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Sample records for sublingual monomeric allergoid

  1. Parietaria sublingual allergoid immunotherapy with a co-seasonal treatment schedule.

    Science.gov (United States)

    D'Anneo, R W; Arena, A; Gammeri, E; Bruno, M E; Falagiani, P; Riva, G; Leonardi, S; La Rosa, M

    2008-01-01

    Sublingual immunotherapy (SLIT) with monomeric allergoid, given according to the standard scheme, resulted effective and safe. However, the achievement of a clinical benefit requires a long time. We thus performed this study using an administration protocol starting in the co-seasonal period with a 3-day build-up phase and lasting only 6 months, in order to obtain the above benefit in a shorter time. The study, prospective, randomised and controlled versus drug therapy, was conducted on 65 rhinitic and/or asthmatic patients allergic to Parietaria with or without other sensitisations. Twenty-four were allocated to 1,000 AU/week, 21 to 3,000 AU/week and 21 to drug therapy. They were treated from April to September 2006. At baseline, 3 and 6 months a Visual Analogue Scale (VAS) was performed to assess the patients' well-being. Drug consumption was evaluated by means of monthly diary cards. Bronchial reactivity was investigated at baseline and 6 months by methacholine challenge test. There was a greater VAS improvement in both the SLIT groups than in the controls after 6 months (p<0.05). In patients taking 3,000 AU/week this was already evident after 3 months. There was a significant reduction in rescue medication consumption between 3 and 6 months (p<0.05) in all three groups. The bronchial reactivity was reduced only in the SLIT groups (p<0.001). No adverse events were observed. At 6 months the allergoid SLIT showed itself to be effective and safe. In addition the subjective clinical benefit was obtained in a more rapid period, i.e. 3 instead of 6 months, when a higher maintenance dose was administered.

  2. 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.

  3. Fentanyl Sublingual Spray

    Science.gov (United States)

    Fentanyl sublingual spray is used to treat breakthrough pain (sudden episodes of pain that occur despite round ... effects of the medication) to narcotic pain medications. Fentanyl is in a class of medications called narcotic ( ...

  4. Date palm pollen allergoid: characterization of its chemical-physical and immunological properties.

    Science.gov (United States)

    Mistrello, G; Harfi, H; Roncarolo, D; Kwaasi, A; Zanoni, D; Falagiani, P; Panzani, R

    2008-01-01

    Date palm (DP) pollen can cause allergic symptoms in people living in different countries. Specific immunotherapy with allergenic extracts by subcutaneous route is effective to cure allergic people. However, the risk of side effects has led to explore safer therapeutic modalities. The aim of our work was to evaluate IgE cross-reactivity between DP and autochthonous palm (European fan palm, EFP) pollen extracts, to chemically modify DP extract with potassium cyanate in order to obtain an allergoid, and to characterize it. By radioallergosorbent test inhibition, immunoblotting (IB) and skin prick test, in vitro and in vivo allergenic activities of native and modified DP extracts were compared. By SDS-PAGE and IB, we compared the protein profile and IgE-binding capacity of both native and modified DP, as well as of EFP extracts. By IB inhibition, IgE cross-reactivity of native DP and EFP extracts was evaluated. By ELISA, the capacity of modified DP-induced IgG to react with native DP extract was determined. Radioallergosorbent test inhibition, IB and skin prick test results demonstrated that modified DP was significantly less allergenic than native DP extract. The SDS-PAGE profile showed that potassium cyanate treatment of DP extract did not alter the molecular weight of its components. In addition, no difference was observed between native DP and EFP extracts. Subsequent IB inhibition data evidenced the existence of a strong IgE cross-reactivity between native DP and EFP extracts. ELISA results indicated that the administration of modified DP in mice was able to induce specific IgG also recognizing native DP extract. Modified DP extract (allergoid) seems to be a good candidate for immunotherapy of patients affected by specific allergy. 2007 S. Karger AG, Basel

  5. Sublingual allergen immunotherapy

    DEFF Research Database (Denmark)

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

    2012-01-01

    -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......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...... in allergic patients. Sublingual allergen immunotherapy (SLIT) has been approved, notably in the European Union, as an effective alternative to subcutaneous allergen immunotherapy (SCIT) for allergic rhinitis patients. Compared with SCIT, SLIT has a better safety profile. This is possibly because oral antigen...

  6. 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...... characteristics, prognostic factors, and clinical course. We present a large national series of histopathologically revised SGTs from the past 35 years in Denmark with clinicopathologic correlation. Twenty nine cases were identified, of which 96.6 % were malignant and 16/28 (57.1 %) were adenoid cystic carcinomas...... (ACC). Patient demography was similar to salivary gland tumors in other locations. All fine needle aspiration cytologies (FNACs) interpreted as benign were from ACCs. Metastatic disease was found in 12.5 % of ACCs at diagnosis with one third of all ACC patients having metastases at the end of follow...

  7. Clinical Applications of Sublingual Immunotherapy.

    Science.gov (United States)

    Edwards, Thomas S; Wise, Sarah K

    2017-12-01

    Sublingual immunotherapy (SLIT) is effective for the treatment of allergic rhinitis and allergic asthma in adults and children. In a limited number of studies, SLIT efficacy has been demonstrated for the treatment of food allergy. SLIT has a higher safety profile versus subcutaneous immunotherapy, although some systemic reactions have been reported. Appropriate patient selection, meticulous patient education, and routine follow-up are key for the safe and effective administration of SLIT. With organization and attention to detail, adding SLIT to one's practice can provide a highly valued patient service. Copyright © 2017 Elsevier Inc. All rights reserved.

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

    NARCIS (Netherlands)

    G.W. Canonica (Giorgio Walter); L. Cox (Linda); R. Pawankar (Ruby); C.E. Baena-Cagnani (Carlos); M.S. Blaiss (Michael); S. Bonini (Sergio); J. Bousquet (Jean); M. Calderon (Moises); E. Compalati (Enrico); S.R. Durham (Stephen); R. Gerth van Wijk (Roy); D. Larenas-Linnemann (Désirée); H. Nelson (Harold); G. Passalacqua (Giovanni); O. Pfaar (Oliver); K. Rosario (Karyna); D. Ryan (Dermot); L. Rosenwasser (Lanny); P. Schmid-Grendelmeier (Peter); G.E. Senna (Gianenrico); E. Valovirta (Erkka); H.P. van Bever (Hugo); P. Vichyanond (Pakit); U. Wahn (Ulrich); O.M. Yusuf (Osman)

    2014-01-01

    textabstractWe 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

  9. Sublingual vs. Oral Captopril in Hypertensive Crisis.

    Science.gov (United States)

    Kaya, Adnan; Tatlisu, Mustafa Adem; Kaplan Kaya, Tugba; Yildirimturk, Ozlem; Gungor, Baris; Karatas, Baran; Yazici, Selcuk; Keskin, Muhammed; Avsar, Sahin; Murat, Ahmet

    2016-01-01

    There are confusing data in literature regarding oral and sublingual captopril effects over blood pressure (BP) decrease. In our study we compared oral and sublingual captopril effectiveness over BP decrease in patients admitted to our Emergency Department with hypertensive urgency. Our study was conducted from January 2012 to January 2013 in patients with hypertensive urgency. In this cross-sectional study after two initial BP measurements, patients were identified as eligible for the study. An initial electrocardiogram was obtained and blood samples were drawn. A total of 212 patients were accepted as eligible for the study, and 25 mg of captopril was randomly given orally or sublingually; BP was measured at 10, 30, and 60 min. We selected the patients to the groups consecutively. A 25% reduction of initial BP 1 h after initiation of the treatment was accepted as an accomplishment. A second 25 mg of captopril was given if the target of 25% reduction of BP was not reached after the first tablet. Intravenous drugs were administered to the patients resistant to the captopril and these patients were excluded from the study. The 10-min systolic BP (SBP), diastolic BP, and mean BP (MBP) decrease was more prominent in the sublingual captopril group (p  0.05). In our study, sublingual captopril was found to decrease BP more efficiently in the first 30 min, but this difference equalized at 60 min. Copyright © 2016 Elsevier Inc. All rights reserved.

  10. 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....

  11. Tinnitus after administration of sublingual immunotherapy

    DEFF Research Database (Denmark)

    Juel, Jacob

    2017-01-01

    BACKGROUND/OBJECTIVES: Sublingual immunotherapy was first described in 1986. Since then, its use has been increased as an alternative to subcutaneously administered immunotherapy in the treatment of allergic rhinitis. The most common side effects are of oropharyngeal and gastrointestinal in natur...

  12. 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.

  13. Sublingual Immunotherapy for Allergic Fungal Sinusitis.

    Science.gov (United States)

    Melzer, Jonathan M; Driskill, Brent R; Clenney, Timothy L; Gessler, Eric M

    2015-10-01

    Allergic fungal sinusitis (AFS) is a condition that has an allergic basis caused by exposure to fungi in the sinonasal tract leading to chronic inflammation. Despite standard treatment modalities, which typically include surgery and medical management of allergies, patients still have a high rate of recurrence. Subcutaneous immunotherapy (SCIT) has been used as adjuvant treatment for AFS. Evidence exists to support the use of sublingual immunotherapy (SLIT) as a safe and efficacious method of treating allergies, but no studies have assessed the utility of SLIT in the management of allergic fungal sinusitis. A record review of cases of AFS that are currently or previously treated with sublingual immunotherapy from 2007 to 2011 was performed. Parameters of interest included serum IgE levels, changes in symptoms, Lund-McKay scores, decreased sensitization to fungal allergens associated with AFS, and serum IgE levels. Ten patients with diagnosed AFS were treated with SLIT. No adverse effects related to the use of SLIT therapy were identified. Decreases in subjective complaints, exam findings, Lund-McKay scores, and serum IgE levels were observed. Thus, sublingual immunotherapy appears to be a safe adjunct to the management of AFS that may improve patient outcomes. © The Author(s) 2015.

  14. Warfarin induced sublingual hematoma: a Ludwig angina mimic.

    Science.gov (United States)

    Pathak, Ranjan; Supplee, Suzanne; Aryal, Madan Raj; Karmacharya, Paras

    2015-01-01

    Sublingual hematoma is a rare but life-threatening complication of oral anticoagulants. It is important to differentiate this from infectious processes like Ludwig's angina. Securing the airway should be a priority and immediate reversal of anticoagulation with close monitoring is required. We present a case of sublingual hematoma secondary to warfarin therapy without airway compromise which was managed conservatively with reversal of INR with oral vitamin K. Although rare, it is crucial to differentiate sublingual hematomas from infectious processes. Reversal of anticoagulation with low threshold for artificial airway placement in the event of airway compromise is the treatment of choice. Copyright © 2015 Elsevier Inc. All rights reserved.

  15. Gum pigmentation: an unusual adverse effect of sublingual immunotherapy

    OpenAIRE

    Goh, Anne; Chiang, Wen Chin; Kang, Liew Woei; Rao, Rajeshwar; Lim, Hwee Hoon; Chng, Chai Kiat

    2014-01-01

    Sublingual immunotherapy has gained acceptance amongst the paediatric community as it is very well tolerated and is safe. The adverse effects of this therapy is minimal consisting mainly of local side effects within the oral cavity such as itching of the mouth, swelling of the lips and less frequently abdominal pain, wheezing and urticaria has been described. This report is to highlight another local side effect of sublingual immunotherapy which has been observed in 3 of our patients. This is...

  16. Same effect of sublingual and oral captopril in hypertensive crisis.

    Science.gov (United States)

    Karakiliç, E; Büyükcam, F; Kocalar, G; Gedik, S; Atalar, E

    2012-11-01

    Hypertensive crisis is a condition characterized by rapid and inappropriate symptomatic elevation of blood pressure (BP) that is commonly seen in Emergency Departments. Oral or sublingual captopril is commonly used in the Emergency Departments. The unpleasant taste of the sublingual drugs causes uncomfortable condition to the patient. Studies showing no difference between oral and sublingual captopril has been ignored so far. Herein we compared the oral and sublingual captopril efficiency in the hypertensive urgencies. In this retrospective observational study, 71 patients admitted with hypertensive urgency to Emergency Departments of two hospitals in 2011 whose blood pressure were recorded before captopril administration and blood pressure were recorded after captopril administration at 0-5-15-30-45-60 minutes were included the study. The reductions of the blood pressure of oral and sublingual captopril groups were compared. There were 28 patients at oral and 43 at sublingual captopril group. The mean age ± SD was 58.13 ± 8.66 years and 41 (57.7%) patients were female. The most common complaints were headache, nausea/vomiting and weakness. 65 (91.5%) patients were using antihypertensive drugs before admitted to hospital. The blood pressure at 0, 5, 15, 30, 45 and 60th minutes of therapy didn't show any difference between oral and sublingual captopril use. There was any difference between oral and sublingual captopril efficiency to control of hypertension in patient with hypertensive urgency. For a more comfortable treatment, oral captopril may be a more convenient choice in the hypertensive urgencies.

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

    DEFF Research Database (Denmark)

    Juel, J.

    2017-01-01

    , 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...... 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....

  18. 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

  19. 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 19......p13, resulting in the t(15;19)(q14;p13) karyotype. NC is poorly differentiated and is likely to be overlooked and misdiagnosed as poorly differentiated squamous cell carcinoma (SCC) when immunohistochemical evaluation of NUT protein expression is omitted. Previously, NC has been found in the parotid...... and submandibular glands and we present the first case in the sublingual gland arising in a 40-year-old woman. We discuss the diagnostic considerations for poorly differentiated carcinomas of the salivary glands and advocate the inclusion of NUT immunohistochemistry in this setting. Not only does the NC diagnosis...

  20. SUBLINGUAL BUPRENORPHINE VS MIDAZOLAM FOR PREMEDICATION IN CHILDREN

    Directory of Open Access Journals (Sweden)

    V.A HASANI

    2000-03-01

    Full Text Available Background. Preanesthetic medication may reduce the risks of adverse psychological and physiological sequel of induction in children. Administration of premedication by sublingual route may provide the best compromise because of relatively rapid absorption without causing pain. In this study sedative and anxitolytic effects of sublingual midazolam and buprenorphine in children were compared. Methods. In a randomized, controlled, double blind clinical trial, one hundred and fifty children aged between 4 to 10 years in first or second class of ASA scheduled for adenotonsillectomy were divided in three equal groups. These groups recieved sublingual bupronorphine 3 µg/kg, midazolam 0.2 mg/kg and no premedication respectively. Cardiorespiratory variables were recorded from the time of premedication to awakening from anesthesia. Anxiety and sedation scores and patients acceptance of mask at induction were recorded using four point rating scales. Time of spontaneous eye opening and postoperative emesis occurrence were also recorded. Findings. Children recieving sublingual midazolam or buprenorphine had similar sedation, anxiety and mask acceptance scores, but different from no premedication group (P < 0.0001. None of the children experienced respiratory depression or oxygen desaturation after drug administration and during postoperative period. Time of spontaneous eye opening was longer in the midazolam group (P < 0.0001.Emetic episodes were similar in all groups. Conclusion. Midazolam is extensively studied and demonstrated that the drug is highly effective in alleviating anxiety and increasing cooperation. We concluded that sublingual buprenorphine is as effective as sublingual midazolam in providing sedation and anxitolysis for pediatric premedication.

  1. Sublingual ketorolac and sublingual piroxicam are equally effective for postoperative pain, trismus, and swelling management in lower third molar removal.

    Science.gov (United States)

    Trindade, Paulo A K; Giglio, Fernando P M; Colombini-Ishikiriama, Bella L; Calvo, Adriana M; Modena, Karin Cristina S; Ribeiro, Debora A; Dionísio, Thiago J; Brozoski, Daniel T; Lauris, José Roberto P; Faria, Flávio Augusto C; Santos, Carlos F

    2012-07-01

    Lower third molar removal provides a clinical model for studying analgesic drugs. The present study's aim was to compare the clinical efficacy of sublingual ketorolac and sublingual piroxicam in managing pain, trismus and swelling after lower third molar extraction in adult volunteers. In this double-blinded, randomized, crossover investigation, 47 volunteers received for 4 days ketorolac sublingually (10 mg 4 times daily) and piroxicam sublingually (20 mg once daily) during 2 separate appointments after lower third molar extraction of symmetrically positioned lower third molars. A surgeon evaluated objective parameters (surgery duration, mouth opening, rescue analgesic medication, and facial swelling) and volunteers documented subjective parameters (postoperative pain and global evaluation), comparing postoperative results for a total of 7 days after surgery. The means of the objective and subjective parameters were compared for statistical significance (P .05). Additionally, values for mouth openings measured just before surgery and immediately after suture removal 7 days later were similar among volunteers (P > .05), and the type of nonsteroidal antiinflammatory drug (NSAID) used in this study showed no significant differences between swellings on the second or seventh days after surgery (P > .05). Pain, trismus, and swelling after lower third molar extraction, independent of surgical difficulty, were successfully controlled by sublingual ketorolac (10 mg 4 times daily) or sublingual piroxicam (20 mg once daily), and no significant differences were observed between the NSAIDs evaluated. Copyright © 2012 Elsevier Inc. All rights reserved.

  2. 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...

  3. Size separation of analytes using monomeric surfactants

    Science.gov (United States)

    Yeung, Edward S.; Wei, Wei

    2005-04-12

    A sieving medium for use in the separation of analytes in a sample containing at least one such analyte comprises a monomeric non-ionic surfactant of the of the general formula, B-A, wherein A is a hydrophilic moiety and B is a hydrophobic moiety, present in a solvent at a concentration forming a self-assembled micelle configuration under selected conditions and having an aggregation number providing an equivalent weight capable of effecting the size separation of the sample solution so as to resolve a target analyte(s) in a solution containing the same, the size separation taking place in a chromatography or electrophoresis separation system.

  4. Sublingual Immunotherapy in Children: An Updated Review

    Directory of Open Access Journals (Sweden)

    Chang-Hung Kuo

    2009-04-01

    Full Text Available Although pharmacological therapy and allergen avoidance are effective means of managing allergic disease, allergen-specific immunotherapy is able to treat not only the symptoms, but also the underlying causes of the disease. Sublingual immuno-therapy (SLIT has been shown to be effective in patients with allergic diseases. It has demonstrated long-term clinical benefits and shown the potential to modify the course of allergic disease in children with rhinitis, conjunctivitis, and asthma. The precise mechanisms of SLIT remain unclear, but antigen-presenting cells in the oral mucosa may induce regulatory T-cells that suppress the allergic immune response by increasing production of interleukin-10. SLIT has also been shown to increase allergen-specific IgG antibodies that antagonize and block the allergic response. SLIT was well tolerated in all reported, double-blinded, placebo-controlled, randomized trials. SLIT is an ideal means of treating the pediatric population because of its excellent safety and good compliance. However, the optimal dose and duration of SLIT require further investigation.

  5. Early events in the fibrillation of monomeric insulin.

    OpenAIRE

    Ahmad, Atta; Uversky, Vladimir N.; Hong, Dongpyo; Fink, Anthony L.

