism that is mediated by the DNA-loaded form of the replicase sliding clamp. In this study, we first revealed that hda translation uses an unusual initiation codon, CUG, located downstream of the annotat...

  15. I222 crystal form of despentapeptide (B26-B30) insulin provides new insights into the properties of monomeric insulin

    Czech Academy of Sciences Publication Activity Database

    Whittingham, J. L.; Youshang, Z.; Žáková, Lenka; Dodson, E. J.; Turkenburg, J. P.; Brange, J.; Dodson, G. G.

    2006-01-01

    Roč. 62, č. 5 (2006), s. 505-511 ISSN 0907-4449 Institutional research plan: CEZ:AV0Z40550506 Keywords : insulin * crystal structure * monomer * despentapeptid Subject RIV: CE - Biochemistry Impact factor: 1.687, year: 2006

  16. Advances and highlights in allergen immunotherapy: On the way to sustained clinical and immunologic tolerance.

    Science.gov (United States)

    Berings, Margot; Karaaslan, Cagatay; Altunbulakli, Can; Gevaert, Philippe; Akdis, Mübeccel; Bachert, Claus; Akdis, Cezmi A

    2017-11-01

    Allergen immunotherapy (AIT) is an effective treatment strategy for allergic diseases and has been used for more than 100 years. In recent years, however, the expectations on concepts, conduct, statistical evaluation, and reporting have developed significantly. Products have undergone dose-response and confirmative studies in adults and children to provide evidence for the optimal dosage, safety, and efficacy of AIT vaccines using subcutaneous and sublingual delivery pathways in large patient cohorts, ensuring solid conclusions to be drawn from them for the advantage of patients and societies alike. Those standards should be followed today, and products answering to them should be preferred over others lacking optimization and proof of efficacy and safety. Molecular and cellular mechanisms of AIT include early mast cell and basophil desensitization effects, regulation of T- and B-cell responses, regulation of IgE and IgG 4 production, and inhibition of responses from eosinophils, mast cells, and basophils in the affected tissues. There were many developments to improve vaccination strategies, demonstration of new molecules involved in molecular mechanisms, and demonstration of new biomarkers for AIT during the last few years. The combination of probiotics, vitamins, and biological agents with AIT is highlighting current advances. Development of allergoids and recombinant and hypoallergenic vaccines to skew the immune response from IgE to IgG 4 and regulation of dendritic cell, mast cell, basophil, innate lymphoid cell, T-cell, and B-cell responses to allergens are also discussed in detail. Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  17. Chemical modification of birch allergen extract leads to a reduction in allergenicity as well as immunogenicity.

    Science.gov (United States)

    Würtzen, Peter Adler; Lund, Lise; Lund, Gitte; Holm, Jens; Millner, Anders; Henmar, Helene

    2007-01-01

    In Europe, specific immunotherapy is currently conducted with vaccines containing allergen preparations based on intact extracts. In addition to this, chemically modified allergen extracts (allergoids) are used for specific allergy treatment. Reduced allergenicity and thereby reduced risk of side effects in combination with retained ability to activate T cells and induce protective allergen-specific antibody responses has been claimed for allergoids. In the current study, we compared intact allergen extracts and allergoids with respect to allergenicity and immunogenicity. The immunological response to birch allergen extract, alum-adsorbed extract, birch allergoid and alum-adsorbed allergoid was investigated in vitro in human basophil histamine release assay and by stimulation of human allergen-specific T cell lines. In vivo, Bet v 1-specific IgG titers in mice were determined after repetitive immunizations. In all patients tested (n = 8), allergoid stimulations led to reduced histamine release compared to the intact allergen extract. However, the allergoid preparations were not recognized by Bet v 1-specific T cell lines (n = 7), which responded strongly to the intact allergen extract. Mouse immunizations showed a clearly reduced IgG induction by allergoids and a strongly potentiating effect of the alum adjuvant. Optimal IgG titers were obtained after 3 immunizations with intact allergen extracts, while 5 immunizations were needed to obtain maximal response to the allergoid. The reduced histamine release observed for allergoid preparations may be at the expense of immunological efficacy because the chemical modifications lead to a clear reduction in T cell activation and the ability to induce allergen-specific IgG antibody responses. Copyright 2007 S. Karger AG, Basel.