    2005-01-01

    Insulin has a largely alpha-helical structure and exists as amixture of hexameric, dimeric, and monomeric states in solution, depending on the conditions: the protein is monomeric in 20% acetic acid. Insulin forms amyloid-like fibrils under a variety of conditions, especially at low pH. In this study we investigated the fibrillation of monomeric human insulin by monitoring changes in CD, attenuated total reflectance-Fourier transform infrared spectroscopy, 8-anilinonaphthalenesulfonic acid fl...

  6. Sublingual Microcirculation is Impaired in Post-cardiac Arrest Patients

    DEFF Research Database (Denmark)

    G. Omar, Yasser; Massey, Michael; Wiuff Andersen, Lars

    2013-01-01

    the microcirculation flow index (MFI) at 6 and 24h in the cardiac arrest patients, and within 6h of emergency department admission in the sepsis and control patients. RESULTS: We evaluated 30 post-cardiac arrest patients, 16 severe sepsis/septic shock patients, and 9 healthy control patients. Sublingual...... markers in the post-cardiac arrest state. METHODS: We prospectively evaluated the sublingual microcirculation in post-cardiac arrest patients, severe sepsis/septic shock patients, and healthy control patients using Sidestream Darkfield microscopy. Microcirculatory flow was assessed using...

  7. 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.

  8. Sublingual lorazepam in the treatment of familial paroxysmal nonkinesigenic dyskinesia.

    Science.gov (United States)

    Dooley, Joseph M; Brna, Paula M

    2004-05-01

    Familial paroxysmal nonkinesigenic dyskinesia (Mount and Reback syndrome) is characterized by episodes of dystonia and chorea, which are precipitated by fatigue, emotional stress, alcohol, or foods. We report two children from a large kindred with this condition who responded to sublingual lorazepam.

  9. Abnormal blood flow in the sublingual microcirculation at high altitude

    NARCIS (Netherlands)

    Martin, Daniel S.; Ince, Can; Goedhart, Peter; Levett, Denny Z. H.; Grocott, Mike P. W.

    2009-01-01

    We report the first direct observations of deranged microcirculatory blood flow at high altitude, using sidestream dark-field imaging. Images of the sublingual microcirculation were obtained from a group of 12 volunteers during a climbing expedition to Cho Oyu (8,201 m) in the Himalayas.

  10. CONGENITAL SUBLINGUAL DERMOID CYST IN A NEONATE: A ...

    African Journals Online (AJOL)

    there is no embryologic link between the two lesions. The differential diagnosis of dermoid cysts of floor of mouth include ranula, thyroglossal duct cyst, cystic hygroma, sialolithiasis or infection of the sublingual and submandibular glands, acute infection or cellulitis of the floor of mouth, benign. Tumours (eg. lipoma, fibroma, ...

  11. 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.

  12. 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.

  13. Effects of Sublingual Captopril in Immediate Treatment of Hypertensive Crisis

    Directory of Open Access Journals (Sweden)

    H. Kazerani

    2007-04-01

    Full Text Available Introduction & Objective: Sublingual captopril was shown to be a safe and effective drug to control hypertensive urgencies. However the exact time and efficacy of lowering blood pressure (BP is a matter of interest and importance. In this study we evaluated the time and efficacy of 25 mg sublingual captopril in lowering blood pressure. Materials & Methods: In a randomized clinical trial 101 patients (34 men, 67 women with blood pressure of 180/110 mmHg (or more who had no finding of major organ damage (heart – brain -eyes –renal were studied by prescription of 25 mg sublingual captopril. Then systolic and diastolic blood pressure was measured at 5, 10, 15, 20, 25, 30, 40, 50, 60, 75, 90, 105, 120 minutes following drug administration. Data analysis was performed using paired t-test and SPSS software. Results: The results showed that almost all the patients had some decrease in BP. After 120 minutes blood pressure dropped about 5% in 30%, and 5-30% in 70% of patients, compared to first measured BP. Maximal effect was observed in 25-30 minutes after drug administration: after 30 minutes systolic pressure dropped in 68.4% and diastolic pressure in 65.3% of patients about 5-25%. 47 patients had low response to therapy after 60 minutes, so they received another 25 mg captopril sublingual, which BP dropped in 45% of them. 19 patients were prescribed IV furosemide after 120 minutes. This group had resistant HTN and 25 cases of them were treated with ACEI previously. BP decreased gradually and not more than 30% of first BP. None of the patients encountered side effects. Conclusion: Sublingual captopril is a good, safe, effective, available and cost effective drug, with very low side effects in treating patients with hypertensive crisis. It is recommended to use this drug instead of Nifedipine in all hypertensive patients.

  14. Ação do mononitrato-5 de isossorbida sublingual durante cinecoronariografia. Comparação com o uso de nitroglicerina sublingual Sublingual isosorbide-5 mononitrate during coronary arteriography. Comparison with sublingual nitroglycerin

    Directory of Open Access Journals (Sweden)

    Anellys E. L. C. Moreira

    1997-10-01

    Full Text Available OBJETIVO: Avaliar o efeito sublingual do mononitrato-5 de isossorbida (MN5IS e nitroglicerina (NTG sobre o diâmetro luminal de artérias coronárias epicárdicas, pressão arterial média e efeitos colaterais. MÉTODOS: Cinqüenta pacientes foram submetidos a cateterismo cardíaco e cinecoronariografia, na condição inicial e 5min após administração sublingual de MN5IS grupo A (GA ou NTG grupo B (GB. RESULTADOS: O diâmetro coronário de referência aumentou em ambos os grupos, sem significância estatística entre os mesmos. Nos GA e GB foram demonstrados uma diminuição (1,66mmHg e um aumento (0,79mmHg na pressão arterial média, respectivamente (p=0,123. Não foram observados efeitos colaterais com o uso destas drogas. CONCLUSÃO: MN5IS sublingual é uma alternativa à administração de NTG durante cinecoronariografia e representa uma alternativa terapêutica para o tratamento de doença cardíaca isquêmica.PURPOSE: To evaluate the effect of sublingual isosorbide-5 mononitrate (ISMN and nitroglycerin (NTG on luminal diameter of epicardial coronary arteries, mean arterial pressure and deleterious effects. METHODS: Fifty patients were submitted to cardiac catheterization and coronary arteriography, at baseline, and 5min after sublingual administration of ISMN, group A (GA or NTG, group B (GB. RESULTS: Reference vessel diameter increased in both groups, without statistical significance. In GA and GB, a decrease (1.66mmHg and an increase (0.79mmHg in mean arterial pressure, respectively, were demonstrated (p=0.123. There were no deleterious effects with the use of these drugs. CONCLUSION: Sublingual ISMN is an alternative to administration of NTG during coronary arteriography, and represents a therapeutic alternative to ischemic heart disease treatment.

  15. Comparison of sublingual and vaginal misoprostol for second-trimester pregnancy terminations.

    Directory of Open Access Journals (Sweden)

    Forozan Milani

    2014-03-01

    Full Text Available Comparing sublingual and vaginal misoprostol in second trimester pregnancy termination.In this study 268 women at 12-24 weeks of gestation candidate for pregnancy termination were enrolled. Women were randomly divided in two groups. The first group received 400 µg sublingual misoprostol and vaginal placebo and the second group received 400 µg vaginal misoprostol and sublingual placebo every 4 hours for a maximum of five doses. The course of misoprostol was repeated if the women did not abort within 24 hours.The median induction-to-abortion interval was shorter in sublingual group (12/72 hours in sublingual and 14/67 hours in vaginal. There was no significant difference in the success rate at 24 and 48 hours and in side effects. The preference for the sublingual route of administration was higher.Both vaginal and sublingual misoprostol are effective for medical abortion in second trimester termination. But it appears from shorter induction interval in sublingual and higher acceptability that sublingual route is a better choice.

  16. The Oligomeric Nature of Triosephosphate Isomerase. Studies of Monomerization

    Science.gov (United States)

    Zárate-Pérez, Francisco; Vázquez-Contreras, Edgar

    2008-02-01

    In this work, we report the implications of the monomerization of triosephosphate isomerase (TIM) from T. cruzi (TcTIM). A monomeric mutant (monoTcTIM) of this species was constructed by genetic engineering, shortening the main loop of interdigitation, which is fundamental for its dimerization. The properties of monoTcTIM were compared with those of the other TIM monomeric versions: genetically engineered mutants, or equilibrium intermediates obtained by chemical denaturation. The stability for almost all the monomeric variants so far reported appears in the same range, and also presents similar structural characteristics. Regarding the catalytic activity of monomeric mutants, when it is present is in several orders of magnitude lower than those observed in their respective wild-type enzyme. The change in the hydrophobic surface of TcTIM after and before monomerization was also studied and corresponds to an extensive area of the interface region, which becomes exposed when monomers are dissociated. This fact could be related with conformational changes in the local environment of the catalytic amino acids responsible for the isomerization of the substrate and consequently the inactivation of its catalytic properties. Comparison of the structural, folding and unfolding properties, as well as stability studies could give answers on why this enzyme is an obligate oligomer.

  17. Gum pigmentation: an unusual adverse effect of sublingual immunotherapy.

    Science.gov (United States)

    Goh, Anne; Chiang, Wen Chin; Kang, Liew Woei; Rao, Rajeshwar; Lim, Hwee Hoon; Chng, Chai Kiat

    2014-07-01

    Sublingual immunotherapy has gained acceptance amongst the paediatric community as it is very well tolerated and is safe. The adverse effects of this therapy is minimal consisting mainly of local side effects within the oral cavity such as itching of the mouth, swelling of the lips and less frequently abdominal pain, wheezing and urticaria has been described. This report is to highlight another local side effect of sublingual immunotherapy which has been observed in 3 of our patients. This is pigmentation of the gums which can occur anytime during the course of the immunotherapy. It resolves on stopping the immunotherapy and is likely due to a local inflammatory process occurring in the gums of these children. There is no associated pain or itching with the pigmentation. It can persist as long as the child is on the immunotherapy.

  18. Therapeutic Effects and Biomarkers in Sublingual Immunotherapy: A Review

    Directory of Open Access Journals (Sweden)

    Takashi Fujimura

    2012-01-01

    Full Text Available Immunotherapy is considered to be the only curative treatment for allergic diseases such as pollinosis, perennial rhinitis, asthma, and food allergy. The sublingual route is widely applied for immunotherapy for allergy, instead of the conventional administration by subcutaneous route. A recent meta-analysis of sublingual immunotherapy (SLIT has shown that this approach is safe, has positive clinical effects, and provides prolonged therapeutic effects after discontinuation of treatment. However, the mechanism of SLIT and associated biomarkers are not fully understood. Biomarkers that change after or during SLIT have been reported and may be useful for response monitoring or as prognostic indicators for SLIT. In this review, we focus on the safety, therapeutic effects, including prolonged effects after treatment, and new methods of SLIT. We also discuss response monitoring and prognostic biomarkers for SLIT. Finally, we discuss immunological mechanisms of SLIT with a focus on oral dendritic cells and facilitated antigen presentation.

  19. Sublingual immunotherapy for pediatric allergic rhinitis: The clinical evidence

    OpenAIRE

    Poddighe, Dimitri; Licari, Amelia; Caimmi, Silvia; Marseglia, Gian Luigi

    2016-01-01

    Allergic rhinitis is estimated to affect 10%-20% of pediatric population and it is caused by the IgE-sensitization to environmental allergens, most importantly grass pollens and house dust mites. Allergic rhinitis can influence patient’s daily activity severely and may precede the development of asthma, especially if it is not diagnosed and treated correctly. In addition to subcutaneous immunotherapy, sublingual immunotherapy (SLIT) represents the only treatment being potentially able to cure...

  20. 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.

  1. 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

  2. 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....

  3. 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...... is considered to have a better safety profile than subcutaneous immunotherapy, SLIT can still cause adverse events requiring clinical supervision for the first administration. Optimization of SLIT, by reducing the administration dose and treatment duration, would improve safety profile. For this purpose...

  4. Synthesis of monomeric and polymeric alkali and alkaline earth ...

    Indian Academy of Sciences (India)

    5, September 2014, pp. 1463–1475. c Indian Academy of Sciences. Synthesis of monomeric and polymeric alkali and alkaline earth metal complexes using a phosphinoselenoic amide ligand in metal coordination sphere. JAYEETA BHATTACHARJEE, RAVI K KOTTALANKA, HARINATH ADIMULAM and TARUN K PANDA.

  5. Homotropic cooperativity of monomeric cytochrome P450 3A4

    Energy Technology Data Exchange (ETDEWEB)

    Baas, Bradley J.; Denisov, Ilia G.; Sligar, Stephen G. (UIUC)

    2010-11-16

    Mechanistic studies of mammalian cytochrome P450s are often obscured by the phase heterogeneity of solubilized preparations of membrane enzymes. The various protein-protein aggregation states of microsomes, detergent solubilized cytochrome or a family of aqueous multimeric complexes can effect measured substrate binding events as well as subsequent steps in the reaction cycle. In addition, these P450 monooxygenases are normally found in a membrane environment and the bilayer composition and dynamics can also effect these catalytic steps. Here, we describe the structural and functional characterization of a homogeneous monomeric population of cytochrome P450 3A4 (CYP 3A4) in a soluble nanoscale membrane bilayer, or Nanodisc [Nano Lett. 2 (2002) 853]. Cytochrome P450 3A4:Nanodisc assemblies were formed and purified to yield a 1:1 ratio of CYP 3A4 to Nanodisc. Solution small angle X-ray scattering was used to structurally characterize this monomeric CYP 3A4 in the membrane bilayer. The purified CYP 3A4:Nanodiscs showed a heretofore undescribed high level of homotropic cooperativity in the binding of testosterone. Soluble CYP 3A4:Nanodisc retains its known function and shows prototypic hydroxylation of testosterone when driven by hydrogen peroxide. This represents the first functional characterization of a true monomeric preparation of cytochrome P450 monooxygenase in a phospholipid bilayer and elucidates new properties of the monomeric form.

  6. Sublingual vein parameters, AFP, AFP-L3, and GP73 in patients with hepatocellular carcinoma.

    Science.gov (United States)

    Zhao, J; Guo, L-Y; Yang, J-M; Jia, J-W

    2015-06-26

    This study evaluated the diagnostic value of alpha-fetoprotein (AFP), AFP heterogeneity 3 (AFP-L3), Golgi protein 73 (GP73), and sublingual vein parameters in hepatocellular carcinoma (HCC). Levels of serum AFP, AFP-L3, GP73, and sublingual vein scores were measured in 34 patients with chronic hepatitis, 65 patients with post-hepatitis B cirrhosis, 71 patients with HCC, and 6 healthy controls. Logistic regression analysis was used to explore potential correlations. Sublingual vein grades in patients with HCC were higher than those in the other three groups; sublingual vein scores were also different between groups; combined diagnosis using AFP, GP73, and sublingual vein grade was superior to the individual parameters alone or when only two were used in different combinations. Thus, sublingual vein grade can be considered as an independent risk factor for diagnosis of HCC. Furthermore, combined detection with AFP, GP73, and sublingual vein grade is simple, inexpensive, and effective. It may therefore be suitable for screening high-risk populations for early diagnosis of HCC.

  7. Development of a sublingual allergy vaccine for grass pollinosis

    Directory of Open Access Journals (Sweden)

    Franco Frati

    2010-06-01

    Full Text Available Franco Frati1,2, Silvia Scurati1, Paola Puccinelli1, Marie David3, Cecile Hilaire4, Maurizio Capecce4, Francesco Marcucci2, Cristoforo Incorvaia51Medical and Scientific Department, Stallergenes, Milan, Italy; 2University Department of Medical and Surgical Specialties and Public Health, Perugia, Italy; 3Laboratoire Stallergenes, Antony, France; 4Marketing Department, Stallergenes, Milan, Italy; 5Allergy/Pulmonary Rehabilitation Unit, ICP Hospital, Milan, ItalyAbstract: Grass pollen is a very common cause of allergic rhinitis and asthma. The only treatment targeting the underlying causes of allergy is immunotherapy (IT. Sublingual immunotherapy (SLIT has been introduced to solve the problem of systemic reactions to subcutaneous IT (SCIT. This article evaluates the characteristics of the allergen extract, Staloral, in terms of practical administration, effectiveness, safety, and mechanism of action. Efficacy data were obtained from double-blind, placebo-controlled studies using Staloral in patients sensitized to grass pollen, while practical administration, cost-effectiveness, and mechanism of action data were provided by well designed studies. The efficacy and safety of Staloral, as demonstrated by review of published studies which used doses up to 1125 times those administered with SCIT, shows that this allergen extract has optimal characteristics for treating patients with seasonal allergies due to grass pollens. The main mechanism of action is the interaction between dendritic cells of the oral mucosa and the subsequent tolerance induced in T-cells.Keywords: allergen extracts, high-dose, efficacy, safety, sublingual immunotherapy

  8. Concurrent Spontaneous Sublingual and Intramural Small Bowel Hematoma due to Warfarin Use

    Directory of Open Access Journals (Sweden)

    Gül Pamukçu Günaydın

    2015-01-01

    Full Text Available Introduction. We present a case of concurrent spontaneous sublingual and intramural small bowel hematoma due to warfarin anticoagulation. Case. A 71-year-old man presented to the emergency department complaining of a swollen, painful tongue. He was on warfarin therapy. Physical examination revealed sublingual hematoma. His international normalized ratio was 11.9. The computed tomography scan of the neck demonstrated sublingual hematoma. He was admitted to emergency department observation unit, monitored closely; anticoagulation was reversed with fresh frozen plasma and vitamin K. 26 hours after his arrival to the emergency department, his abdominal pain and melena started. His abdomen tomography demonstrated intestinal submucosal hemorrhage in the ileum. He was admitted to surgical floor, monitored closely, and discharged on day 4. Conclusion. Since the patient did not have airway compromise holding anticoagulant, reversing anticoagulation, close monitoring and observation were enough for management of both sublingual and spontaneous intramural small bowel hematoma.

  9. Parotid and submandibular/sublingual salivary flow during high dose radiotherapy

    NARCIS (Netherlands)

    Burlage, FR; Coppes, RP; Meertens, H; Stokman, MA; Vissink, A

    2001-01-01

    It was studied whether differences in acute radiosensitivity exist between parotid and submandibular/sublingual glands. The results revealed that salivary flow rates decreased dramatically during the first 2 weeks of radiotherapy. Neither recovery nor significant differences were observed between

  10. 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.

  11. 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

  12. Efficacy and safety of sublingual immunotherapy with grass allergen tablets for seasonal allergic rhinoconjunctivitis

    NARCIS (Netherlands)

    Dahl, Ronald; Kapp, Alexander; Colombo, Giselda; deMonchy, Jan G. R.; Rak, Sabina; Emminger, Waltraud; Rivas, Montserrat Fernandez; Ribel, Mette; Durham, Stephen R.

    Background: Allergen immunotherapy (desensitization) by injection is effective for seasonal allergic rhinitis and has been shown to induce long-term disease remission. The sublingual route also has potential, although definitive evidence from large randomized controlled trials has been lacking.

  13. effect of pre-operative sub-lingual misoprostol versus intravenous ...

    African Journals Online (AJOL)

    2012-09-09

    Sep 9, 2012 ... EFFECT OF PRE-OPERATIVE SUB-LINGUAL MISOPROSTOL VERSUS INTRAVENOUS OXYTOCIN ON CAESAREAN. OPERATION BLOOD LOSS ... infusion of oxytocin in reducing blood loss at Caesarean section operation. However, occurrence of ..... WHO Reproductive Health Library; Geneva: World.

  14. Safety and tolerability of grass pollen tablets in sublingual immunotherapy--a phase-1 study

    DEFF Research Database (Denmark)

    Larsen, T H; Poulsen, Lars K.; Melac, M

    2006-01-01

    A single-centre, randomized, double-blind, placebo-controlled study. Aims: To compare the safety and tolerability of four different sublingual immunotherapy (SLIT) regimes in grass pollen allergic rhinitis....

  15. Pharmaceutical and pharmacokinetic characterization of a novel sublingual buprenorphine/naloxone tablet formulation in healthy volunteers

    OpenAIRE

    Fischer, Andreas; J?nsson, Martin; Hjelmstr?m, Peter

    2013-01-01

    Abstract Context Bitter taste, as well as dissolve time, presents a significant challenge for the acceptability of formulations for oral transmucosal drug delivery. Objective To characterize a novel sublingual tablet formulation of buprenorphine/naloxone with regards to pharmacokinetics, dissolve time and formulation acceptability. Methods Dry mixing techniques were employed to produce a small and fast dissolving buprenorphine/naloxone sublingual tablet formulation, OX219 (Zubsolv?), using su...

  16. COMPARISON OF SUBLINGUAL THERAPEUTIC VACCINE WITH ANTIBIOTICS FOR THE PROPHYLAXIS OF RECURRENT URINARY TRACT INFECTIONS

    OpenAIRE

    María Fernanda Lorenzo-Gómez; María Fernanda Lorenzo-Gómez; María Fernanda Lorenzo-Gómez; Bárbara ePadilla-Fernández; María Begoña García-Cenador; Álvaro Julio Virseda Rodríguez; Álvaro Julio Virseda Rodríguez; Isidoro eMartín-García; Alfonso eSánchez-Escudero; Manuel José Vicente-Arroyo; José Antonio Mirón-Canelo

    2015-01-01

    Objective: To evaluate the clinical impact of the prophylactic treatment with sublingual immunostimulation in the prevention of recurrent urinary tract infections (rUTIs) compared with the use of antibiotics.Material and Methods: Retrospective cohort study evaluating the clinical records of 669 women with rUTIs; 339 had a 6-month prophylaxis with antibiotics and 360 had a 3-month prophylaxis with a sublingual bacterial preparation (MV 140-Uromune®). The time after the prophylaxis-period until...

  17. Comparison of sublingual therapeutic vaccine with antibiotics for the prophylaxis of recurrent urinary tract infections

    OpenAIRE

    Lorenzo-G?mez, Mar?a F.; Padilla-Fern?ndez, B?rbara; Garc?a-Cenador, Mar?a B.; Virseda-Rodr?guez, ?lvaro J.; Mart?n-Garc?a, Isidoro; S?nchez-Escudero, Alfonso; Vicente-Arroyo, Manuel J.; Mir?n-Canelo, Jos? A.

    2015-01-01

    Objective: To compare the clinical impact of a prophylactic treatment with sublingual immunostimulation in the prevention of recurrent urinary tract infections (rUTIs) with the use of antibiotics. Material and Methods: Retrospective cohort study evaluating the medical records of 669 women with rUTIs; 339 had a 6-month prophylaxis with antibiotics and 360 a 3-month prophylaxis with a sublingual bacterial preparation (MV 140-Uromune®). The time frame after the prophylaxis-period until the ap...

  18. Electrical and optical properties of monomeric and polymerized fullerenes. Review

    CERN Document Server

    Makarova, T L

    2001-01-01

    Paper presents the survey of properties of monomeric and polymerized fullerenes as materials with semiconducting zone structures. Electronic structure of fullerenes is studied in detail. One analyzes the absorption spectra of fullerenes. Paper contains data on the transport parameters of fullerenes and discusses, as well, models of conductivity in these materials. Peculiar attention is given to the processes occurring in fullerenes under polymerization through photoexcitation, charge transfer and pressure

  19. Sublingual immunotherapy for pediatric allergic rhinitis: The clinical evidence.

    Science.gov (United States)

    Poddighe, Dimitri; Licari, Amelia; Caimmi, Silvia; Marseglia, Gian Luigi

    2016-02-08

    Allergic rhinitis is estimated to affect 10%-20% of pediatric population and it is caused by the IgE-sensitization to environmental allergens, most importantly grass pollens and house dust mites. Allergic rhinitis can influence patient's daily activity severely and may precede the development of asthma, especially if it is not diagnosed and treated correctly. In addition to subcutaneous immunotherapy, sublingual immunotherapy (SLIT) represents the only treatment being potentially able to cure allergic respiratory diseases, by modulating the immune system activity. This review clearly summarizes and analyzes the available randomized, double-blinded, placebo-controlled trials, which aimed at evaluating the effectiveness and the safety of grass pollen and house dust mite SLIT for the specific treatment of pediatric allergic rhinitis. Our analysis demonstrates the good evidence supporting the efficacy of SLIT for allergic rhinitis to grass pollens in children, whereas trials regarding pediatric allergic rhinitis to house dust mites present lower quality, although several studies supported its usefulness.

  20. Subcutaneous and Sublingual Immunotherapy in Allergic Asthma in Children

    Directory of Open Access Journals (Sweden)

    Sophia Tsabouri

    2017-04-01

    Full Text Available This review presents up-to-date understanding of immunotherapy in the treatment of children with allergic asthma. The principal types of allergen immunotherapy (AIT are subcutaneous immunotherapy (SCIT and sublingual immunotherapy (SLIT. Both of them are indicated for patients with allergic rhinitis and/or asthma, who have evidence of clinically relevant allergen-specific IgE, and significant symptoms despite reasonable avoidance measures and/or maximal medical therapy. Studies have shown a significant decrease in asthma symptom scores and in the use of rescue medication, and a preventive effect on asthma onset. Although the safety profile of SLIT appears to be better than SCIT, the results of some studies and meta-analyses suggest that the efficacy of SCIT is better and that SCIT has an earlier onset than SLIT in children with allergic asthma. Severe, not controlled asthma, and medical error were the most frequent causes of SCIT-induced adverse events.

  1. Serum IL-9 levels and sublingual immunotherapy: preliminary report.

    Science.gov (United States)

    Ciprandi, G; De Amici, M; Marseglia, G L

    2011-01-01

    Th9 is a new T cell subset characterized by IL-9 production. It has been reported that serum IL-9 levels are related with symptom severity in patients with allergic rhinitis (AR). This study is aimed at investigating whether serum IL-9 may be modulated by sublingual immunotherapy (SLIT) in patients with persistent AR due to Parietaria allergy. Twenty-one AR patients (9 males, median age 41 years) successfully treated with SLIT and 52 AR patients (25 males, median age 34 years) treated only with drugs were evaluated during the pollen season. Serum IL-9 was dosed in all patients. SLIT-treated patients showed significantly lower serum IL-9 levels than untreated AR patients (p <0.0001). In conclusion, this preliminary study shows that a single pre-seasonal SLIT course might modulate serum IL-9.

  2. 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.

  3. Treating allergic rhinitis by sublingual immunotherapy: a review

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    Cristoforo Incorvaia

    2012-06-01

    Full Text Available OBJECTIVE: Allergic rhinitis (AR is a disease with high and increasing prevalence. The management of AR includes allergen avoidance, anti-allergic drugs, and allergen specific immunotherapy (AIT, but only the latter works on the causes of allergy and, due to its mechanisms of action, modifies the natural history of the disease. Sublingual immunotherapy (SLIT was proposed in the 1990s as an option to traditional, subcutaneous immunotherapy. MATERIAL AND METHODS: We reviewed all the available controlled trials on the efficacy and safety of SLIT. RESULTS AND CONCLUSION: Thus far, more than 60 trials, globally evaluated in 6 meta-analyses, showed that SLIT is an effective and safe treatment for AR. However, it must be noted that to expect clinical efficacy in the current practice SLIT has to be performed following the indications from controlled trials, that is, sufficiently high doses to be regularly administered for at least 3 consecutive years.

  4. 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.

  5. Early events in the fibrillation of monomeric insulin.

    Science.gov (United States)

    Ahmad, Atta; Uversky, Vladimir N; Hong, Dongpyo; Fink, Anthony L

    2005-12-30

    Insulin has a largely alpha-helical structure and exists as a mixture of hexameric, dimeric, and monomeric states in solution, depending on the conditions: the protein is monomeric in 20% acetic acid. Insulin forms amyloid-like fibrils under a variety of conditions, especially at low pH. In this study we investigated the fibrillation of monomeric human insulin by monitoring changes in CD, attenuated total reflectance-Fourier transform infrared spectroscopy, 8-anilinonaphthalenesulfonic acid fluorescence, thioflavin T fluorescence, dynamic light scattering, and H/D exchange during the initial stages of the fibrillation process to provide insight into early events involving the monomer. The results demonstrate the existence of structural changes occurring before the onset of fibril formation, which are detectable by multiple probes. The data indicate at least two major populations of oligomeric intermediates between the native monomer and fibrils. Both have significantly non-native conformations, and indicate that fibrillation occurs from a beta-rich structure significantly distinct from the native fold.

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

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    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.

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

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    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.

  8. 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.

  9. Kinetics of synthesis of monomeric betaines in aqueous solutions

    Science.gov (United States)

    Kazantsev, O. A.; Baruta, D. S.; Kamorin, D. M.; Shirshin, K. V.; Shirshin, K. K.; Kolosov, E. S.

    2016-05-01

    In the nucleophilic addition of N-(3-dimethylaminopropyl)methacrylamide to acrylic acid (1 : 1) in aqueous solutions, forming monomeric β-propiobetaine, the dependence of the initial rate on the starting reagent concentration was found to have a pronounced maximum (whose position does not depend on the temperature at 30-70°C). In the case of the addition of N, N-dimethylaminoethyl methacrylate, the dependence was exponential. The dependences of equilibrium conversions on the starting reagent concentrations were of the same type and had a maximum for both systems. The detected concentration effects are related to the peculiarities of the pre-reaction association of the reagents.

  10. 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.

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

    Science.gov (United States)

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

    2015-12-01

    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 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. • Sublingual nitroglycerin administration results in significant coronary artery dilatation. • Nitroglycerin increases the number of evaluable coronary branches. • Image quality is improved the most in smaller coronary branches. • Nitroglycerin increases the diagnostic accuracy of coronary CT angiography. • Most side effects are mild and do not require medical intervention.

  12. Sublingual desmopressin is efficient and safe in the therapy of lithiasic renal colic.

    Science.gov (United States)

    Pricop, Catalin; Branisteanu, Dumitru D; Orsolya, Martha; Puia, Dragos; Matei, Anca; Checherita, Ionel Alexandru

    2016-02-01

    To evaluate the effects of newer sublingual desmopressin administration in lithiasic renal colic, alone or combined with a nonsteroidal anti-inflammatory drug (NSAID). Prospective single-blind study including an initial number of 249 patients with lithiasic renal colic was randomized as follows: group NSAID (71 patients) received ketorolac tromethamine (ketorolac) 30 mg im and sublingual placebo (vitamin C), groups D1 and D2 (57 and 62 patients) received sublingual desmopressin (Minirin Melt), 60 and 120 μg, respectively, whereas group C (59 patients) received a combination of 30 mg im ketorolac and 60 μg sublingual desmopressin. Pain intensity was assessed using the visual analogue scale before and thirty minutes after drug administration. Patients experiencing pain aggravation were rescued and excluded from the study. Dropout incidence was higher in the NSAID group than in the groups treated with desmopressin in monotherapy or combined with ketorolac (p desmopressin and ketorolac. The higher dose of desmopressin and the combination therapy decreased pain intensity with 56 and 59%, respectively, significantly more than the 47% decrease obtained with ketorolac alone (p desmopressin is at least as potent as NSAID in the treatment of lithiasic renal colic. The combination of sublingual desmopressin and NSAID has additive analgesic effects.

  13. Salivary lactoferrin is transferred into the brain via the sublingual route.

    Science.gov (United States)

    Hayashi, Takashi; To, Masahiro; Saruta, Juri; Sato, Chikatoshi; Yamamoto, Yuko; Kondo, Yusuke; Shimizu, Tomoko; Kamata, Yohei; Tsukinoki, Keiichi

    2017-07-01

    Lactoferrin (LF) is produced by exocrine glands including salivary gland, and has various functions including infection defense. However, the transfer of LF from peripheral organs into the brain remains unclear. To clarify the kinetics of salivary LF (sLF), we investigated the consequences of sialoadenectomy and bovine LF (bLF) sublingual administration in rats. The salivary glands were removed from male Wistar rats, and we measured rat LF levels in the blood and brain at 1 week post-surgery. We also examined the transfer of LF into the organs of the rats after sublingual administration of bLF. Rat LF levels in the blood and brain were significantly reduced by sialoadenectomy. Sublingual bLF administration significantly increased bLF levels in the brain, which then decreased over time. These results indicate that LF is transferred from the sublingual mucosa to the brain, in which favorable effects of sLF on brain will be expected via the sublingual mucosa.

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

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    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.

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

    Science.gov (United States)

    Albertini, Aurélie A; Mérigoux, Cécile; Libersou, Sonia; Madiona, Karine; Bressanelli, Stéphane; Roche, Stéphane; Lepault, Jean; Melki, Ronald; Vachette, Patrice; Gaudin, Yves

    2012-02-01

    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.

  16. 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.

  17. 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.

  18. 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.

  19. 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.

  20. Light-induced structural changes in a monomeric bacteriophytochrome.

    Science.gov (United States)

    Takala, Heikki; Niebling, Stephan; Berntsson, Oskar; Björling, Alexander; Lehtivuori, Heli; Häkkänen, Heikki; Panman, Matthijs; Gustavsson, Emil; Hoernke, Maria; Newby, Gemma; Zontone, Federico; Wulff, Michael; Menzel, Andreas; Ihalainen, Janne A; Westenhoff, Sebastian

    2016-09-01

    Phytochromes sense red light in plants and various microorganism. Light absorption causes structural changes within the protein, which alter its biochemical activity. Bacterial phytochromes are dimeric proteins, but the functional relevance of this arrangement remains unclear. Here, we use time-resolved X-ray scattering to reveal the solution structural change of a monomeric variant of the photosensory core module of the phytochrome from Deinococcus radiodurans. The data reveal two motions, a bend and a twist of the PHY domain with respect to the chromophore-binding domains. Infrared spectroscopy shows the refolding of the PHY tongue. We conclude that a monomer of the phytochrome photosensory core is sufficient to perform the light-induced structural changes. This implies that allosteric cooperation with the other monomer is not needed for structural activation. The dimeric arrangement may instead be intrinsic to the biochemical output domains of bacterial phytochromes.

  1. mKikGR, a monomeric photoswitchable fluorescent protein.

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    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.

  2. 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.

  3. Light-induced structural changes in a monomeric bacteriophytochrome

    Directory of Open Access Journals (Sweden)

    Heikki Takala

    2016-09-01

    Full Text Available Phytochromes sense red light in plants and various microorganism. Light absorption causes structural changes within the protein, which alter its biochemical activity. Bacterial phytochromes are dimeric proteins, but the functional relevance of this arrangement remains unclear. Here, we use time-resolved X-ray scattering to reveal the solution structural change of a monomeric variant of the photosensory core module of the phytochrome from Deinococcus radiodurans. The data reveal two motions, a bend and a twist of the PHY domain with respect to the chromophore-binding domains. Infrared spectroscopy shows the refolding of the PHY tongue. We conclude that a monomer of the phytochrome photosensory core is sufficient to perform the light-induced structural changes. This implies that allosteric cooperation with the other monomer is not needed for structural activation. The dimeric arrangement may instead be intrinsic to the biochemical output domains of bacterial phytochromes.

  4. Sublingual immunotherapy in polysensitized patients: effect on quality of life.

    Science.gov (United States)

    Ciprandi, G; Cadario, G; Valle, C; Ridolo, E; Verini, M; Di Gioacchino, M; Minelli, M; Gangemi, S; Sillano, V; Colangelo, C; Pravettoni, V; Pellegrino, R; Borrelli, P; Fiorina, A; Carosso, A; Gasparini, A; Riario-Sforza, G G; Incorvaia, C; Puccinelli, P; Scurati, S; Frati, F

    2010-01-01

    Quality of life (QOL) is an important issue in allergic rhinitis and has been evaluated in a number of studies that have shown how it is impaired in untreated patients and improved by effective treatment. However, there are no data concerning QOL after sublingual immunotherapy (SLIT) in polysensitized patients. To evaluate the effect, in real-life clinical practice, of SLIT on QOL in a population of polysensitized patients with allergic rhinitis. We prospectively evaluated 167 consecutively enrolled polysensitized patients with allergic rhinitis. QOL was measured in all cases with the Rhinoconjunctivitis Quality of Life Questionnaire at baseline and after 1 year of SLIT (performed in approximately 70% of cases using single allergen extracts provided by the same manufacturer). The most frequent causes of sensitization were grass pollen, Parietaria, and house dust mites. The mean number of sensitizations per patient was 3.65. SLIT was performed with 1 extract in 123 patients (73.6%), with 2 extracts in 31 patients (18.6%), and with more than 2 extracts in 13 patients (7.8%). The mean values of all the QOL items improved significantly (P < .01 in all cases), with the following reductions noted: activities, 3.96 to 2.89; sleep, 2.07 to 1.56; general problems, 2.16 to 1.5; practical problems, 3.69 to 2.58; nasal symptoms, 3.57 to 2.50; eye symptoms, 2.92 to 1.83; and emotional aspects, 2.2 to 1.44. This study provides evidence that QOL can be improved in polysensitized patients treated with SLIT, and that the use of just 1 or 2 allergen extracts seems to be sufficient and effective in terms of improving QOL.

  5. CONFORMATIONAL FLEXIBILITY OF AQUEOUS MONOMERIC AND DIMERIC INSULIN - A MOLECULAR-DYNAMICS STUDY

    NARCIS (Netherlands)

    MARK, AE; BERENDSEN, HJC; VANGUNSTEREN, WF

    1991-01-01

    A series of molecular dynamics simulations have been used to investigate the nature of monomeric and dimeric insulin in aqueous solution. It is shown that in the absence of crystal contacts both monomeric and dimeric insulin have a high degree of intrinsic flexibility. Neither of the two monomer

  6. Evidence for the existence of trimeric and monomeric Photosystem I complexes in thylakoid membranes from cyanobacteria

    NARCIS (Netherlands)

    Kruip, Jochen; Bald, Dirk; Boekema, Egbert; Rögner, Matthias

    In cyanobacteria, solubilization of thylakoid membranes by detergents yields both monomeric and trimeric Photosystem I (PS I) complexes in variable amounts. We present evidence for the existence of both monomeric and trimeric PSI in cyanobacterial thylakoid membranes with the oligomeric state

  7. Sublingual immunotherapy not effective in house dust mite-allergic children in primary care

    NARCIS (Netherlands)

    de Bot, Cindy M. A.; Moed, Heleen; Berger, Marjolein Y.; Roder, Esther; Hop, Wim C. J.; de Groot, Hans; de Jongste, Johan C.; van Wijk, Roy Gerth; Bindels, Patrick J. E.; van der Wouden, Johannes C.