  18. A randomized controlled trial of the effect of sublingual orally disintegrating olanzapine versus oral olanzapine on body mass index: the PLATYPUS Study

    NARCIS (Netherlands)

    Karagianis, J.; Grossman, L.; Landry, J.; Reed, V. A.; de Haan, L.; Maguire, G. A.; Hoffmann, V. P.; Milev, R.

    2009-01-01

    BACKGROUND: Patients with schizophrenia and bipolar disorder have frequently reported weight gain during olanzapine treatment. Previous studies have observed a decrease in weight gain, or weight loss, in patients switching from standard olanzapine tablets (SOT) to orally disintegrating olanzapine

  19. Elucidation of Arctigenin Pharmacokinetics and Tissue Distribution after Intravenous, Oral, Hypodermic and Sublingual Administration in Rats and Beagle Dogs: Integration of In Vitro and In Vivo Findings

    OpenAIRE

    Jie Li; Jie Li; Jie Li; Xin Li; Xin Li; Xin Li; Yu-Shan Ren; Yu-Shan Ren; Yuan-Yuan Lv; Yuan-Yuan Lv; Yuan-Yuan Lv; Jun-Sheng Zhang; Jun-Sheng Zhang; Jun-Sheng Zhang; Xiao-Li Xu

    2017-01-01

    Although arctigenin (AG) has diverse bioactivities, such as anti-oxidant, anti-inflammatory, anti-cancer, immunoregulatory and neuroprotective activities, its pharmacokinetics have not been systematically evaluated. The purpose of this work was to identify the pharmacokinetic properties of AG via various experiments in vivo and in vitro. In this research, rats and beagle dogs were used to investigate the PK (pharmacokinetics, PK) profiles of AG with different drug-delivery manners, including ...

  20. Distinct alterations in sublingual microcirculatory blood flow and hemoglobin oxygenation in on-pump and off-pump coronary artery bypass graft surgery

    NARCIS (Netherlands)

    Atasever, Bektaş; Boer, Christa; Goedhart, Peter; Biervliet, Jules; Seyffert, Jan; Speekenbrink, Ron; Schwarte, Lothar; de Mol, Bas; Ince, Can

    2011-01-01

    The authors hypothesized that cardiopulmonary bypass (CPB) (on-pump) is associated with more severe changes in the microcirculatory blood flow and tissue oxygenation as compared with off-pump coronary artery bypass surgery. An observational study. A university hospital and teaching hospital.

  1. In vitro evidence of efficacy and safety of a polymerized cat dander extract for allergen immunotherapy.

    Science.gov (United States)

    Morales, María; Gallego, Mayte; Iraola, Victor; Taulés, Marta; de Oliveira, Eliandre; Moya, Raquel; Carnés, Jerónimo

    2017-02-24

    Allergy to cat epithelia is highly prevalent, being the major recommendation for allergy sufferers its avoidance. However, this is not always feasible. Allergen specific immunotherapy is therefore recommended for these patients. The use of polymerized allergen extracts, allergoids, would allow to achieve the high allergen doses suggested to be effective while maintaining safety. Cat native extract and its depigmented allergoid were manufactured and biochemically and immunochemically characterized. Protein and chromatographic profiles showed significant modification of the depigmented allergoid with respect to its corresponding native extract. However, the presence of different allergens (Fel d 1, Fel d 2, Fel d 3, Fel d 4 and Fel d 7) was confirmed in the allergoid. Differences in IgE-binding capacity were observed as loss of biological potency and lower stability of the IgE-allergen complex on surface plasmon resonance. The allergoid induced production of IgG antibodies able to block IgE-binding to native extract. Finally, studies carried out with peripheral-blood mononuclear cells from cat allergic patients showed that the allergoid induced IFN-γ and IL-10 production similar to that induced by native extract. Cat depigmented allergoid induced production of cytokines involved in a Th1 and Treg response, was able to induce production of IgG-antibodies that blocks IgE-binding to cat native extract, and showed reduced interaction with IgE, suggesting greater safety than native extract while maintaining in vitro efficacy.

  2. Reduced in vitro T-cell responses induced by glutaraldehyde-modified allergen extracts are caused mainly by retarded internalization of dendritic cells.