    Background: Sublingual immunotherapy (SLIT) as a therapy for the treatment of allergic rhinitis in children might be acceptable as an alternative for subcutaneous immunotherapy. However, the efficacy of SLIT with house dust mite extract is not well established. Objective: To investigate whether SLIT

  8. Sublingual immunotherapy with grass pollen is not effective in symptomatic youngsters in primary care

    NARCIS (Netherlands)

    Roder, Esther; Berger, Marjolein Y.; Hop, Wim C. J.; Bernsen, Roos M. D.; de Groot, Hans; van Wijk, Roy Gerth

    Background: Sublingual immunotherapy (SLIT) is considered safer and more convenient than subcutaneous therapy and therefore has been proposed as especially suitable for children and in primary care. Most efficacy studies in children lack power to be conclusive, and all have been performed in

  9. 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

  10. 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

    IMPORTANCE: The house dust mite (HDM) sublingual allergen immunotherapy (SLIT) tablet is a potential novel treatment option for HDM allergy-related asthma. OBJECTIVES: To evaluate the efficacy and adverse events of the HDM SLIT tablet vs placebo for asthma exacerbations during an inhaled corticos...

  11. Neutrophils negatively regulate induction of mucosal IgA responses after sublingual immunization.

    Science.gov (United States)

    Jee, J; Bonnegarde-Bernard, A; Duverger, A; Iwakura, Y; Cormet-Boyaka, E; Martin, T L; Steiner, H E; Bachman, R C; Boyaka, P N

    2015-07-01

    Induction of mucosal immunoglobulin-A (IgA) capable of providing a first line of defense against bacterial and viral pathogens remains a major goal of needle-free vaccines given via mucosal routes. Innate immune cells are known to play a central role in induction of IgA responses by mucosal vaccines, but the relative contribution of myeloid cell subsets to these responses has not firmly been established. Using an in vivo model of sublingual vaccination with Bacillus anthracis edema toxin (EdTx) as adjuvant, we examined the role of myeloid cell subsets for mucosal secretory IgA responses. Sublingual immunization of wild-type mice resulted in a transient increase of neutrophils in sublingual tissues and cervical lymph nodes. These mice later developed Ag-specific serum IgG responses, but not serum or mucosal IgA. Interestingly, EdTx failed to increase neutrophils in sublingual tissues and cervical lymph nodes of IKKβ(ΔMye) mice, and these mice developed IgA responses. Partial depletion of neutrophils before immunization of wild-type mice allowed the development of both mucosal and serum IgA responses. Finally, co-culture of B cells with neutrophils from either wild-type or IKKβ(ΔMye) mice suppressed secretion of IgA, but not IgM or IgG. These results identify a new role for neutrophils as negative regulators of IgA responses.

  12. Pharmaceutical and pharmacokinetic characterization of a novel sublingual buprenorphine/naloxone tablet formulation in healthy volunteers.

    Science.gov (United States)

    Fischer, Andreas; Jönsson, Martin; Hjelmström, Peter

    2015-01-01

    Bitter taste, as well as dissolve time, presents a significant challenge for the acceptability of formulations for oral transmucosal drug delivery. To characterize a novel sublingual tablet formulation of buprenorphine/naloxone with regards to pharmacokinetics, dissolve time and formulation acceptability. Dry mixing techniques were employed to produce a small and fast dissolving buprenorphine/naloxone sublingual tablet formulation, OX219 (Zubsolv®), using sucralose and menthol as sweetener and flavor to mask the bitter taste of the active ingredients. Two cross-over studies were performed in healthy volunteers to evaluate pharmacokinetics, dissolve time and acceptability of OX219 5.7/1.4 mg tablets compared to the commercially available buprenorphine/naloxone formulations Suboxone® tablets and films (8/2 mg). Buprenorphine exposure was equivalent in OX219 and Suboxone tablets. Sublingual dissolve times were significantly shorter for OX219 than for Suboxone tablets and were similar to Suboxone films. The OX219 formulation received significantly higher subjective ratings for taste and overall acceptability than both Suboxone formulations. OX219 was preferred over Suboxone tablet and film formulations by 77.4% and 88.9% of subjects, respectively. A sublingual tablet formulation with an improved acceptability has been successfully developed.

  13. Comparison of Drug Acceptance and Anxiety Between Intranasal and Sublingual Midazolam Sedation.

    Science.gov (United States)

    Shanmugaavel, A Karthikeyan; Asokan, Sharath; John, J Baby; Priya, P R Geetha; Raaja, M Thirumalai

    2016-01-01

    The purpose of the study was to assess and compare the changes in anxiety level and drug acceptance after intranasal and sublingual midazolam sedation. Forty three- to seven-year-olds were randomly assigned to Group A (N equals 20; 0.2 mg/kg intranasal midazolam sedation) or Group B (N equals 20; 0.2 mg/kg sublingual midazolam sedation) sedation. The anxiety levels at various time periods were assessed from recorded videos using the Venham clinical anxiety scale by two pediatric dentists. The acceptance of the drug administration was assessed using a four-point scale. The Wilcoxon signed rank test and Mann-Whitney U test were used for statistical analysis using SPSS 17.0 software. There was a significant decrease in anxiety level from baseline to 20 minutes after drug administration in Group A (Pintranasal route of drug administration. Both intranasal and sublingual administrations of midazolam were equally effective in reducing the child's anxiety. The sublingual route of drug administration was better accepted than the intranasal route.

  14. Sublingual nitroglycerin used in routine tilt testing provokes a cardiac output-mediated vasovagal response

    NARCIS (Netherlands)

    Gisolf, J.; Westerhof, B.E.; Dijk, N. van; Wesseling, K.H.; Wieling, W.; Karemaker, J.M.

    2004-01-01

    Objectives We set out to determine the effect of sublingual nitroglycerin (NTG), as used during routine tilt testing in patients with unexplained syncope, on hemodynamic characteristics and baroreflex control of heart rate (HR) and systemic vascular resistance (SVR). Background Nitroglycerin is used

  15. 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.)

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

    Science.gov (United States)

    2013-06-06

    ... HUMAN SERVICES Food and Drug Administration Determination That SUBOXONE (Buprenorphine Hydrochloride and... (buprenorphine hydrochloride (HCl) and naloxone HCl) sublingual tablets, 2 milligrams (mg)/0.5 mg and 8 mg/2 mg... to approve abbreviated new drug applications (ANDAs) for buprenorphine HCl and naloxone HCl...

  17. Changes in sublingual microcirculatory flow index and vessel density on ascent to altitude

    NARCIS (Netherlands)

    Martin, Daniel S.; Goedhart, Peter; Vercueil, Andre; Ince, Can; Levett, Denny Z. H.; Grocott, Mike P. W.

    2010-01-01

    We hypothesized that ascent to altitude would result in reduced sublingual microcirculatory flow index (MFI) and increased vessel density. Twenty-four subjects were studied using sidestream dark-field imaging, as they ascended to 5300 m; one cohort remained at this altitude (n = 10), while another

  18. effect of pre-operative sub-lingual misoprostol versus intravenous ...

    African Journals Online (AJOL)

    2012-09-09

    Sep 9, 2012 ... infusion of oxytocin in reducing blood loss at Caesarean section operation. However, .... is the type 2 error, σ is the standard deviation, and d .... Table 3. Comparison of means of intravenous oxytocin versus sub-lingual misoprostol. Variable. Diff of mean. Std Error. Signif. 95%. CI. IV. Oxytoc. Sub-ling.

  19. Preparation and physicochemical evaluation of a new tacrolimus tablet formulation for sublingual administration

    NARCIS (Netherlands)

    Srinarong, Parinda; Pham, Bao T; Holen, Maru; van der Plas, Afke; Schellekens, Reinout C A; Hinrichs, Wouter L J; Frijlink, Henderik W

    The aim of this study was to develop a new fast-disintegrating tablet formulation containing 1mg tacrolimus for sublingual application. First, solid dispersions containing tacrolimus (2.5%, 5% and 10% w/w) incorporated in Ac-Di-Sol®and carriers (inulin 1.8kDa and 4kDa, and polyvinylpyrrolidone (PVP)

  20. Revised Dose Schema of Sublingual Buprenorphine in the Treatment of the Neonatal Opioid Abstinence Syndrome

    Science.gov (United States)

    Kraft, Walter K.; Dysart, Kevin; Greenspan, Jay S.; Gibson, Eric; Kaltenbach, Karol; Ehrlich, Michelle E.

    2010-01-01

    AIMS Over half of infants exposed to opioids in utero develop neonatal abstinence syndrome (NAS) of severity to require pharmacologic therapy. Current treatments are associated with prolonged hospitalization. We sought to optimize the dose of sublingual buprenorphine in the treatment of NAS. DESIGN Randomized, phase 1, open-label, active-control clinical trial comparing sublingual buprenorphine to oral morphine. SETTING Large, urban, tertiary care hospital. PARTICIPANTS Twenty-four term infants requiring pharmacological treatment for NAS. MEASUREMENTS Outcomes were neonatal safety, length of treatment, and length of hospitalization. FINDINGS Sublingual buprenorphine was safe and effective. Infants treated with buprenorphine had a 23-day length of treatment compared to 38 days for those treated with morphine (p=0.01), representing a 40% reduction. Length of hospital stay in the buprenorphine group was reduced 24%, from 42 to 32 days (p=0.05). CONCLUSIONS Sublingual buprenorphine was safe in NAS, with a substantial efficacy advantage over standard of care therapy with oral morphine. PMID:20925688

  1. 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

  2. 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.

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

    Directory of Open Access Journals (Sweden)

    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.

  4. Reference ranges for serum total and monomeric prolactin for the current generation Abbott Architect assay.

    Science.gov (United States)

    Whitehead, S J; Cornes, M P; Ford, C; Gama, R

    2015-01-01

    Exclusion of macroprolactinaemia, a well-recognised interference, as the cause of hyperprolactinaemia is essential to avoid potential misdiagnosis and mismanagement of patients. We have derived gender-specific serum total and post-polyethylene glycol (PEG) precipitation monomeric reference ranges for the recently re-standardised Abbott Architect prolactin assay. Prolactin was measured in serum samples obtained from males (n=49) and females (n=52) using the current Abbott Architect immunoassay pre- and post-PEG precipitation. Gender-specific reference ranges were derived for total and monomeric (post-PEG) prolactin. Routine patients' samples (n=175) with a serum total prolactin >700 mIU/L were screened for macroprolactinaemia to assess classification compared with our previous post-PEG precipitation percentage recovery-based approach. Reference ranges for serum total prolactin were 58-419 mIU/L (male) and 63-561 mIU/L (female). Male and female monomeric prolactin reference ranges were 32-309 mIU/L and 39-422 mIU/L, respectively. Mean (SD) post-PEG percentage recovery of the IS 84/500 prolactin standard was 80 (2.3)%. Of 175 patients' samples screened for macroprolactinaemia, 149 had monomeric prolactin concentrations (median monomeric prolactin=1035 mIU/L; median recovery=83%) above the gender-specific reference range. Monomeric prolactin concentrations (median monomeric prolactin=162 mIU/L; median recovery=20%) in the remaining 26 were within the reference ranges. One patient classified as macroprolactin positive and another classified as macroprolactin negative would not have been identified as such using the previous recovery-based approach. The use of post-PEG monomeric reference ranges not only identifies hyperprolactinaemia due solely to macroprolactinaemia but has the added advantage of identifying patients who have simultaneous true monomeric hyperprolactinaemia and elevated concentrations of macroprolactin. © The Author(s) 2014 Reprints and permissions

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

    Science.gov (United States)

    Lara-Gonzalez, Samuel; Estrella, Priscilla; Portillo, Carmen; Cruces, María E.; Jimenez-Sandoval, Pedro; Fattori, Juliana; Migliorini-Figueira, Ana C.; Lopez-Hidalgo, Marisol; Diaz-Quezada, Corina; Lopez-Castillo, Margarita; Trasviña-Arenas, Carlos H.; Sanchez-Sandoval, Eugenia; Gómez-Puyou, Armando; Ortega-Lopez, Jaime; Arroyo, Rossana; Benítez-Cardoza, Claudia G.; Brieba, Luis G.

    2015-01-01

    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. PMID:26618356

  6. 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.

  7. 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.

  8. 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.

  9. Adverse reactions and tolerability of high-dose sublingual allergen immunotherapy

    Directory of Open Access Journals (Sweden)

    Moral A

    2016-06-01

    Full Text Available Angel Moral,1 Victoria Moreno,2 Francisco Girón,3 David El-Qutob,4 José D Moure,5 Manuel Alcántara,6 Antonia Padial,7 Alberto G Oehling,8 Carmen Millán,9 Fernando de la Torre10 1Allergy Service, Hospital Virgen del Valle, Toledo, 2Allergy Service, Hospital Blanca Paloma, Huelva, 3Consulta Privada, Granada, 4Allergy Service, Clínica Atenea, Castellón, 5Pediatric Department, Complejo Hospitalario Universitario de Santiago, A Coruña, 6Allergy Service, Complejo Hospitalario de Jaén, Jaén, 7Allergy Service, Hospital Infanta Sofía, Madrid, 8Centro de Alergia y Asma Balear, Mallorca, 9Consulta Privada, Cádiz, 10ALK-Abelló, SA, Madrid, Spain Background: Sublingual allergen immunotherapy is an effective treatment against allergic respiratory disease. Many studies have shown the safety of this type of therapy, although the factors that might affect the tolerability of high-dose sublingual immunotherapy have not been well established. The aim of this study was to determine the factors that affect the tolerability of sublingual allergen immunotherapy.Patients and methods: A total of 183 subjects aged ≥5 years, diagnosed with allergic rhinitis with/without mild to moderate asthma due to sensitization to grass, olive pollen, or mites, were included in this open, retrospective, multicentric, noninterventional study. Sublingual immunotherapy was administered for at least 3 months.Results: The most frequent adverse reaction was oral pruritus (13.7% of the patients. Most of the reactions were local (84.7% and immediate (93.5% and occurred during the initiation phase (60.6%. All reactions were mild to moderate in severity. No serious adverse reactions were registered. When comparing factors with potential influence on the occurrence of adverse reactions, the results between the groups of subjects with and without adverse reactions showed no statistically significant differences in sex (P=0.6417, age (P=0.1801, years since the disease was first

  10. Preparative refolding of small monomeric outer membrane proteins.

    Science.gov (United States)

    Schwarzer, Tom Sebastian; Hermann, Maria; Krishnan, Swati; Simmel, Friedrich C; Castiglione, Kathrin

    2017-04-01

    The outer membrane of gram-negative bacteria constitutes an important hurdle for the transport of hydrophobic molecules into the cell. Mass flux is often facilitated by various outer membrane proteins. These proteins are of biotechnological importance because they could help to improve the performance of whole-cell biocatalysts or be incorporated into artificial cell-like systems. The characterization and understanding of their transport properties greatly benefits from the possibility to express and purify these proteins. We investigated folding parameters for the refolding of four small monomeric outer membrane proteins from Escherichia coli (OmpW) and different pseudomonads (AlkL, OprG and TodX). To this aim we screened a number of inexpensive detergents and detergent concentrations, folding additives as well as protein concentrations. Interestingly, detergents with a C12 chain were most effective in promoting the folding reaction, particularly the negatively charged N-Lauroylsarcosine for OmpW, OprG and TodX as well as the zwitterionic N,N-Dimethyl-n-dodecylamine N-oxide (LDAO) for AlkL. The addition of 1 M urea (AlkL, OmpW), 0.1 M glutamate (OprG) or 0.1 M glycine (TodX) could further improve the folding efficiency. In order to be able to reproducibly produce larger amounts of the proteins, we then established the folding in a miniaturized stirred-tank reactor system combined with a liquid handler. This approach led to a near-complete refolding of OprG (96%), a very good folding of AlkL (84%) and OmpW (71%), only TodX folding was more variable with a final folding efficiency of 52%, all obtained at a final protein concentration of 0.5 g/L. Copyright © 2017 Elsevier Inc. All rights reserved.

  11. 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

    - 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...... of easy and non-invasive quantification tools. With capillaroscopy it is possible to visualize the sublingual capillaries by sidestream dark field imaging and estimates the dimensions of the glycocalyx by measuring the perfused boundary region (PBR). We evaluated the glycocalyx thickness non-invasively...... 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...

  12. 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

  13. 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

    BACKGROUND: Allergen-specific immunotherapy is the only curative treatment for type I allergy. It can be administered subcutaneously (SCIT) or sublingually (SLIT). The clinical efficacy of these two treatment modalities appears to be similar, but potential differences in the immunological...... 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...... was observed starting 10 months after treatment was commenced. At 24 months, T cell responses showed IL-5 levels significantly below the before treatment baseline. No significant reduction of IL-5 was observed in the SLIT or untreated group. However, a significant transient increase in IL-10 production after...

  14. Rectal and sublingual administration of tacrolimus: a single-dose pharmacokinetic study in healthy volunteers

    Science.gov (United States)

    Stifft, Frank; Vanmolkot, Floris; Scheffers, Ingrid; van Bortel, Luc; Neef, Cees; Christiaans, Maarten

    2014-01-01

    Aims The immunosuppressant tacrolimus is usually administered orally. When this is not feasible, other routes of administration may be useful. Previous research suggested that tacrolimus may be applied sublingually or rectally. Pharmacokinetic data are sparse. The aim of this study was to investigate and compare the pharmacokinetics of these alternative formulations with orally administered tacrolimus. Methods Three single, fixed-dose formulations of tacrolimus were administered in a random sequence in 18 healthy subjects, using a cross-over study design. For sublingual administration, 3 mg of powder obtained from oral capsules was applied under the tongue for a period of 15 min without swallowing, with mouth rinsing afterwards. For rectal administration, a suppository containing 15 mg of the oral powder was used. Oral administration consisted of 7 mg of instant-release tacrolimus capsules (Prograf). Main pharmacokinetic outcome parameters were compared by anova. Results Sublingual administration showed no clinically significant exposure, contrary to rectal administration, where all subjects had clinically relevant exposure, with a lower relative bioavailability (78%), a lower maximal blood concentration and a later time of maximal blood concentration compared with oral administration. Conclusions Sublingual administration of a single dose of tacrolimus does not result in systemic exposure if care is taken not to swallow saliva and to rinse the oral cavity afterwards. Rectal administration of tacrolimus results in clinically relevant systemic exposure and might represent an alternative formulation in case oral administration is not feasible. When used as a topical agent, systemic side-effects should be considered. PMID:24809233

  15. Rigid swelling of sublingual caruncle area due to the salivary gland duct obstruction by a sialolith*

    Science.gov (United States)

    Bernardes Filho, Fred; Martins, Gustavo; Alves, Andreia Oliveira; da Costa, José Ronaldo Vieira; Azulay, David Rubem; Azulay-Abulafia, Luna

    2014-01-01

    Sialolithiasis is the presence of calculus within the ductal system of a salivary gland. Among the diagnostic methods are inspection, palpation, checking the amount of saliva secreted and the identification of a sialolith. The authors present the case of a 37-year-old female patient with edema of the submandibular area and a bulging sublingual caruncle due to a calculus that obstructed the salivary gland ostium. PMID:25387506

  16. 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.