    Science.gov (United States)

    Heydenreich, Bärbel; Bellinghausen, Iris; Lorenz, Steffen; Henmar, Helene; Strand, Dennis; Würtzen, Peter A; Saloga, Joachim

    2012-06-01

    Although allergen-specific immunotherapy is a clinically effective therapy for IgE-mediated allergic diseases, the risk of IgE-mediated adverse effects still exists. For this reason, chemically modified allergoids have been introduced, which may destroy IgE-binding sites while T-cell activation should be retained. The aim of the study was to analyse the differences between intact allergens and differently modified/aggregated allergoids concerning their internalization as well as T-cell and basophil activation. For this purpose human monocyte-derived immature dendritic cells (DC) were incubated with Phleum pratense or Betula verrucosa pollen extract or with the corresponding allergoids, modified with formaldehyde or glutaraldehyde. After an additional maturation process, the antigen-loaded mature DC were co-cultured with autologous CD4(+) T cells. Allergenicity was tested by leukotriene release from basophils. In addition, the uptake of intact allergens and allergoids by immature DC was analysed. The proliferation of, as well as the interleukin-4 (IL-4), IL-10, IL-13 and interferon-γ production by, CD4(+) T cells which had been stimulated with glutaraldehyde allergoid-treated DC was reduced compared with CD4(+) T cells stimulated with intact allergen-treated or formaldehyde allergoid-treated DC. In line with this, glutaraldehyde-modified allergoids were more aggregated and were internalized more slowly. Furthermore, only the allergoids modified with glutaraldehyde induced a decreased leukotriene release by activated basophils. These findings suggest that IgE-reactive epitopes were destroyed more efficiently by modification with glutaraldehyde than with formaldehyde under the conditions chosen for these investigations. Glutaraldehyde-modified allergoids also displayed lower T-cell stimulatory capacity, which is mainly the result of greater modification/aggregation and diminished uptake by DC. © 2012 The Authors. Immunology © 2012 Blackwell Publishing Ltd.

  3. Isolation and biochemical characterisation of monomeric and dimeric photosystem II complexes from spinach and their relevance to the organisation of photosystem II in vivo

    NARCIS (Netherlands)

    Hankamer, B; Nield, J; Zheleva, D; Boekema, E; Jansson, S; Barber, J

    1997-01-01

    Membranes enriched in photosystem II were isolated from spinach and further solubilised using n-octyl beta-D-glucopyranoside (OctGlc) and n-dodecyl beta-D-maltoside (DodGlc(2)). The OctGlc preparation had high rates of oxygen evolution and when subjected to size-exclusion HPLC and sucrose density

  4. Expression, purification, crystallization and preliminary X-ray analysis of eCGP123, an extremely stable monomeric green fluorescent protein with reversible photoswitching properties

    International Nuclear Information System (INIS)

    Don Paul, Craig; Traore, Daouda A. K.; Byres, Emma; Rossjohn, Jamie; Devenish, Rodney J.; Kiss, Csaba; Bradbury, Andrew; Wilce, Matthew C. J.; Prescott, Mark

    2011-01-01

    eCGP123, an extremely stable GFP with photoswitching properties, has been expressed, purified and crystallized. A diffraction data set has been collected at 2.10 Å resolution. Enhanced consensus green protein variant 123 (eCGP123) is an extremely thermostable green fluorescent protein (GFP) that exhibits useful negative reversible photoswitching properties. eCGP123 was derived by the application of both a consensus engineering approach and a recursive evolutionary process. Diffraction-quality crystals of recombinant eCGP123 were obtained by the hanging-drop vapour-diffusion method using PEG 3350 as the precipitant. The eCGP123 crystal diffracted X-rays to 2.10 Å resolution. The data were indexed in space group P1, with unit-cell parameters a = 74.63, b = 75.38, c = 84.51 Å, α = 90.96, β = 89.92, γ = 104.03°. The Matthews coefficient (V M = 2.26 Å 3 Da −1 ) and a solvent content of 46% indicated that the asymmetric unit contained eight eCGP123 molecules

  5. Evidence for the monomerization of spore photoproduct to two thymines by the light-independent 'spore repair' process in Bacillus subtilis

    International Nuclear Information System (INIS)

    Van Wang, T.-C.; Rupert, C.S.

    1977-01-01

    Ultraviolet irradiation of bacterial spores induces a unique DNA photoproduct, which yields mostly 5-thyminyl-5,6-dihydrothymine (Thy(α-5)hThy, or TDHT) on acid hydrolysis. One of the possible mechanisms for the observed removal of the photoproduct on spore germination ivolves its direct conversion back to two adjacent thymine residues, and additional evidence is presented in support of this theory. Studies were made of the fate of the TDHT radioactivity in irradiated, germinated B. subtilis spores labelled with 3 H-thymine or 14 C-thymine, and of the homogeneity of the thymine-peak radioactivity. The radioactivity disappearing from the TDHT peak on germination seemed to be stoichiometrically recovered in the thymine peak, and no new materials were detected under the thymine-peak radioactivity. No intermediates were detected in B. subtilis mutant 25D4 (hcr 42 - recA 1 - ), a strain which had given some promise of accumulating intermediates from an incomplete repair process. (U.K.)

  6. Synthesis and characterization of monomeric and polymeric Cu(II) complexes of 3,4-ethylenedioxythiophene-functionalized with cyclam ligand

    International Nuclear Information System (INIS)

    Velauthamurty, Kuhamoorthy; Higgins, Simon J.; Rajapakse, R.M. Gamini; Bandara, H.M.N.; Shimomura, Masaru

    2010-01-01

    A functionalized EDOT derivative with 1,4,8,11-tetraazacyclotetradecane (cyclam) ligand pendant to the ethylene bridge (4) and its complexes [M(4)(BF 4 ) 2 ], where M(II) = Cu(II), was prepared and characterized. Their electrochemical copolymerization with EDOT was studied. The electro-co-polymerized films were characterized by electrochemical methods, X-ray photoelectron spectroscopy and by X-ray fluorescence spectroscopy. The co-polymerization method was found to afford a good control of the metal concentration in the polymer matrix and represents a good technique for preparing electronically conductive polymers containing redox-active metal complexes.

  7. The influence of monomeric resin and filler characteristics on the performance of experimental resin-based composites (RBCs) derived from a commercial formulation.

    LENUS (Irish Health Repository)

    Hahnel, Sebastian

    2012-04-01

    To explore experimental RBCs derived from a successful commercially available RBC (Grandio) to investigate resin monomer blend and filler parameters (volume fraction, density and diameter) on RBC performance.

  8. Molecular structure and infrared spectra of the monomeric 3-(methoxy)-1,2-benzisothiazole 1,1-dioxide (methyl pseudosaccharyl ether)

    Science.gov (United States)

    Kaczor, Agnieszka; Almeida, Rui; Gómez-Zavaglia, Andrea; Cristiano, Maria de Lurdes S.; Fausto, Rui

    2008-03-01

    The computational description of saccharin (1,2-benzisothiazol-3(2 H)-one-1,1-dioxide) and its derivatives is difficult due to the presence of hypervalent S dbnd O bonds in their structures. Therefore, in this investigation, the HF, DFT/B3LYP and MP2 methods were used to predict the geometry and the infrared spectrum of the saccharyl derivative 3-(methoxy)-1,2-benzisothiazole 1,1-dioxide (MBID). Their relative predictive capabilities were then evaluated by comparing the obtained results with experimentally available data, namely the newly obtained IR spectra of MBID isolated in low-temperature inert matrices. For each method, different basis sets [6-31++G(d,p), 6-31++G(3df,3pd), 6-311++G(d,p), 6-311++G(2df,2pd), 6-311++G(3df,3pd), aug-cc-pVDZ and aug-cc-pVTZ] were considered. The best overall agreement has been achieved at the B3LYP/6-311++G(3df,3pd) and B3LYP/6-31++G(3df,3pd) levels of theory, showing the adequacy of the B3LYP functional to describe the investigated properties in this type of compounds and stressing the relevance of including high-order polarization functions in the basis set. The chosen level of theory [B3LYP/6-311++G(3df,3pd)] was applied to analyze the vibrational spectra and the geometry of the title molecule. In agreement with the experiment, the C sbnd O sbnd C linkage in MBID is predicted by these calculations to exhibit considerably short (1.320 Å) and long (1.442 Å) (N dbnd )C sbnd O and (H 3)C sbnd O bonds, respectively, and a hybridization of the central oxygen atom close to sp 2 (the C sbnd O sbnd C angle is predicted to be ca. 117°). This C sbnd O sbnd C bonding pattern fits the well-known high reactivity of MBID upon thermal rearrangement, which has been shown to result in easy selective [1,3']-isomerization of the compound.

  9. Comparison between the efficacy of dimeric and monomeric non-ionic contrast media (iodixanol vs iopromide) in urography in patients with macroscopic haematuria

    International Nuclear Information System (INIS)

    Stacul, F.; Cova, M.; Pravato, M.; Floriani, I.