  17. Variability in sublingual microvessel density and flow measurements in healthy volunteers.

    Science.gov (United States)

    Hubble, Sheena M A; Kyte, Hayley L; Gooding, Kim; Shore, Angela C

    2009-02-01

    As sublingual microvascular indices are increasingly heralded as new resuscitation end-points, better population data are required to power clinical studies. This paper describes improved methods to quantify sublingual microvessel flow and density in images obtained by sidestream dark field (SDF) technology in healthy volunteers, including vessels under 10 microm in diameter. Measurements of sublingual capillary density and flow were obtained by recording three 15-second images in 20 healthy volunteers over three days. Two independent observers quantified capillary density by using two methods: total vessel length (mm/mm2) and counting (number/mm). Both intraoral and temporal variabilities within subject and observer reproducibilities were determined by using coefficients of variability and reproducibility indices. For small (1-10 microm), medium (11-20 microm), and large (21-50 microm) diameter, mean vessel density with standard deviations (SDs) in volunteers was 21.3(+/- 4.9), 5.2 (+/- 1.2), and 2.7 (+/- 0.9) mm/mm2, respectively. Also, 94.0 +/- 1.4% of small vessels, 94.5 +/- 1.4% of medium vessels, and 94.5+/- 4.0% of large vessels had continuous perfusion. Within subjects, the means of all measurements over three days varied less than 13, 22, and 35% in small, medium, and large vessels, respectively. Interobserver reproducibility was good, especially for capillary (1-10 microm) density and flow measurements. Our methods of microvessel flow and density quantification have low observer variability and confirm the stability of microcirculatory measurements over time. These results facilitate the development of SDF-acquired sublingual microvascular indices as feasible microperfusion markers in shock resuscitation.

  18. The Proteomes of Human Parotid and Submandibular/Sublingual Gland Salivas Collected as the Ductal Secretions

    OpenAIRE

    Denny, Paul; Hagen, Fred K.; Hardt, Markus; Liao, Lujian; Yan, Weihong; Arellanno, Martha; Bassilian, Sara; Bedi, Gurrinder S.; Boontheung, Pinmannee; Cociorva, Daniel; Delahunty, Claire M.; Denny, Trish; Dunsmore, Jason; Faull, Kym F.; Gilligan, Joyce

    2008-01-01

    Saliva is a body fluid with important functions in oral and general health. A consortium of three research groups catalogued the proteins in human saliva collected as the ductal secretions: 1166 identifications—914 in parotid and 917 in submandibular/sublingual saliva—were made. The results showed that a high proportion of proteins that are found in plasma and/or tears are also present in saliva along with unique components. The proteins identified are involved in numerous molecular processes...

  19. The impact of the site of blood sampling on pharmacokinetic parameters following sublingual dosing to dogs.

    Science.gov (United States)

    Sohlberg, E; Halldin, M M; Annas, A; Königsson, K; Jansson, B; Pehrson, R; Borg, N

    2013-01-01

    Drugs are most commonly administered orally, but some potential drug candidates are not suited for oral administration due to poor absorption, high first pass metabolism or gastrointestinal side effects. The interest for transmucosal dosing for systemic drug delivery is increasing, e.g. buccal, sublingual and nasal routes. The evaluation of the systemic plasma concentration and the derivation of the pharmacokinetic parameters of candidate compounds in preclinical studies are essential for drug development. The effect of site of blood sampling on the measured drug concentration, in both animals and humans, is to some extent known but it is not always taken into consideration in the design of pharmacological and toxicological studies. Blood samples were collected both from leg and jugular veins from beagle dogs following a single sublingual dosing of Compound A in order to determine the impact of different sites of blood sampling on plasma pharmacokinetics. Plasma was prepared by centrifugation and plasma concentrations of Compound A were determined by protein precipitation and liquid chromatography followed by mass spectrometric detection. The pharmacokinetic parameters were calculated by non-compartment methods. Sampling from the jugular vein resulted in higher and more variable exposure during the absorption phase compared to sampling from a leg vein. The plasma exposure in the jugular vein, in terms of C(max), was 4-fold compared to that in the leg vein and an approximately 2-fold bioavailability was observed. The aim of this investigation was to determine the impact of the different sites of blood sampling on assessing systemic plasma exposure and pharmacokinetic parameters for Compound A following sublingual dosing to dogs. The results demonstrate the significant impact that the site of blood sampling has on PK parameters, and raise concerns of using the jugular vein as a site of sampling after sublingual and other transmucosal routes of dosing in the head

  20. 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.

  1. Fast-disintegrating sublingual tablets: Effect of epinephrine load on tablet characteristics

    OpenAIRE

    Rawas-Qalaji, Mutasem M.; Estelle, F.; Simons, R.; Simons, Keith J.

    2006-01-01

    The aim of this study was to evaluate the effect of increasing epinephrine load on the characteristics of fast-disintegrating sublingual tablets for the potential emergency treatment of anaphylaxis. Four tablet formulations, A, B, C, and D, containing 0%, 6%, 12%, and 24% of epinephrine bitartrate, respectively, and microcrystalline cellulose:low-substituted hydroxypropyl cellulose (9∶1), were prepared by direct compression, at a range of compression forces. Tablet weight variation, content u...

  2. Sublingual microcirculatory changes during high-volume hemofiltration in hyperdynamic septic shock patients.

    Science.gov (United States)

    Ruiz, Carolina; Hernandez, Glenn; Godoy, Cristian; Downey, Patricio; Andresen, Max; Bruhn, Alejandro

    2010-01-01

    Previous studies have suggested that high volume hemofiltration (HVHF) may contribute to revert hypotension in severe hyperdynamic septic shock patients. However, arterial pressure stabilization occurs due to an increase in systemic vascular resistance, which could eventually compromise microcirculatory blood flow and perfusion. The goal of this study was to determine if HVHF deteriorates sublingual microcirculation in severe hyperdynamic septic shock patients. This was a prospective, non-randomized study at a 16-bed, medical-surgical intensive care unit of a university hospital. We included 12 severe hyperdynamic septic shock patients (norepinephrine requirements > 0.3 μg/kg/min and cardiac index > 3.0 L/min/m2) who underwent a 12-hour HVHF as a rescue therapy according to a predefined algorithm. Sublingual microcirculation (Microscan for NTSC, Microvision Medical), systemic hemodynamics and perfusion parameters were assessed at baseline, at 12 hours of HVHF, and 6 hours after stopping HVHF. Microcirculatory flow index increased after 12 hours of HVHF and this increase persisted 6 hours after stopping HVHF. A similar trend was observed for the proportion of perfused microvessels. The increase in microcirculatory blood flow was inversely correlated with baseline levels. There was no significant change in microvascular density or heterogeneity during or after HVHF. Mean arterial pressure and systemic vascular resistance increased while lactate levels decreased after the 12-hour HVHF. The use of HVHF as a rescue therapy in patients with severe hyperdynamic septic shock does not deteriorate sublingual microcirculatory blood flow despite the increase in systemic vascular resistance.

  3. [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.

  4. Hyperoxia does not affect oxygen delivery in healthy volunteers while causing a decrease in sublingual perfusion.

    Science.gov (United States)

    Smit, B; Smulders, Y M; Eringa, E C; Gelissen, H P M M; Girbes, A R J; de Grooth, H J S; Schotman, H H M; Scheffer, P G; Oudemans-van Straaten, H M; Spoelstra-de Man, A M E

    2017-12-06

    To determine the human dose-response relationship between a stepwise increase in arterial oxygen tension and its associated changes in oxygen delivery and sublingual microcirculatory perfusion METHODS: Fifteen healthy volunteers breathed increasing oxygen fractions for 10 minutes to reach arterial oxygen tensions of baseline (breathing air), 20 kPa, 40 kPa, 60 kPa and max kPa (breathing oxygen). Systemic hemodynamics were measured continuously by the volume-clamp method. At the end of each period, the sublingual microcirculation was assessed by Sidestream Darkfield Imaging RESULTS: Systemic oxygen delivery was unchanged throughout the study (Pslope =0.8). Perfused vessel density decreased in a sigmoidal fashion (max -15% while breathing oxygen, SD18, Pslope =0.001). Cardiac index decreased linearly (max -10%, SD10, Pslope <0.001) due to a reduction in heart rate (max -10%, SD7, Pslope =0.009). There were no changes in stroke volume or mean arterial pressure. Most changes became apparent above an arterial oxygen tension of 20 kPa CONCLUSIONS: In healthy volunteers, supraphysiological arterial oxygen tensions have no effect on systemic oxygen delivery. Sublingual microcirculatory perfused vessel density decreased in a dose-dependent fashion. All hemodynamic changes appear negligible up to an arterial oxygen tension of 20 kPa This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  5. Sublingual Nucleotides Prolong Run Time to Exhaustion in Young Physically Active Men

    Directory of Open Access Journals (Sweden)

    Sergej M. Ostojic

    2013-11-01

    Full Text Available Although dietary nucleotides have been determined to be required for normal immune function, there is limited direct interventional evidence confirming performance-enhancing effects of sublingual nucleotides in humans. A double-blind, placebo-controlled, randomized trial was conducted to evaluate the effect of sublingual nucleotides (50 mg/day administered for 14 days in thirty young healthy physically active males, on endurance performance and immune responses. Fasting white blood cell count, natural killer cells (NKC number, NKC cytotoxic activity, and serum immunoglobulin (IgA, IgM, IgG, and time to exhaustion, peak rate of perceived exertion, peak heart rate, and peak running speed during the exercise test were measured at baseline (day 0 and post-intervention (day 14. Time to exhaustion, as well as serum immunoglobulin A and NKC cytotoxic activity, were significantly higher at day 14 (p < 0.05 in participants supplemented with nucleotides compared with those who consumed placebo. No significant differences in other parameters were observed between groups at post-intervention. No volunteers withdrew before the end of the study nor reported any vexatious side effects of supplementation. The results of the present study suggest that sublingual nucleotides may provide pertinent benefit as both an ergogenic and immunostimulatory additive in active males.

  6. Grass pollen sublingual immunotherapy for seasonal rhinoconjunctivitis: a randomized controlled trial.

    Science.gov (United States)

    Lima, M Torres; Wilson, D; Pitkin, L; Roberts, A; Nouri-Aria, K; Jacobson, M; Walker, S; Durham, S

    2002-04-01

    Previous studies suggest that sublingual immunotherapy (SLIT) represents a safer alternative to injection immunotherapy but equivalent efficacy is yet to be confirmed. To evaluate the efficacy and safety of SLIT in grass pollen-induced seasonal rhinoconjunctivitis. A randomized, placebo-controlled trial in 56 adults over 18 months. Outcome measures included diary scores of seasonal symptoms and medication use, overall assessments, conjunctival and intradermal provocation tests and serum antibody measurements. To investigate possible mechanisms, sublingual biopsies were taken for measurement of local T cells, antigen-presenting cells and IL-12 mRNA expression. There were no significant differences between the immunotherapy (IT) and placebo groups for diary symptom scores (P = 0.48) or rescue medication (P = 0.19). The patients' overall assessment of hayfever severity compared with previous years showed a highly significant improvement in favour of the IT group (P pollen sublingual immunotherapy was well tolerated. Although there was no significant change in diary scores, the improvement in overall assessments, which correlated with inhibition of the late skin response and increases in serum IgG4 : IgE ratio, indicates the need for larger, dose-ranging studies.

  7. Effect of monomeric adiponectin on cardiac function and perfusion in anesthetized pig.

    Science.gov (United States)

    Grossini, Elena; Prodam, Flavia; Walker, Gillian Elisabeth; Sigaudo, Lorenzo; Farruggio, Serena; Bellofatto, Kevin; Marotta, Patrizia; Molinari, Claudio; Mary, David; Bona, Gianni; Vacca, Giovanni

    2014-07-01

    Adiponectin, the most abundant adipokine released by adipose tissue, appears to play an important role in the regulation of vascular endothelial and cardiac function. To date, however, the physiological effects of human monomeric adiponectin on the coronary vasculature and myocardial systo-diastolic function, as well as on parasympathetic/sympathetic involvement and nitric oxide (NO) release, have not yet been investigated. Thus, we planned to determine the primary in vivo effects of human monomeric adiponectin on coronary blood flow and cardiac contractility/relaxation and the related role of autonomic nervous system, adiponectin receptors, and NO. In 30 anesthetized pigs, human monomeric adiponectin was infused into the left anterior descending coronary artery at constant heart rate and arterial blood pressure, and the effects on coronary blood flow, left ventricular systo-diastolic function, myocardial oxygen metabolism, and NO release were examined. The mechanisms of the observed hemodynamic responses were also analyzed by repeating the highest dose of human monomeric adiponectin infusion after autonomic nervous system and NO blockade, and after specific adiponectin 1 receptor antagonist administration. Intracoronary human monomeric adiponectin caused dose-related increases of coronary blood flow and cardiac function. Those effects were accompanied by increased coronary NO release and coronary adiponectin levels. Moreover, the vascular effects of the peptide were prevented by blockade of β2-adrenoceptors and NO synthase, whereas all effects of human monomeric adiponectin were prevented by adiponectin 1 receptor inhibitor. In conclusion, human monomeric adiponectin primarily increased coronary blood flow and cardiac systo-diastolic function through the involvement of specific receptors, β2-adrenoceptors, and NO release. © 2014 Society for Endocrinology.

  8. Budgetary impact of the utilization of buprenorphine/naloxone sublingual film and tablet for Medicaid in the United States.

    Science.gov (United States)

    Asche, Carl V; Clay, Emilie; Kharitonova, Elizaveta; Zah, Vladimir; Ruby, Jane; Aballéa, Samuel

    2015-01-01

    The buprenorphine/naloxone combination for the treatment of opioid dependence is available in a film or tablet formulation. Recent retrospective studies demonstrated that treatment with the sublingual film formulation is associated with improved treatment retention and lower healthcare costs. In March 2013, generic buprenorphine/naloxone tablets were approved in the US. A budget impact model was built to compare healthcare expenditures for different market shares of sublingual film and tablet. A Markov model was developed to track a cohort of opioid dependent patients treated with sublingual film or tablet through the following treatment phases: initiation, maintenance, discontinuation, off-treatment and reinitiation. Transition probabilities and costs for each phase were estimated from the MarketScan Medicaid database for the period between 1 March 2010 and 30 June 2012. The total expenditure for the plan and expenditure per plan member per month were predicted over 5 years. Two market share scenarios were considered: 1) sublingual film is progressively replaced by generic tablet (current situation) and 2) the sublingual film holds a market share of 100%. Predicted total costs over 5 years were $6400 million when the sublingual film holds a market share of 100% (as per Scenario 2) which is lower than when sublingual film is progressively replaced by generic tablet (current situation as per Scenario 1) by $64 million. These savings were mostly driven by inpatient care ($56 million saved over 5 years), followed by emergency room care ($27 million) and pharmaceutical costs ($24 million). Costs of outpatient care attenuated the difference as they were predicted to be higher by $44 million in Scenario 2. The reduction in total cost per member per month reached $0.027 in the fifth year. Results were most sensitive to price rebates and to the probability of non-psychiatric hospitalization. While using the sublingual film formulation for more patients treated with

  9. Randomized double-blind placebo-controlled trial of sublingual immunotherapy in children with house dust mite allergy in primary care: Study design and recruitment

    NARCIS (Netherlands)

    C.M.A. de Bot (Cindy); H. Moed (Heleen); M.Y. Berger (Marjolein); E. Röder (Esther); H. de Groot (Hans); J.C. de Jongste (Johan); R. Gerth van Wijk (Roy); J.C. van der Wouden (Hans)

    2008-01-01

    textabstractBackground. For respiratory allergic disorders in children, sublingual immunotherapy has been developed as an alternative to subcutaneous immunotherapy. Sublingual immunotherapy is more convenient, has a good safety profile and might be an attractive option for use in primary care. A

  10. Randomized double-blind placebo-controlled trial of sublingual immunotherapy in children with house dust mite allergy in primary care : study design and recruitment

    NARCIS (Netherlands)

    de Bot, Cindy M. A.; Moed, Heleen; Berger, Marjolein Y.; Roder, Esther; de Groot, Hans; de Jongste, Johan C.; van Wijk, Roy Gerth; van der Wouden, Johannes C.

    2008-01-01

    Background: For respiratory allergic disorders in children, sublingual immunotherapy has been developed as an alternative to subcutaneous immunotherapy. Sublingual immunotherapy is more convenient, has a good safety profile and might be an attractive option for use in primary care. A randomized

  11. Sustained 3-year efficacy of pre- and coseasonal 5-grass-pollen sublingual immunotherapy tablets in patients with grass pollen-induced rhinoconjunctivitis

    DEFF Research Database (Denmark)

    Didier, Alain; Worm, Margitta; Horak, Friedrich

    2011-01-01

    Seasonal allergic rhinoconjunctivitis affects millions of persons. The efficacy of allergen sublingual immunotherapy (SLIT) was demonstrated in previous short-term studies.......Seasonal allergic rhinoconjunctivitis affects millions of persons. The efficacy of allergen sublingual immunotherapy (SLIT) was demonstrated in previous short-term studies....

  12. 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.

  13. The efficacy of sublingual immunotherapy for respiratory allergy is not affected by different dosage regimens in the induction phase.

    Science.gov (United States)

    Sambugaro, R; Puccinelli, P; Burastero, S E; Di Rienzo, V

    2003-01-01

    Sublingual administration of allergens is a safe and effective alternative to subcutaneous immunotherapy in patients with respiratory allergies. A drawback to this therapeutic approach is the relatively long and complex management of the induction phase. To determine whether different induction regimens affect the outcome of sublingual immunotherapy. Adult and pediatric patients with allergic rhinoconjunctivitis and/or asthma were included in the study. Ten subjects served as controls and received symptomatic treatments. Forty-three subjects were allocated to sublingual immunotherapy, with three different induction protocols (8-, 15- and 20-day, respectively). Symptom and medication scores, skin test results and (in asthmatic patients) FEV1 values were monitored for two years. Adverse effects were recorded. All induction regimens produced a significant improvement in symptom and medication usage (p protocol is safe and effective. Our results encourage the usage of shorter induction regimens, which produce better compliance with this therapy.

  14. Novel Type II and Monomeric NAD+ Specific Isocitrate Dehydrogenases: Phylogenetic Affinity, Enzymatic Characterization, and Evolutionary Implication

    OpenAIRE

    Wang, Peng; Lv, Changqi; Zhu, Guoping

    2015-01-01

    NAD+ use is an ancestral trait of isocitrate dehydrogenase (IDH), and the NADP+ phenotype arose through evolution as an ancient adaptation event. However, no NAD+-specific IDHs have been found among type II IDHs and monomeric IDHs. In this study, novel type II homodimeric NAD-IDHs from Ostreococcus lucimarinus CCE9901 IDH (OlIDH) and Micromonas sp. RCC299 (MiIDH), and novel monomeric NAD-IDHs from Campylobacter sp. FOBRC14 IDH (CaIDH) and Campylobacter curvus (CcIDH) were reported for the fir...