    2003-01-01

    Non-ionic dimers induce less diuresis than non-ionic monomers, resulting in increased opacification of the urinary tract in intravenous urography. This trial compared the diagnostic efficacy of iodixanol and iopromide in patients with macroscopic haematuria. One hundred consecutive patients with normal renal function and macroscopic haematuria entered a double blind, comparative, randomised, parallel trial. Contrast media were given with bolus injection in doses of 300 mgI/kg b.w. Radiographs were blindly evaluated by three radiologists who analysed different parameters (calyceal density and filling, papillary blush detection, delineation of collecting ducts, renal pelvis opacification, visualisation of ureters, bladder density, bladder distention) and estimated the diagnostic confidence (whether abnormal findings were definitely absent, probably absent, doubtful, probably present or certainly present). Radiological diagnoses were compared with final diagnoses. Results were summarised as the ratio of the odds of having a worse performance of iopromide vs iodixanol. Iodixanol showed a significantly better calyceal density and filling [odds ratio (OR): 1.96; 95% confidence interval (CI): 1.60-2.41], a significantly better pelvis opacification (OR 2.91; CI 2.02-4.18) and a significantly more frequent papillary blush detection (OR 1.95; CI 1.29-2.95). Iopromide showed a significantly better ureteral visualisation (OR 0.67; CI 0.48-0.92) and a significantly higher bladder distention (OR 0.59; CI 0.36-0.99). Iodixanol allowed a significantly higher diagnostic confidence as to calyceal evaluation (OR 1.35; CI 1.01-1.79). No significant differences were found with regard to other parameters. The results confirmed theoretical expectations. The higher opacification provided by iodixanol allowed better results and a higher diagnostic confidence in the upper excretory pathway. (orig.)

  10. Experimental and time-dependent density functional theory characterization of the UV-visible spectra of monomeric and μ-oxo dimeric ferriprotoporphyrin IX.

    Science.gov (United States)

    Kuter, David; Venter, Gerhard A; Naidoo, Kevin J; Egan, Timothy J

    2012-10-01

    Speciation of ferriprotoporphyrin IX, Fe(III)PPIX, in aqueous solution is complex. Despite the use of its characteristic spectroscopic features for identification, the theoretical basis of the unique UV-visible absorbance spectrum of μ-[Fe(III)PPIX](2)O has not been explored. To investigate this and to establish a structural and spectroscopic model for Fe(III)PPIX species, density functional theory (DFT) calculations were undertaken for H(2)O-Fe(III)PPIX and μ-[Fe(III)PPIX](2)O. The models agreed with related Fe(III)porphyrin crystal structures and reproduced vibrational spectra well. The UV-visible absorbance spectra of H(2)O-Fe(III)PPIX and μ-[Fe(III)PPIX](2)O were calculated using time-dependent DFT and reproduced major features of the experimental spectra of both. Transitions contributing to calculated excitations have been identified. The features of the electronic spectrum calculated for μ-[Fe(III)PPIX](2)O were attributed to delocalization of electron density between the two porphyrin rings of the dimer, the weaker ligand field of the axial ligand, and antiferromagnetic coupling of the Fe(III) centers. Room temperature magnetic circular dichroism (MCD) spectra have been recorded and are shown to be useful in distinguishing between these two Fe(III)PPIX species. Bands underlying major spectroscopic features were identified through simultaneous deconvolution of UV-visible and MCD spectra. Computed UV-visible spectra were compared to deconvoluted spectra. Interpretation of the prominent bands of H(2)O-Fe(III)PPIX largely conforms to previous literature. Owing to the weak paramagnetism of μ-[Fe(III)PPIX](2)O at room temperature and the larger number of underlying excitations, interpretation of its experimental UV-visible spectrum was necessarily tentative. Nonetheless, comparison with the calculated spectra of antiferromagnetically coupled and paramagnetic forms of the μ-oxo dimer of Fe(III)porphine suggested that the composition of the Soret band involves a mixture of π→π* and π→d(π) charge transfer transitions. The Q-band and charge transfer bands appear to amalgamate into a mixed low energy envelope consisting of excitations with heavily admixed π→π* and charge transfer transitions.

  11. “Covalent Hydration” Reactions in Model Monomeric Ru 2,2'-Bipyridine Complexes: Thermodynamic Favorability as a Function of Metal Oxidation and Overall Spin States

    Energy Technology Data Exchange (ETDEWEB)

    Ozkanlar, Abdullah; Cape, Jonathan L.; Hurst, James K.; Clark, Aurora E.