  15. 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

  16. 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.

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

    Directory of Open Access Journals (Sweden)

    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

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

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    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.

  19. Adverse reaction to sublingual Parietaria vaccine following an ultra-rush induction.

    Science.gov (United States)

    Scala, G; Ciccarelli, A; Calabrò, C

    2014-05-01

    In the treatment of respiratory allergies Sublingual Immunotherapy (SLIT) represents a valid alternative to Subcutaneous Immunotherapy (SCIT) for its better safety profile. We describe a case of acute severe asthma following the first maintenance dose of SLIT in a boy allergic to Parietaria pollen. At the initiation of therapy, the patient was in healthy condition and his asthma appeared to be under control. An ultra-rush induction had given no reaction. Despite the good safety profile of SLIT, clinicians should be aware of the risk of adverse effects when prescribing SLIT for respiratory allergies.

  20. Sublingual misoprostol versus intravenous oxytocin in the management of postpartum hemorrhage

    Directory of Open Access Journals (Sweden)

    Beigi A

    2009-11-01

    Full Text Available "n Normal 0 false false false EN-US X-NONE AR-SA MicrosoftInternetExplorer4 /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-qformat:yes; mso-style-parent:""; mso-padding-alt:0in 5.4pt 0in 5.4pt; mso-para-margin:0in; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:11.0pt; font-family:"Calibri","sans-serif"; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"Times New Roman"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:Arial; mso-bidi-theme-font:minor-bidi;} Background: Postpartum hemorrhage is a major cause of maternal mortality and morbidity. It has been identified that active management of third stage of labor is an effective way in preventing postpartum hemorrhage. This randomized controlled trial was conducted to compare sublingual misoprostol versus intravenous oxytocin in the management of postpartum hemorrhage in nulliparous women."n"nMethods: In this randomized controlled trial conducted in Arash hospital from 2006 to 2009, Five hundred forty two nulliparous pregnant women were enrolled. They were randomized to receive either 400 microgram sublingual misoprostol or 20 IU oxytocin intravenously, immediately after the birth of newborn. "n"nResults: Post partum Hemorrhage was significantly lower in women who received sublingual misoprostol (p<0.0001. Patients who received misoprostol had shorter length of third stage of labor (6.45 minute in misoprostol Vs 6.9 minute in oxytocin group, p=0.003. Comparison of hemoglobin levels in two groups before and after delivery showed that there is a significant lesser hemoglobin drop in misoprostol group p=0.046. Side effects were more common in misoprostol group (p<0.0001. However, they were not serious; shivering (35.66% in

  1. A Rare Primary Neuroendocrine Tumor (Typical Carcinoid of the Sublingual Gland

    Directory of Open Access Journals (Sweden)

    Kenji Yamagata

    2016-01-01

    Full Text Available A typical carcinoid is extremely rare in the oral cavity. We here present a case of a typical carcinoid arising in the sublingual gland of a 62-year-old woman. The tumor was removed by primary excision with 10 mm surgical margins and submandibular dissection. Examination of the tumor showed medium-sized tumor cells that were positive for CD56 and chromogranin A, with no necrosis, and with a mitotic count less than 1/10 HPF. A pathological diagnosis of typical carcinoid was made from both morphological and immunological examinations. One year after excision surgery, there was no tumor recurrence or neck metastasis.

  2. Dose-adjusted plasma concentrations of sublingual buprenorphine are lower during than after pregnancy.

    Science.gov (United States)

    Bastian, Jaime R; Chen, Huijun; Zhang, Hongfei; Rothenberger, Scott; Tarter, Ralph; English, Dennis; Venkataramanan, Raman; Caritis, Steve N

    2017-01-01

    Buprenorphine is a Food and Drug Administration-approved maintenance therapy for opioid use disorders and is increasingly being used in pregnant women with opioid use disorders as an alternative to methadone. Dosing of buprenorphine in pregnant women is based on the regimen recommended for nonpregnant females and males. Limited data are available defining the pharmacokinetic properties of sublingual buprenorphine administered during pregnancy. This study evaluated the impact of physiological changes associated with pregnancy on the pharmacokinetics of sublingual buprenorphine during and after pregnancy. Pregnant women (n = 13), between 180/7 and 376/7 weeks' singleton gestation, receiving sublingual buprenorphine twice daily for opioid use disorders were studied. Pharmacokinetic-2 studies were performed between 18 and 25 weeks (n = 7), pharmacokinetic-3 studies were performed between 31 and 37 weeks (n = 11), and pharmacokinetic-P was performed 4-18 weeks postpartum (n = 10). On the day of the study, blood was withdrawn prior to the daily morning dose of buprenorphine and at 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 8, and 12 hours after the dose. Buprenorphine plasma concentrations were analyzed by liquid chromatography tandem mass spectrometric detection. All pharmacokinetic parameters were observed or estimated using Microsoft Excel. Statistical analyses were performed to identify significant changes in study participants' buprenorphine pharmacokinetic parameter estimates over the duration of the study. Univariate linear and generalized linear mixed models were used to investigate changes in these measures over time, some of which were log transformed for normality. Dose-normalized (plasma concentration per dose) buprenorphine plasma concentrations were significantly lower during pregnancy (pharmacokinetic-2 plus pharmacokinetic-3) than during the postpartum period (pharmacokinetic-P). Specific pharmacokinetic parameters (and level of significance) were as follows: the

  3. 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......: The most dominant immunological changes on a cellular level was a decrease in IL-5 in the SCIT group and a significant, transient increase of IL-10 observed after 10 months of treatment in both treated groups. The distinct routes of AIT administration may induce different immune-modulatory mechanisms...

  4. Monomeric and dendritic second generation Grubbs- and Hoveyda-Grubbs-type catalysts for olefin metathesis Metallodendrimers Special Issue

    NARCIS (Netherlands)

    Pijnenburg, Niels J M; Tomás-Mendivil, Eder; Mayland, Kimberley E.; Kleijn, Henk; Lutz, Martin; Spek, Anthony L.; Van Koten, Gerard; Klein Gebbink, Bert

    2014-01-01

    The synthesis and characterization of monomeric and dendritic Grubbs II and Hoveyda-Grubbs II-based complexes are reported. These complexes were synthesized via a route based on the connection of monomeric or dendritic N-alkyl-N′-mesitylimidazol-2-ylidene pre-ligands to Grubbs I or Hoveyda-Grubbs I

  5. Monomeric GLP-1/GIP/glucagon triagonism corrects obesity, hepatosteatosis, and dyslipidemia in female mice

    DEFF Research Database (Denmark)

    Jall, Sigrid; Sachs, Stephan; Clemmensen, Christoffer

    2017-01-01

    OBJECTIVE: Obesity is a major health threat that affects men and women equally. Despite this fact, weight-loss potential of pharmacotherapies is typically first evaluated in male mouse models of diet-induced obesity (DIO). To address this disparity we herein determined whether a monomeric peptide...

  6. mScarlet : a bright monomeric red fluorescent protein for cellular imaging

    NARCIS (Netherlands)

    Bindels, D.S.; Haarbosch, L.; van Weeren, L.; Postma, M.; Wiese, K.E.; Mastop, M.; Aumonier, S.; Gotthard, G.; Royant, A.; Hink, M.A.; Gadella Jr, T.W.J.

    2017-01-01

    We report the engineering of mScarlet, a truly monomeric red fluorescent protein with record brightness, quantum yield (70%) and fluorescence lifetime (3.9 ns). We developed mScarlet starting with a consensus synthetic template and using improved spectroscopic screening techniques; mScarlet's

  7. A novel method to highly versatile monomeric PNA building blocks by multi component reactions

    NARCIS (Netherlands)

    Dömling, Alexander; Chi, Kai-Zu; Barrère, Mathieux

    1999-01-01

    A novel approach to monomeric PNA building blocks by a solution phase Ugi multi component reaction (MCR) is described. The reaction is easily performed in 96 well plates. The products precipitate from the reaction solution and are thus obtained in high yields and purity. Those products are not

  8. 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.

  9. 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.

  10. Efficacy of alprazolam sublingual tablets in the treatment of the acute phase of panic disorders.

    Science.gov (United States)

    Márquez, Miguel; Arenoso, Hector; Caruso, Norberto

    2011-01-01

    Panic disorder affects 2-5% of the general population. In Argentina, one million people would be affected with a 91% rate of psychiatric comorbidity. AIM; To compare efficacy parameters between sublingual (ALP-SL) and conventional (ALP-CT) tablets of alprazolam in the treatment of acute phase of panic disorder with and without agoraphobia. A comparative, multicenter (6 sites), double blind, randomized study was carried out. A total of 190 outpatients with (n=117) and without (n=73) agoraphobia were treated with ALP-SL or ALP-CT for 12 weeks. Outcome was assessed with the Clinical Global Impressions (CGI-S/CGI-I), Hamilton Rating Scale for Anxiety (HAM-A), Arizona Sexual Experiences Scale (ASEX), Patient Global Impression (PGI), Psychological General Well-Being Index (PGWBI), Panic Disorder Severity Scale (PDSS) also by the number of panic attacks and extension and intensity of panic attacks and anticipatory anxiety. RESULTS. Both treatments resulted in statistically significant clinical improvement in all measures. ASEX presented no changes during the study. The average dose of alprazolam for 12 weeks was 1.36 ± 0.70 mg/day (1.39 ± 0.77 ALP-CT and 1.33 ± 0.64 ALP-SL). With ALP-SL, panic attacks were shorter (p Alprazolam has been demonstrated to have efficacy, safety and good tolerability in the treatment of the acute phase of panic disorder, the sublingual tablets showing some comparative advantages.

  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. Safety, tolerability and clinical efficacy of ultra-rush sublingual immunotherapy among patients suffering from allergic rhinitis.

    Science.gov (United States)

    Balaji, R; Parasuramalu, B G; Chandregowda, B V; Gangaboraiah

    2014-01-01

    Conventional immunotherapy for allergy with 3-5 years of treatment period has poor compliance. Ultra-rush sublingual immunotherapy with a shorter period of treatment can have better compliance. There are very few studies on ultra-rush sublingual immunotherapy all over the world. (1) To determine allergen sensitivity among allergic rhinitis patients. (2) To assess safety, tolerability and clinical efficacy of ultra-rush sublingual immunotherapy. The present study was conducted in Allergy clinic, KIMS Hospital & Research Centre, Bangalore, India from January 2010 to June 2011. After obtaining Institutional Ethics Committee approval, 40 allergic rhinitis patients (according to ARIA guidelines) in the 18-60 years age group who were positive for aeroallergens in skin prick test were recruited for ultra-rush sublingual immunotherapy (20min initial phase and 4-month maintenance phase) and followed for 8 months with symptom and treatment diary. Out of 40 patients, the majority, 36 (90.00%) patients were sensitive to house dust mites. Six patients had seven immediate adverse reactions and seven patients had eight delayed adverse reactions. All subsided without medication or with symptomatic oral medications. All patients tolerated ultra-rush SLIT and there was significant decrease in both symptom-score and treatment received in these patients. Ultra-rush SLIT regimen has excellent safety, tolerability and clinical efficacy among allergic rhinitis patients. Copyright © 2012 SEICAP. Published by Elsevier Espana. All rights reserved.

  14. Comparing vaginal and sublingual administration of misoprostol for labour induction in women with intra-uterine fetal death.

    NARCIS (Netherlands)

    Geels, Y.P.; Gouberville, M.C. de; Visser, L.; Asten, H.A.G.H. van

    2010-01-01

    The objective of this study was to compare complications and effectiveness of induction after vaginal and sublingual administration of misoprostol for labor induction in women with intra-uterine fetal death (IUFD). In a district hospital in Ghana, 23 women with IUFD who underwent labor induction

  15. 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.

  16. The effect of pre-procedure sublingual nitroglycerin on radial artery diameter and Allen's test outcome - Relevance to transradial catheterization.

    Science.gov (United States)

    Chong, Aun-Yeong; Lo, Ted; George, Sudhakar; Ratib, Karim; Mamas, Mamas; Nolan, James

    2017-07-29

    The radial artery is increasingly used for cardiac procedures, but is a relatively small vessel that is prone to spasm when instrumented. Intra-arterial nitroglycerine has been shown to reduce radial spasm but first requires arterial access. We investigated the effect of pre-procedure sublingual nitroglycerin (NTG) on the diameter of the radial artery in a large cohort of patients. 305 subjects underwent ultrasound measurement of their radial and ulnar arteries in both arms before and after the administration of 800μg of sublingual NTG. The Allen's test was also performed in the subjects prior to and after NTG. Radial artery diameter in this Caucasian study group is larger than that reported for other populations. The administration of sublingual NTG significantly increased the size of the right radial artery from 2.88±0.36mm to 3.36±0.40mm in men and from 2.23±0.37 up to 2.74±0.36mm in women. There were also significant increases in left radial, right and left ulnar artery diameters in males and females with NTG. There was no significant effect of NTG on blood pressure. In all patients with an unfavourable Allen's test, retesting following sublingual NTG resulted in transition to a favourable Allen's. Caucasian populations have larger calibre radial arteries compared to other geographic areas. Sublingual NTG is effective at dilating the radial artery in both men and women. This may make radial artery puncture and cannulation less challenging and should be considered in all patients in the absence of contraindications. The results of Allen's testing are dynamic and its usefulness for screening prior to transradial access is undetermined. Copyright © 2017 Elsevier Inc. All rights reserved.

  17. 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.

  18. 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....

  19. Monomeric carbohydrates production from olive tree pruning biomass: modeling of dilute acid hydrolysis.

    Science.gov (United States)

    Puentes, Juan G; Mateo, Soledad; Fonseca, Bruno G; Roberto, Inês C; Sánchez, Sebastián; Moya, Alberto J

    2013-12-01

    Statistical modeling and optimization of dilute sulfuric acid hydrolysis of olive tree pruning biomass has been performed using response surface methodology. Central composite rotatable design was applied to assess the effect of acid concentration, reaction time and temperature on efficiency and selectivity of hemicellulosic monomeric carbohydrates to d-xylose. Second-order polynomial model was fitted to experimental data to find the optimum reaction conditions by multiple regression analysis. The monomeric d-xylose recovery 85% (as predicted by the model) was achieved under optimized hydrolysis conditions (1.27% acid concentration, 96.5°C and 138 min), confirming the high validity of the developed model. The content of d-glucose (8.3%) and monosaccharide degradation products (0.1% furfural and 0.04% 5-hydroxymethylfurfural) provided a high quality subtract, ready for subsequent biochemical conversion to value-added products. Copyright © 2013 Elsevier Ltd. All rights reserved.

  20. Barrel fluctuation and oxygen diffusion pathways in the monomeric fluorescent proteins

    Science.gov (United States)

    Regmi, Chola; Chapagain, Prem; Bhandari, Yuba; Chemmama, Ilan; Gerstman, Bernard

    2012-02-01

    Fluorescent proteins are valuable tools as biochemical markers for studying cellular processes. Improving the photostability of the FPs is highly desirable in biochemical, biomedical and cell biology. Oxygen is necessary for the proper maturation of the chromophore in fluorescent proteins (FPs), but photobleaching of FPs is also oxygen sensitive. The photobleaching of the monomeric variant of RFPs has been attributed to the lack of proper shielding against oxygen or other small molecules, ions or halides. We use molecular dynamics simulation to investigate the protein barrel fluctuations in mCherry, one of the most useful monomeric mFruit variant of RFPs. We also employ oxygen diffusion simulations to search for possible pathways of oxygen to the chromophore. The ultimate goal is to use the results of these calculations to propose amino acid substitutions that will block the oxygen pathways and prevent photobleaching in the engineered proteins.

  1. Sublingual tacrolimus administration provides similar drug exposure to per-oral route employing lower doses in liver transplantation: a pilot study.

    Science.gov (United States)

    Solari, S; Cancino, A; Wolff, R; Norero, B; Vargas, J I; Barrera, F; Guerra, J F; Martínez, J; Jarufe, N; Soza, A; Arrese, M; Benitez, C

    2017-05-01

    Per-oral tacrolimus administration is not always practicable. Sublingual administration is a potential alternative, but its feasibility and effectiveness compared with oral route has not been established. To compare tacrolimus drug exposure after sublingual and oral administration in liver transplant recipients. Experimental, open-label, non-randomised, cross-over study. Tacrolimus exposure was evaluated in 32 liver transplant recipients receiving oral administration. 12 h tacrolimus area-under-the-curve (AUC0-12 h ) was calculated using tacrolimus blood concentrations at 0-0.5-1-2-4-6-8-12 hrs post-dose. Recipients were switched to sublingual administration, and dose was adjusted to reach similar trough levels, new AUC0-12 h was calculated. Correlation between AUC0-12 h and trough levels was determined for both oral and sublingual phases. Similar trough levels were accomplished with oral and sublingual administration (6.68 ± 2 ng/mL vs. 6.62 ± 1.9 ng/mL (P = 0.8)). Although concentration 2 h post dose was higher in oral phase (15.36 ± 7.14 vs. 13.18 ± 5.64, P = 0.015), AUC0-12 h was similar in both phases (116.6 ± 34.6 vs. 111.5 ± 36.93 ng/mL* h, P = 0.19). Daily dose of tacrolimus required in sublingual phase was 37% lower than that used in oral phase (P tacrolimus when employing sublingual route. Good correlation between AUC0-12 h and trough levels was observed in sublingual phase (r2 = 0.74). Twenty-two recipients were maintained on sublingual administration after the end of study (mean follow-up: 18.7 ± 5.8 months). No difference in liver function tests or rejection rates was found during follow-up period. Sublingual administration of tacrolimus is feasible and provides similar drug exposure compared with oral administration. In our study, at long-term follow-up, sublingual administration was not associated with liver transplant rejection. © 2017 John Wiley & Sons Ltd.

  2. Effect of Buprenorphine Implants on Illicit Opioid Use Among Abstinent Adults With Opioid Dependence Treated With Sublingual Buprenorphine: A Randomized Clinical Trial.

    Science.gov (United States)

    Rosenthal, Richard N; Lofwall, Michelle R; Kim, Sonnie; Chen, Michael; Beebe, Katherine L; Vocci, Frank J

    2016-07-19

    The effectiveness of buprenorphine treatment of opioid dependence is limited by suboptimal medication adherence, abuse, and diversion. To determine whether 6-month buprenorphine implants are noninferior to daily sublingual buprenorphine as maintenance treatment for opioid-dependent patients with stable abstinence. Outpatient, randomized, active-controlled, 24-week, double-blind, double-dummy study conducted at 21 US sites from June 26, 2014, through May 18, 2015. Outpatients were prescribed daily sublingual buprenorphine for 6 months or more, were abstinent while taking 8 mg/d or less of sublingual buprenorphine for 90 days or longer, and were determined to be clinically stable by their physician. Participants were randomized to receive sublingual buprenorphine plus 4 placebo implants or sublingual placebo plus four 80-mg buprenorphine hydrochloride implants (expected efficacy, 24 weeks). The primary end point was between-group difference in proportion of responders (≥4 of 6 months without opioid-positive urine test result [monthly and 4 times randomly] and self-report). The noninferiority established for the lower bound of the 95% confidence interval was greater than -0.20 (P buprenorphine with placebo implants and 87 to buprenorphine implants with sublingual placebo; 165 of 177 (93.2%) completed the trial. Eighty-one of 84 (96.4%) receiving buprenorphine implants and 78 of 89 (87.6%) receiving sublingual buprenorphine were responders, an 8.8% difference (1-sided 97.5% CI, 0.009 to ∞; P buprenorphine implants and 64 of 89 (71.9%) receiving sublingual buprenorphine maintained opioid abstinence (hazard ratio, 13.8; 95% CI, 0.018-0.258; P = .03). Non-implant-related and implant-related adverse events occurred in 48.3% and 23% of the buprenorphine implant group and in 52.8% and 13.5% of participants in the sublingual buprenorphine group, respectively. Among adults with opioid dependence maintaining abstinence with a stable dose of sublingual buprenorphine

  3. Monomeric platinum(II) hydroxides supported by sterically dominant α-diimine ligands.

    Science.gov (United States)

    Lohr, Tracy L; Piers, Warren E; Parvez, Masood

    2012-05-07

    The use of two new highly sterically bulky α-diimine ligands for the stabilization of neutral, monomeric platinum(II) hydroxo complexes is described. Halide abstraction from LPtCl(2) complexes of these ligands in the presence of water, followed by deprotonation of the cationic aquo complex, leads to LPt(OH)Cl and LPt(OH)(2). The latter can be reprotonated with HNTf(2) to yield a highly fluxional hydroxoaquoplatinum(II) cation.

  4. 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...... of sublingual tablets, the residence time of the model substance in the oral cavity was significantly longer than following administration of chewing gum. The residence time following administration of lozenges was found to be the shortest....

  5. Dust Mite-Induced Perennial Allergic Rhinitis in Pediatric Patients and Sublingual Immunotherapy.

    Science.gov (United States)

    Anderson, Halie M; Wood, Robert A; Busse, William W

    Allergic rhinitis (AR) is a common illness in children and can impair their quality of life. Furthermore, many children remain symptomatic despite maximizing systemic antihistamine and topical therapies. It is at this clinical juncture that immunotherapy may be considered. The efficacy and safety associated with both subcutaneous (SCIT) and sublingual (SLIT) approaches are reviewed and positioned as treatment options for pediatric patients, with specific focus on current literature as it relates to SLIT in children, including those with perennial allergic rhinitis. Although there is more extensive experience with SLIT treatment in Europe, grass and ragweed tablet forms of SLIT are approved in the US. Approaches to the care of pediatric patients with allergic rhinitis are presented. Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  6. Influence of sublingual captopril on plasma catecholamine levels during hypertensive emergencies and cold immersion.

    Science.gov (United States)

    Polonia, J J; Monteiro, A; Esteves, A; Cunha, M E; Santos, M L; Coutinho, J; Coelho, J L; Brandao, F A; Cerqueira-Gomes, M

    1988-03-11

    Experimental evidence of captopril-induced inhibition of sympathetic activity, mediated by decrease in angiotensin II production, is presented. The blood pressure, plasma catecholamine, plasma renin activity, and plasma aldosterone responses to a single dose of sublingual captopril in 23 patients with hypertensive emergencies were evaluated. The major correlation found was between the captopril-induced decrease in blood pressure and the decrease in plasma norepinephrine levels (r = 0.57, p less than 0.01). In another 11 hypertensive patients with normal or high renin levels, captopril lowered by 65 percent the increase in plasma norepinephrine induced by cold immersion of the forearm. In both circumstances, plasma renin and aldosterone levels changed in accordance with the expected inhibition of angiotensin converting enzyme activity. These data suggest that, in selected circumstances in hypertensive patients, captopril exhibits a depressive influence on sympathetic activity along with the inhibition of the renin-angiotensin system.

  7. 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.

  8. Effect of vasopressin on sublingual microcirculation in a patient with distributive shock.

    Science.gov (United States)

    Dubois, Marc J; De Backer, Daniel; Creteur, Jacques; Anane, Sami; Vincent, Jean-Louis

    2003-06-01

    To assess the sublingual microcirculation in a patient during vasopressin administration for a distributive shock after cardiopulmonary bypass. Case-report in the Department of Intensive Care of a university hospital. A 53 year-old man developed severe distributive shock after cardiac transplant, requiring massive doses of vasopressor agents. Vasopressin administered twice at a dose of 0.02 U/min increased mean blood pressure and allowed partial weaning of other vasopressor drugs. Microcirculatory alterations were assessed by orthogonal polarization spectral technique: 50% and 60% of capillaries were perfused at baseline, and these proportions did not worsen when vasopressin was administered. Despite its strong vasopressor effects vasopressin infusion did not worsen microcirculatory alterations in this patient with distributive shock following cardiac surgery.

  9. A Case of Sublingual Dermoid Cyst: Extending the Limits of the Oral Approach

    Directory of Open Access Journals (Sweden)

    Nobuo Ohta

    2012-01-01

    Full Text Available We present the case of a dermoid cyst with an oral and a submental component in a 21-year-old Japanese woman who presented with complaints of a mass in the oral cavity and difficulty in chewing and swallowing solid foods for about 2 years. MRI shows a 55 × 65 mm well-circumscribed cystic mass extending from the sublingual area to the mylohyoid muscle. Under general anesthesia and with nasotracheal intubation, the patient underwent surgical removal of the mass. Although the cyst was large and extending mylohyoid muscle, intraoral midline incision was performed through the mucosa overlying the swelling and the cyst was separated from the surrounding tissues with appropriate traction and countertraction and successfully removed without extraoral incision. Oral approach in surgical enucleation is useful procedure to avoid cosmetic problems in large and extending mylohyoid muscle cyst.

  10. 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.

  11. 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.

  12. 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.

  13. Fluorescence correlation spectroscopy shows that monomeric polyglutamine molecules form collapsed structures in aqueous solutions

    Science.gov (United States)

    Crick, Scott L.; Jayaraman, Murali; Frieden, Carl; Wetzel, Ronald; Pappu, Rohit V.

    2006-01-01

    We have used fluorescence correlation spectroscopy measurements to quantify the hydrodynamic sizes of monomeric polyglutamine as a function of chain length (N) by measuring the scaling of translational diffusion times (τD) for the peptide series (Gly)-(Gln)N-Cys-Lys2 in aqueous solution. We find that τD scales with N as τoNν and therefore ln(τD) = ln(τo) + νln(N). The values for ν and ln(τo) are 0.32 ± 0.02 and 3.04 ± 0.08, respectively. Based on these observations, we conclude that water is a polymeric poor solvent for polyglutamine. Previous studies have shown that monomeric polyglutamine is intrinsically disordered. These observations combined with our fluorescence correlation spectroscopy data suggest that the ensemble for monomeric polyglutamine is made up of a heterogeneous collection of collapsed structures. This result is striking because the preference for collapsed structures arises despite the absence of residues deemed to be hydrophobic in the sequence constructs studied. Working under the assumption that the driving forces for collapse are similar to those for aggregation, we discuss the implications of our results for the thermodynamics and kinetics of polyglutamine aggregation, a process that has been implicated in the molecular mechanism of Huntington's disease. PMID:17075061

  14. Comparison between effects of intravenous lidocaine and sublingual nifedipine on preventing blood pressure increase in laryngoscopy

    Directory of Open Access Journals (Sweden)

    Gholamreza Mohseni

    2010-06-01

    Full Text Available Gholamreza Mohseni1, Azam Kolyaei2, Morteza Farshchian3, Mansour Rezaei4, Negin Ghadami51Anesthesiologist, assistant professor, 2Anesthetist, 3Orthopedist, assistant professor, 4Biostatistician, assistant professor, 5General practitioner, Kermanshah University of Medical Sciences, Kermanshah, IranIntroduction: Arrhythmia during surgery most frequently occurs during laryngoscopy and intratracheal intubation. Many surgical procedures require intratracheal intubation, which results in hemodynamic changes. These changes in ill patients and patients with limited coronary flow reserve are associated with serious events.Materials and methods: A randomized clinical trial was performed on 124 healthy patients who were elective surgery candidates at Taleghani hospital in Kermanshah. Patients were allocated randomly to each equal group of 62 patients with 95% significance and 90% power of test-retest for sample size. The patients had no history of disease or use of special medications. Drugs commonly used for laryngoscopy and intubation to prevent hemodynamic complications, intravenous lidocaine and sublingual nifedipine, were compared with independent and paired t-tests.Results: This comparison suggested that while the mean age, weight, and sex distribution in our two groups were the same, mean changes in systolic and diastolic blood pressure and heart rate increases in the lidocaine group were 12.6%, 7.5%, and 16.5%, and in the nifedipine group, 17.7%, 11.0%, and 23.5% (P value = 0.0052, 0.189, and 0.0001, respectively. Conclusion: According to the results of our study, intravenous lidocaine is more effective than sublingual nifedipine for preventing hemodynamic changes while performing laryngoscopy or intratracheal intubation.Keywords: hemodynamic changes, laryngoscopy

  15. Sublingual sufentanil, a new opportunity for the improvement of postoperative pain management in Italy.

    Science.gov (United States)

    Sacerdote, P; Coluzzi, F; Fanelli, A

    2016-04-01

    Despite the availability of national and international guidelines, adequate postoperative pain (POP) management is still a challenge in Italy. One of the potential reasons for the high incidence of surgical patients complaining moderate to severe pain is the difficult application of the currently recommended analgesic techniques in clinical practice. In particular, morphine, the most commonly used systemic opioid in the POP treatment, has some unfavorable pharmacodynamic and pharmacokinetic characteristics for POP management, suggesting a potential relevant improvement by using different opioids. Many of sufentanil properties make it particularly suitable for POP control: a high affinity for the µ opioid receptor, the highest therapeutic index compared to any other opioid used in clinical practice and the absence of clinically relevant active metabolites. The elevated potency, together with the high lipophilicity of sufentanil, allow the preparation of a nanotablet, 3 mm of diameter and 0.75 mm of thickness, containing 15 µg of active drug. The sublingual route allows a longer time of drug plasmatic permanence in comparison to IV route, overcoming the need for continuous dosing. The patient-controlled system, considered in the present review, is preprogrammed to deliver one sublingual tablet of sufentanil with a 20-minute lockout period with a radiofrequency identification thumb tag allowing only the patient to activate the on demand button. Phase II and III studies have assessed the efficacy of this system in POP management, showing that it was considered more satisfactory than the IV PCA morphine system by both patients and nurses. The introduction of this simple and innovative system of patient-controlled analgesic administration could represent an opportunity for Italy to update the current practice in POP management.

  16. 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

  17. COMPARISON OF SUBLINGUAL THERAPEUTIC VACCINE WITH ANTIBIOTICS FOR THE PROPHYLAXIS OF RECURRENT URINARY TRACT INFECTIONS

    Directory of Open Access Journals (Sweden)

    María Fernanda Lorenzo-Gómez

    2015-06-01

    Full Text Available Objective: To evaluate the clinical impact of the prophylactic treatment with sublingual immunostimulation in the prevention of recurrent urinary tract infections (rUTIs compared with the use of antibiotics.Material and Methods: Retrospective cohort study evaluating the clinical records of 669 women with rUTIs; 339 had a 6-month prophylaxis with antibiotics and 360 had a 3-month prophylaxis with a sublingual bacterial preparation (MV 140-Uromune®. The time after the prophylaxis-period until the appearance of a new infection (assessed by uroculture was scored during one year. Absolute risk reduction (ARR and number needed to treat (NNT were also calculated.Results: All patients (100% treated with antibiotics experienced a new UTI during the scoring period of 12 months, being the mean time free of UTI 29 (±38 days. In the group treated with the bacterial preparation, only 35 (9.7% patients experienced UTI in the same period. Kaplan-Meier curves comparing the accumulated survival (disease-free time between both groups were significant (P < 0.0001. ARR was 90.28 % (87.18-93.38 and NNT 1.1 (1.1-1.1.Conclusions: These results suggest that the treatment with the bacterial preparation reduces rUTIs very effectively, arising as an effective strategy to reduce the frequency of rUTIs. It reduces antibiotic consumption, matching the current recommendations due to the raise of antimicrobial resistance. Randomized, double-blind and placebo-controlled, clinical trials are needed to establish more accurately the clinical impact of this bacterial preparation in patients with rUTIs.

  18. 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

  19. [Failure of sublingual immunotherapy to treat latex allergy. A report of a case].

    Science.gov (United States)

    Morfin Maciel, Blanca María; Castillo Morfin, Blanca María

    2008-01-01

    Natural rubber latex has been in widespread use for over a century. Reports of immediate hypersensitivity to latex have increased dramatically since the first case was reported in 1979, specially in persons with cumulative latex exposure. A 13 year old male was referred to our office. He had been wearing orthodontic rubber bands for two years. The previous year he started having itchy, red and watery eyes, with sneezing and runny nose when he was exposed to rubber products. Then he developed oral edema and lip ulcers. Finally, he experienced cough, wheezing, chest tightness and dyspnea. The patient had no history of undergoing surgery, and his mother denied pacifier use. He had no history of fruit and vegetables allergy. Physical examination revealed conjunctival hyperemia, with fine papillary response in the upper tarsal plate, hyaline rhinorrhea, turbinate hypertrophy and perioral ulcers. Skin prick test were positive for latex and Quercus albus. Patch test with latex glove was negative, but positive with rubber tourniquet. Total IgE was 365 UI/mL. Latex-specific IgE testing confirmed the diagnosis. Spirometric values were normal. He started rush sublingual immunotherapy with latex extract. When he had finished, he traveled abroad. At immigration the inspectors examined him with latex gloves. Immediately he developed anaphylaxis, needing urgent medical attention. Although the efficacy and safety of sublingual immunotherapy for latex allergy has been demonstrated, the most effective strategy is complete avoidance of latex-containing products. World Public Health Services must promote the use of synthetic elastomer gloves in airports worldwide.

  20. Sublingual Immunotherapy Induces Regulatory Function of IL-10-Expressing CD4+CD25+Foxp3+ T Cells of Cervical Lymph Nodes in Murine Allergic Rhinitis Model

    Directory of Open Access Journals (Sweden)

    Takaya Yamada

    2012-01-01

    Full Text Available Sublingual immunotherapy (SLIT has been considered to be a painless and efficacious therapeutic treatment of allergic rhinitis which is known as type I allergy of nasal mucosa. Nevertheless, its mechanisms need to be further investigated. In this study, we constructed an effective murine model of sublingual immunotherapy in allergic rhinitis, in which mice were sublingually administered with ovalbumin (OVA followed by intraperitoneal sensitization and nasal challenge of OVA. Sublingually treated mice showed significantly decreased specific IgE responses as well as suppressed Th2 immune responses. Sublingual administration of OVA did not alter the frequency of CD4+CD25+ regulatory T cells (Tregs, but led to upregulation of Foxp3- and IL-10-specific mRNAs in the Tregs of cervical lymph nodes (CLN, which strongly suppressed Th2 cytokine production from CD4+CD25− effector T cells in vitro. Furthermore, sublingual administration of plasmids encoding the lymphoid chemokines CCL19 and CCL21-Ser DNA together with OVA suppressed allergic responses. These results suggest that IL-10-expressing CD4+CD25+Foxp3+ Tregs in CLN are involved in the suppression of allergic responses and that CCL19/CCL21 may contribute to it in mice that received SLIT.

  1. Efficacy and safety of sublingual fentanyl orally disintegrating tablets in patients with breakthrough pain: multicentre prospective study.

    Science.gov (United States)

    Guitart, Jordi; Vargas, Isabel; De Sanctis, Vicente; Ferreras, Julia; Fuentes, Jose; Salazar, Rafael; Vázquez, Juan M; Folch, Jordi; Moya, Jordi; Ribera, Hermann; Rodelas, Francisco; Tomás, Albert; Arilla, María; Coma, Joan; Aberasturi, Teresa; Sintes, Dolores; Lombán, Ester

    2013-09-01

    The aim of this study was to evaluate the effectiveness and safety of sublingual fentanyl oral disintegrating tablets (sublingual fentanyl ODT) for the treatment of breakthrough pain (BTP), cancer or non-cancer related, in terms of relief of pain intensity, adverse events (AEs) and patient satisfaction, and to further examine the clinical and epidemiological profile of patients with BTP in a clinical setting. A multicentre, prospective, open-label study was conducted in 19 pain units from Catalonia hospitals (Spain) over a 1-month period. Opioid-tolerant adult patients experiencing episodes of BTP intensity >5 on a visual analogue scale (VAS) during the 12-24 h before screening or AEs related to their previous rescue medication for BTP received sublingual fentanyl ODT in the course of routine clinical practice and completed a 30-day study period consisting of five assessment points: days 0 (baseline), 3, 7, 15 and 30. The efficacy was assessed by collecting pain intensity and pain relief data at baseline and at each assessment. AEs were recorded by investigators throughout the study during clinic visits and telephone follow-ups. For all patients, titration was begun with an initial dose of 100 μg. No more than two doses were allowed to treat an episode and patients might wait at least 4 h before treating another BTP episode with sublingual fentanyl ODT. The dose was increased by 100 μg multiples up to 400 μg as needed; and by 200 μg multiples up from 400 to 800 μg, the maximum titration step. A total of 182 patients were enrolled and 177 (97.2 %) completed the study: 37 had breakthrough cancer pain (BTcP) and 145 had breakthrough non-cancer pain (BTncP). The mean pain intensity showed a statistically significant improvement at the first assessment point and at all assessments thereafter (p < 0.0001). At the end of the study, the time lag between administration and first effect of sublingual fentanyl ODT was ≤10 min in 69.0 % (60 % BTcP and 71.2 % BTncP). The

  2. Nitroglycerin Sublingual

    Science.gov (United States)

    ... ergotamine (in Cafergot, in Migergot), and methylergonovine (Methergine) heparin; medications for high blood pressure, heart failure, or ... such as weekly pill minders and those for eye drops, creams, patches, and inhalers) are not child-resistant ...

  3. Pharmepéna-Psychonautics: Human intranasal, sublingual and oral pharmacology of 5-methoxy-N,N-dimethyl-tryptamine.

    Science.gov (United States)

    Ott, J

    2001-01-01

    Summarized are psychonautic bioassays (human self-experiments) of pharmepéna--crystalline 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT; O-Me-bufotenine), at times combined with crystalline beta-carbolines (harmaline or harmine). These substances were administered via intranasal, sublingual and oral routes, by way of pharmacological modeling of diverse South American shamanic inebriants (principally the snuffs epéna/nyakwana, prepared from barks of diverse species of Virola.) Intranasal, sublingual and oral psychoactivity of 5-MeO-DMT, and the 1967 Holmstedt-Lindgren hypothesis of the paricá-effect--intranasal potentiation of tryptamines by concomitant administration of monoamine-oxidase-inhibiting (MAOI) beta-carbolines from stems of Banisteriopsis caapi admixed with the snuffs--have been confirmed by some 17 psychonautic bioassays. Salient phytochemical and psychonautic literature is reviewed.