    2011-09-05

    Density functional theory (DFT) has been used to investigate the plausibility of water addition to the simple mononuclear ruthenium complexes, [(NH{sub 3}){sub 3}(bpy)Ru=O]{sup 2+}/{sup 3+} and [(NH{sub 3}){sub 3}(bpy)RuOH]{sup 3+}, in which the OH fragment adds to the 2,2{prime}-bipyridine (bpy) ligand. Activation of bpy toward water addition has frequently been postulated within the literature, although there exists little definitive experimental evidence for this type of 'covalent hydration'. In this study, we examine the energetic dependence of the reaction upon metal oxidation state, overall spin state of the complex, as well as selectivity for various positions on the bipyridine ring. The thermodynamic favorability is found to be highly dependent upon all three parameters, with free energies of reaction that span favorable and unfavorable regimes. Aqueous addition to [(NH{sub 3}){sub 3}(bpy)Ru=O]{sup 3+} was found to be highly favorable for the S = 1/2 state, while reduction of the formal oxidation state on the metal center makes the reaction highly unfavorable. Examination of both facial and meridional isomers reveals that when bipyridine occupies the position trans to the ruthenyl oxo atom, reactivity toward OH addition decreases and the site preferences are altered. The electronic structure and spectroscopic signatures (EPR parameters and simulated spectra) have been determined to aid in recognition of 'covalent hydration' in experimental systems. EPR parameters are found to uniquely characterize the position of the OH addition to the bpy as well as the overall spin state of the system.

  12. Synthesis of novel monomeric graphene quantum dots and corresponding nanocomposite with molecularly imprinted polymer for electrochemical detection of an anticancerous ifosfamide drug.

    Science.gov (United States)

    Bali Prasad, Bhim; Kumar, Anil; Singh, Ragini

    2017-08-15

    This paper reports a typical synthesis of a nanocomposite of functionalized graphene quantum dots and imprinted polymer at the surface of screen-printed carbon electrode using N-acryloyl-4-aminobenzamide, as a functional monomer, and an anticancerous drug, ifosfamide, as a print molecule (test analyte). Herein, graphene quantum dots in nanocomposite practically induced the electrocatalytic activity by lowering the oxidation overpotential of test analyte and thereby amplifying electronic transmission, without any interfacial barrier in between the film and the electrode surface. The differential pulse anodic stripping signal at functionalized graphene quantum dots based imprinted sensor was realized to be about 3- and 7-fold higher as compared to the traditionally made imprinted polymers prepared in the presence and the absence of graphene quantum dots (un-functionalized), respectively. This may be attributed to a pertinent synergism in between the positively charged functionalized graphene quantum dots in the film and the target analyte toward the enhancement of electro-conductivity of the film and thereby the electrode kinetics. In fact, the covalent attachment of graphene quantum dots with N-acryloyl-4-aminobenzamide molecules might exert an extended conjugation at their interface facilitating electro conducting to render the channelized pathways for the electron transport. The proposed sensor is practically applicable to the ultratrace evaluation of ifosfamide in real (biological/pharmaceutical) samples with detection limit as low as 0.11ngmL -1 (S/N=3), without any matrix effect, cross-reactivity, and false-positives. Copyright © 2017 Elsevier B.V. All rights reserved.

  13. Field Evaluation of Solvent-Free Sampling with Di-n-butylamine for the Determination of Airborne Monomeric and Oligomeric 1,6-Hexamethylene Diisocyanate

    Science.gov (United States)

    2014-03-27

    ISO Guide 34:2009 and ISO / IEC 17025 :2005) for HDI oligomers. Per the manufacturer, a single ASSETTM sampler may be used for over 8 hours which leads...hexamethylene diisocyanate (HDI). During this study, the Supelco ASSETTM EZ4-NCO Dry Sampler was compared to the Omega Specialty Instrument Company ISO ...detection (HPLC-MS); 2) do ASSETTM and ISO -CHEK® samplers collect equivalent HDI monomer and oligomer concentrations; and 3) what is the relative cost of

  14. The Caenorhabditis elegans pericentriolar material components SPD-2 and SPD-5 are monomeric in the cytoplasm before incorporation into the PCM matrix

    DEFF Research Database (Denmark)

    Wueseke, Oliver; Bunkenborg, Jakob; Hein, Marco Y

    2014-01-01

    mostly as a monomer but also forms complexes with the PP2A-regulatory proteins RSA-1 and RSA-2, which are required for microtubule organization at centrosomes. These results suggest that the interactions between SPD-2, SPD-5, and PLK-1 do not result in formation of cytoplasmic complexes, but instead...

  15. Characterization of the tumor-promoting activity of m-chloroperoxybenzoic acid in SENCAR mouse skin and its inhibition by gallotannin, oligomeric proanthocyanidin, and their monomeric units

    Science.gov (United States)

    Guilan Chen; Elisabeth M. Perchellet; Xiao Mei Gao; Fatima K. Johnson; Amy W. Davis; Steven W. Newell; Richard W. Hemingway; Vittorio Bottari; Jean-Pierre Perchellett

    1996-01-01

    m-Chloroperoxybenzoic acid (CPBA). Which induces ornithine decarboxylase activity as much as 12-0- terradecanoyIp horbol-13-acetate (TPA ). was tested for its ability to induce DNA synthesis. bydroperoxide (HPx) production. and tumor promotion in mouse epidermis in vivo. After an early inhibition. CPBA stimulates DNA synthesis. A response which is maintained between 16...

  16. CoMo sulphide-catalyzed hydrodeoxygenation of lignin model compounds: An extended reaction network for the conversion of monomeric and dimeric substrates

    NARCIS (Netherlands)

    Jongerius, A.L.; Jastrzebski, R; Bruijnincx, P.C.A.; Weckhuysen, B.M.

    2012-01-01

    In the present work, extensive hydrodeoxygenation (HDO) studies with a commercial sulfided CoMo/Al2O3 catalyst were performed on a library of ligninmodel compounds at 50 bar hydrogen pressure and 300 °C in dodecane, using a batch autoclave system. The catalyst was activated under hydrogen atmosphere

  17. The monomeric, tetrameric, and fibrillar organization of Fib: the dynamic building block of the bacterial linear motor of Spiroplasma melliferum BC3.

    Science.gov (United States)

    Cohen-Krausz, Sara; Cabahug, Pamela C; Trachtenberg, Shlomo

    2011-07-08

    Spiroplasmas belong to the class Mollicutes, representing the minimal, free-living, and self-replicating forms of life. Spiroplasmas are helical wall-less bacteria and the only ones known to swim by means of a linear motor (rather than the near-universal rotary bacterial motor). The linear motor follows the shortest path along the cell's helical membranal tube. The motor is composed of a flat monolayered ribbon of seven parallel fibrils and is believed to function in controlling cell helicity and motility through dynamic, coordinated, differential length changes in the fibrils. The latter cause local perturbations of helical symmetry, which are essential for net directional displacement in environments with a low Reynolds number. The underlying fibrils' core building block is a circular tetramer of the 59-kDa protein Fib. The fibrils' differential length changes are believed to be driven by molecular switching of Fib, leading consequently to axial ratio and length changes in tetrameric rings. Using cryo electron microscopy, diffractometry, single-particle analysis of isolated ribbons, and sequence analyses of Fib, we determined the overall molecular organization of the Fib monomer, tetramer, fibril, and linear motor of Spiroplasma melliferum BC3 that underlies cell geometry and motility. Fib appears to be a bidomained molecule, of which the N-terminal half is apparently a globular phosphorylase. By a combination of reversible rotation and diagonal shift of Fib monomers, the tetramer adopts either a cross-like nonhanded conformation or a ring-like handed conformation. The sense of Fib rotation may determine the handedness of the linear motor and, eventually, of the cell. A further change in the axial ratio of the ring-like tetramers controls fibril lengths and the consequent helical geometry. Analysis of tetramer quadrants from adjacent fibrils clearly demonstrates local differential fibril lengths. Copyright © 2011 Elsevier Ltd. All rights reserved.

  18. FT-IR, FT-Raman, UV spectra and DFT calculations on monomeric and dimeric structure of 2-amino-5-bromobenzoic acid.

    Science.gov (United States)

    Karabacak, Mehmet; Cinar, Mehmet

    2012-02-01

    In this work, the molecular conformation, vibrational and electronic transition analysis of 2-amino-5-bromobenzoic acid (2A5BrBA) were presented for the ground state using experimental techniques (FT-IR, FT-Raman and UV) and density functional theory (DFT) employing B3LYP exchange correlation with the 6-311++G(d,p) basis set. FT-IR and FT-Raman spectra were recorded in the regions of 400-4000 cm(-1) and 50-4000 cm(-1), respectively. There are four conformers, C1, C2, C3 and C4 for this molecule. The geometrical parameters, energies and wavenumbers have been obtained for all four conformers. The computational results diagnose the most stable conformer of 2A5BrBA as the C1 form. The complete assignments of fundamental vibrations were performed on the basis of the total energy distribution (TED) of the vibrational modes, calculated with scaled quantum mechanics (SQM) method. Raman activities calculated by DFT method have been converted to the corresponding Raman intensities using Raman scattering theory. The UV spectra of investigated compound were recorded in the region of 200-400 nm for ethanol and water solutions. The electronic properties were evaluated with help of time-dependent DFT (TD-DFT) theoretically and results were compared with experimental observations. The thermodynamic properties of the studied compound at different temperatures were calculated, revealing the correlations between standard heat capacity, standard entropy, standard enthalpy changes and temperatures. The observed and the calculated geometric parameters, vibrational wavenumbers and electronic transitions were compared with observed data and found to be in good agreement. Copyright © 2011 Elsevier B.V. All rights reserved.

  19. Cloning and characterization of a gene encoding Rac/Rop-like monomeric guanosine 5'-triphosphate-binding protein from Scoparia dulcis.

    Science.gov (United States)

    Mitamura, Toshiaki; Shite, Masato; Yamamura, Yoshimi; Kurosaki, Fumiya

    2009-06-01

    A cDNA clone, designated Sd-racrop (969 bp), was isolated from seedlings of Scoparia dulcis. This gene contains an open reading frame encoding the protein of 197 amino acid residues with high homology to Rac/Rop small guanosine 5'-triphosphate-binding proteins from various plant sources. In Southern hybridization analysis, the restriction digests prepared from genomic DNA of S. dulcis showed a main signal together with a few weakly hybridized bands. The transcriptional level of Sd-racrop showed a transient decrease by exposure of the leaf tissues of S. dulcis to the ethylene-generating reagent 2-chloroethylphosphonic acid. However, an appreciable increase in gene expression was reproducibly observed upon treatment of the plant with methyl jasmonate. These results suggest that the Sd-racrop product plays roles in ethylene- and methyl jasmonate-induced responses of S. dulcis accompanying the change in the transcriptional level, however, the cellular events mediated by this protein toward these external stimuli would be regulated by various mechanisms.

  20. The monomeric orphan nuclear receptor Schistosoma mansoni Ftz-F1 dimerizes specifically and functionally with the schistosome RXR homologue, SmRXR1

    International Nuclear Information System (INIS)

    Bertin, Benjamin; Caby, Stephanie; Oger, Frederik; Sasorith, Souphatta; Wurtz, Jean-Marie; Pierce, Raymond J.

    2005-01-01

    In an attempt to understand development and differentiation processes of the parasitic blood fluke Schistosoma mansoni, several members of the nuclear receptor superfamily were cloned, including SmFtz-F1 (S. mansoni Fushi Tarazu-factor 1). The Ftz-F1 nuclear receptor subfamily only contains orphan receptors that bind to their response element as monomers. Whereas SmFtz-F1 displays these basic functional properties, we have identified an original and specific interaction between SmFtz-F1 and the schistosome RXR homologue, SmRXR1. The mammalian two-hybrid assay showed that the D, E, and F domains of SmFtz-F1 were capable of interacting specifically with the E domain of SmRXR1 but not with that of mouse RXRα. Using three-dimensional LBD homology modelling and structure-guided mutagenesis, we were able to demonstrate the essential role of exposed residues located in the dimerization interfaces of both receptors in the maintenance of the interaction. Cotransfection experiments with constructions encoding full-length nuclear receptors show that SmRXR1 potentiates the transcriptional activity of SmFtz-F1 from various promoters. Nevertheless, the lack of identification of a dimeric response element for this SmFtz-F1/SmRXR1 heterodimer seems to indicate a 'tethering' mechanism. Thus, our results suggest for the first time that a member of the Ftz-F1 family could heterodimerize functionally with a homologue of the universal heterodimerization partner of nuclear receptors. This unique property confirms that SmFtz-F1 may be involved in the development and differentiation of schistosome-specific structures