  4. 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

    2017-01-01

    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...

  5. 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

    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...... 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......: The risk-benefit ratio validates the use of 300 IR tablets in clinical practice in all of these patient subgroups, regardless of severity profile, sensitization status and presence of asthma....

  6. Sublingual immunotherapy with once-daily grass allergen tablets: a randomized controlled trial in seasonal allergic rhinoconjunctivitis.

    Science.gov (United States)

    Durham, Stephen R; Yang, William H; Pedersen, Martin R; Johansen, Niels; Rak, Sabina

    2006-04-01

    Specific immunotherapy is the only treatment modality that has the potential to alter the natural course of allergic diseases. Sublingual immunotherapy has been developed to facilitate access to this form of treatment and to minimize serious adverse events. To investigate the efficacy and safety of sublingual grass allergen tablets in seasonal allergic rhinoconjunctivitis. A multinational, multicenter, randomized, placebo-controlled trial conducted during 2002 and 2003. Fifty-five centers in 8 countries included 855 participants age 18 to 65 years who gave a history of grass pollen-induced allergic rhinoconjunctivitis and had a positive skin prick test and elevated serum allergen-specific IgE to Phleum pratense. Participants were randomized to 2500, 25,000, or 75,000 SQ-T grass allergen tablets (GRAZAX; ALK-Abelló, Hørsholm, Denmark) or placebo for sublingual administration once daily. Mean duration of treatment was 18 weeks. Average rhinoconjunctivitis scores during the season showed moderate reductions of symptoms (16%) and medication use (28%) for the grass allergen tablet 75,000 SQ-T (P = .0710; P = .0470) compared with placebo. Significantly better rhinoconjunctivitis quality of life scores (P = .006) and an increased number of well days (P = .041) were also observed. Efficacy was increased in the subgroup of patients who completed the recommended preseasonal treatment of at least 8 weeks before the grass pollen season (symptoms, 21%, P = .0020; and medication use, 29%, P = .0120). No safety concerns were observed. This study confirms dose-dependent efficacy of the grass allergen tablet. Although further studies are required, the greater tolerability of the tablet may permit immunotherapy to be available to a much broader group of patients with impaired quality of life caused by grass pollen allergy. For patients with grass pollen allergy, sublingual immunotherapy is well tolerated and can reduce symptoms and improve quality of life.

  7. Sublingual targeting of STING with 3'3'-cGAMP promotes systemic and mucosal immunity against anthrax toxins.

    Science.gov (United States)

    Martin, Tara L; Jee, Junbae; Kim, Eunsoo; Steiner, Haley E; Cormet-Boyaka, Estelle; Boyaka, Prosper N

    2017-04-25

    Anthrax is caused by Bacillus anthracis, a zoonotic bacterial pathogen affecting humans and livestock worldwide. The current human anthrax vaccine, anthrax vaccine adsorbed (AVA), is an injected vaccine with a cumbersome administration schedule and fails to promote mucosal immunity. Bacterial enterotoxins, which stimulate production of the cyclic nucleotide cAMP are effective experimental mucosal vaccine adjuvants, but their inherent toxicity has precluded their use in humans. We investigated whether cyclic dinucleotides that target Stimulator of Interferon Gamma Genes (STING) in mammalian cells could represent an alternative to bacterial enterotoxins as adjuvant for sublingual immunization and promotion of mucosal immunity and secretory IgA responses in addition to systemic immunity. We found that sublingual immunization of mice with Bacillus anthracis protective antigen (PA) and the STING ligand 3'3'-cGAMP promotes PA-specific serum IgG Ab responses of the same magnitude as those induced after immunization with PA and the experimental adjuvant cholera toxin (CT). Interestingly, this STING ligand also promoted serum anti-PA IgA and IgA-producing cells in the bone marrow. Furthermore, the saliva of mice immunized with the STING ligand exhibited similar levels of PA-specific IgA Abs as groups immunized with CT as adjuvant. The adjuvant activity of 3'3'-cGAMP was associated with mixed Th1, Th2, and Th17 responses. This STING ligand also induced rapid IFN-β and IL-10 responses in sublingual tissues and cervical lymph nodes, and TGF-β responses in the cervical lymph nodes, which could contribute to promoting IgA responses after sublingual immunization. Copyright © 2017 Elsevier Ltd. All rights reserved.

  8. A systematic review and economic evaluation of subcutaneous and sublingual allergen immunotherapy in adults and children with seasonal allergic rhinitis

    OpenAIRE

    Meadows, A.; Kaambwa, B.; Novielli, N.; Huissoon, A.; Fry-Smith, A; Meads, C; P. Barton; Dretzke, J

    2013-01-01

    © Queen’s Printer and Controller of HMSO 2013 Severe allergic rhinitis uncontrolled by conventional medication can substantially affect quality of life. Immunotherapy involves administering increasing doses of a specific allergen, with the aim of reducing sensitivity and symptomatic reactions. Recent meta-analyses have concluded that both subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT) are more effective than placebo in reducing symptoms. It is uncertain which route o...

  9. Clinical evaluation of sublingual administration of dust mite drops in the treatment of allergic asthma and allergic rhinitis of children.

    Science.gov (United States)

    Yin, G-Q; Jiang, W-H; Wu, P-Q; He, C-H; Chen, R-S; Deng, L

    2016-10-01

    This study focuses on evaluating the clinical effects of sublingual dust mite drops for the treatment of allergic asthma in children. 156 pediatric patients with allergic rhinitis and asthma were randomly divided into control and observation groups (78 cases each). For the control group the standard global initiative for asthma (GINA) asthma control scheme was adopted; meanwhile, the observation group patients received the standard GINA combined with sublingual administration of dust mite drops, once per day, gradually increasing the dose to reach a high maintenance level. After six months the sublingual drops were stopped and then the effects of the treatments on both groups of patients were compared. The symptoms of asthma and rhinitis in the daytime and nighttime for both groups decreased gradually with time. However, the observation group's outcome at the 6th, 12th and 24th month were significantly better than those of the control group (p 0.05). But at the 24th month, the observation group had significantly higher rates of complete and good control (p 0.05); however, the levels of IL-2 increased gradually and improved more in the observation group (p allergic rhinitis and asthma can improve clinical symptoms, increase the efficiency rate and increase the serum IL-2 level, and does not cause an increase in adverse reactions or IgE levels in treated children.

  10. Voriconazole more likely than posaconazole increases plasma exposure to sublingual buprenorphine causing a risk of a clinically important interaction.

    Science.gov (United States)

    Fihlman, Mari; Hemmilä, Tuija; Hagelberg, Nora M; Kuusniemi, Kristiina; Backman, Janne T; Laitila, Jouko; Laine, Kari; Neuvonen, Pertti J; Olkkola, Klaus T; Saari, Teijo I

    2016-11-01

    This study aimed to determine possible effects of voriconazole and posaconazole on the pharmacokinetics and pharmacological effects of sublingual buprenorphine. We used a randomized, placebo-controlled crossover study design with 12 healthy male volunteers. Subjects were given a dose of 0.4 mg (0.6 mg during placebo phase) sublingual buprenorphine after a 5-day oral pretreatment with either (i) placebo, (ii) voriconazole 400 mg twice daily on the first day and 200 mg twice daily thereafter or (iii) posaconazole 400 mg twice daily. Plasma and urine concentrations of buprenorphine and its primary active metabolite norbuprenorphine were monitored over 18 h and pharmacological effects were measured. Compared to placebo, voriconazole increased the mean area under the plasma concentration-time curve (AUC 0-∞ ) of buprenorphine 1.80-fold (90 % confidence interval 1.45-2.24; P Voriconazole, unlike posaconazole, increased the urinary excretion of norbuprenorphine 1.58-fold (90 % confidence interval 1.18-2.12; P Voriconazole, and to a minor extent posaconazole, increase plasma exposure to sublingual buprenorphine, probably via inhibition of cytochrome P450 3 A and/or P-glycoprotein. Care should be exercised in the combined use of buprenorphine with triazole antimycotics, particularly with voriconazole, because their interaction can be of clinical importance.

  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. 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.

  13. 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

    proteins, so called carboproteins. The hypothesis is that the template pre-organizes the secondary structure elements and directs the formation of a tertiary structure, thus achieving structural economy in the combination of peptide, linker, and template. We speculate that the structural information from...... 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...

  14. 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.

  15. mScarlet: a bright monomeric red fluorescent protein for cellular imaging.

    Science.gov (United States)

    Bindels, Daphne S; Haarbosch, Lindsay; van Weeren, Laura; Postma, Marten; Wiese, Katrin E; Mastop, Marieke; Aumonier, Sylvain; Gotthard, Guillaume; Royant, Antoine; Hink, Mark A; Gadella, Theodorus W J

    2017-01-01

    We report the engineering of mScarlet, a truly monomeric red fluorescent protein with record brightness, quantum yield (70%) and fluorescence lifetime (3.9 ns). We developed mScarlet starting with a consensus synthetic template and using improved spectroscopic screening techniques; mScarlet's crystal structure reveals a planar and rigidified chromophore. mScarlet outperforms existing red fluorescent proteins as a fusion tag, and it is especially useful as a Förster resonance energy transfer (FRET) acceptor in ratiometric imaging.

  16. Role of BAFF in pediatric patients with allergic rhinitis during sublingual immunotherapy.

    Science.gov (United States)

    Luo, Renzhong; Liu, Wenlong; Wang, Jie; Chen, Yanqiu; Sun, Changzhi; Zhou, Lifeng; Li, Yan; Deng, Li

    2014-08-01

    Sublingual immunotherapy (SLIT) is the only therapeutic option for allergic rhinitis (AR) that modifies the immunological process to an allergen, rather than treating symptoms simply. However, its regulatory mechanisms are largely unknown. B-cell-activating factor of the TNF family (BAFF) plays very important roles in the development, differentiation, and proliferation of B cells and T cells. The aim of this study was to identify the role of BAFF during SLIT in pediatric patients with AR. Seventy-two house dust mite (HDM)-sensitized pediatric patients with AR were enrolled in this study. Thirty-six pediatric patients received HDM allergen extract for SLIT and 36 pediatric patients received placebo. Serum and nasal aspirate of different time points during treatment was collected and used for enzyme-linked immunosorbent assay (ELISA) of BAFF and related cytokines, respectively. Peripheral blood mononuclear cells were collected and stimulated by HDM allergen with or without rhBAFF after 12 months of treatment. Our results showed that the expression of BAFF protein decreased during the SLIT treatment compared with that in the placebo group after 6 months of therapy, and this trend lasted for 12 months. The decreased BAFF expression was positively related to Th2 cytokines and increased IL-10 expression. BAFF was also related to local production of IgA. In vitro experiments showed that BAFF can promote Th2 cytokines and inhibit IL-10 expression by PBMCs. During SLIT, BAFF expression was decreased and related to low Th2 cytokine expression and enhanced IL-10 expression. Besides, BAFF may contribute to local production of IgA. Our results suggested that BAFF may be an important biomarker during SLIT. Authors' summary. Sublingual immunotherapy (SLIT) is the only therapeutic option for allergic rhinitis (AR) that modifies the immunological process to an allergen, rather than simply treating symptoms. However, its regulatory mechanisms are largely unknown. B

  17. 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

  18. From CO2 to dimethyl carbonate with dialkyldimethoxystannanes: the key role of monomeric species.

    Science.gov (United States)

    Kalhor, Mahboubeh Poor; Chermette, Henry; Chambrey, Stéphane; Ballivet-Tkatchenko, Danielle

    2011-02-14

    The formation of dimethyl carbonate (DMC) from CO(2) and methanol with the dimer [n-Bu(2)Sn(OCH(3))(2)](2) was investigated by experimental kinetics in support of DFT calculations. Under the reaction conditions (357-423 K, 10-20 MPa), identical initial rates are observed with three different reacting mixtures, CO(2)/toluene, supercritical CO(2), and CO(2)/methanol, and are consistent with the formation of monomeric di-n-butyltin(iv) species. An intramolecular mechanism is, therefore, proposed with an Arrhenius activation energy amounting to 104 ± 10 kJ mol(-1) for DMC synthesis. DFT calculations on the [(CH(3))(2)Sn(OCH(3))(2)](2)/CO(2) system show that the exothermic insertion of CO(2) into the Sn-OCH(3) bond occurs by a concerted Lewis acid-base interaction involving the tin center and the oxygen atom of the methoxy ligand. The Gibbs energy diagrams highlight that, under the reaction conditions, the dimer-monomer equilibrium is significantly shifted towards monomeric species, in agreement with the experimental kinetics. Importantly, the two Sn-OCH(3) bonds are prompt to insert CO(2). These results provide new insight into the reaction mechanism and catalyst design to enhance the turnover numbers.

  19. Dimeric and monomeric surfactants derived from sulfur-containing amino acids.

    Science.gov (United States)

    Faustino, Célia M C; Calado, António R T; Garcia-Rio, Luís

    2010-11-15

    Anionic urea-based dimeric (gemini) surfactants derived from the amino acids L-cystine, D-cystine and DL-cystine, as well as monomeric surfactants derived from L-cysteine, L-methionine and L-cysteic acid were synthesized and their solution properties characterized by electrical conductivity, equilibrium surface tension, and steady-state fluorescence spectroscopy techniques. The geminis studied showed the lowest critical micelle concentration (cmc) values, however the monomeric cysteine counterpart exhibited superior efficiency in lowering surface tension, an unusual finding that can be attributed to the free sulfhydryl group. Chirality seems to play a role in the surface active properties of the gemini surfactants, but not on micelle formation. All the surfactants studied showed a higher preference for adsorption at the air/water interface rather than to form micelles, a fact that may be related to the urea moiety. The polarity of the interfacial region, measured with the solvatochromic probe E(T)(30) (Reichardt's betaine dye), was similar to sodium dodecyl sulphate (SDS) micelles. Copyright © 2010 Elsevier Inc. All rights reserved.

  20. 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.

  1. Allosteric Partial Inhibition of Monomeric Proteases. Sulfated Coumarins Induce Regulation, not just Inhibition, of Thrombin

    Science.gov (United States)

    Verespy III, Stephen; Mehta, Akul Y.; Afosah, Daniel; Al-Horani, Rami A.; Desai, Umesh R.

    2016-01-01

    Allosteric partial inhibition of soluble, monomeric proteases can offer major regulatory advantages, but remains a concept on paper to date; although it has been routinely documented for receptors and oligomeric proteins. Thrombin, a key protease of the coagulation cascade, displays significant conformational plasticity, which presents an attractive opportunity to discover small molecule probes that induce sub-maximal allosteric inhibition. We synthesized a focused library of some 36 sulfated coumarins to discover two agents that display sub-maximal efficacy (~50%), high potency (thrombin (>150-fold). Michaelis-Menten, competitive inhibition, and site-directed mutagenesis studies identified exosite 2 as the site of binding for the most potent sulfated coumarin. Stern-Volmer quenching of active site-labeled fluorophore suggested that the allosteric regulators induce intermediate structural changes in the active site as compared to those that display ~80–100% efficacy. Antithrombin inactivation of thrombin was impaired in the presence of the sulfated coumarins suggesting that allosteric partial inhibition arises from catalytic dysfunction of the active site. Overall, sulfated coumarins represent first-in-class, sub-maximal inhibitors of thrombin. The probes establish the concept of allosteric partial inhibition of soluble, monomeric proteins. This concept may lead to a new class of anticoagulants that are completely devoid of bleeding. PMID:27053426

  2. 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.

  3. Decreased Levels of VAMP2 and Monomeric Alpha-Synuclein Correlate with Duration of Dementia.

    Science.gov (United States)

    Vallortigara, Julie; Whitfield, David; Quelch, William; Alghamdi, Amani; Howlett, David; Hortobágyi, Tibor; Johnson, Mary; Attems, Johannes; O'Brien, John T; Thomas, Alan; Ballard, Clive G; Aarsland, Dag; Francis, Paul T

    2016-01-01

    Alpha-synuclein (α-syn) aggregations are the key pathological hallmark of dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), but are also frequently present in Alzheimer's disease (AD). Much remains unknown about the role of α-syn in the synapse and the wider role of synaptic dysfunction in these dementias. Changes in concentrations of key 'SNAP (Soluble N-ethylmaleimide Sensitive Factor Attachment Protein) Receptor' (SNARE) proteins as a consequence of alterations in the aggregation state of α-syn may contribute to synaptic dysfunction in patients with DLB, PDD, and AD and result in impaired cognition. We have studied a large cohort (n = 130) of autopsy confirmed DLB, PDD, AD, and control brains. Using semi-quantitative western blotting, we have demonstrated significant changes across the diagnostic groups of DLB, PDD, and AD in the SNARE and vesicle proteins syntaxin, Munc18, VAMP2, and monomeric α-syn in the prefrontal cortex, with a significant reduction of Munc18 in AD patients (p score before death (p = 0.016). We also identified a significant negative correlation between the duration of dementia and the levels of the binding partners VAMP2 (p = 0.0004) and monomeric α-syn (p = 0.0002). Our findings may indicate that an upregulation of SNARE complex related proteins occurs in the early stages of disease as an attempt at compensating for failing synapses, prior to widespread deposition of pathological α-syn.

  4. Monomeric CXCL12 outperforms its dimeric and wild type variants in the promotion of human endothelial progenitor cells' function.

    Science.gov (United States)

    Chang, Shuang; Li, Yaning; Yuan, Fang; Qu, Meijie; Song, Yaying; Zhang, Zhijun; Yang, Guo-Yuan; Wang, Yongting

    2017-06-24

    CXCL12 overexpression improves neurobehavioral recovery during post-ischemic stroke through multiple mechanisms including promoting endothelial progenitor cells function in animal models. It has been proposed that the monomer and dimer forms possess differential chemotactic and regulatory function. The aim of present study is to explore whether a monomeric or dimeric CXCL12 plays a different role in the endothelial progenitor cells proliferation, migration, and tube-formation in vitro. In this study, we transferred monomeric, dimeric and wild type CXCL12 gene into endothelial progenitor cells via lentiviral vectors. We investigated endothelial progenitor cells function following the interaction of CXCL12/CXCR4 or CXCL12/CXCR7 and downstream signaling pathways. Our results showed that the monomeric CXCL12 transfected endothelial progenitor cells had enhanced ability in cell proliferation, migration, and tube-formation compared to that in dimeric or wild type controls (p function of migration, but not proliferation or tube-formation, was significantly reduced in the monomeric CXCL12 transfected endothelial progenitor cells when the cells were pre-treated with either CXCR4 inhibitor AMD3100 or siCXCR7 (p function was partially regulated by CXCL12/CXCR4 and CXCL12/CXCR7 signal pathways. Our study demonstrated that monomeric CXCL12 was the fundamental form, which played important roles in endothelial progenitor cells' proliferation, migration, and tube-formation. Copyright © 2017 Elsevier Inc. All rights reserved.

  5. Sublingual immunotherapy in asthma and rhinoconjunctivitis; systematic review of paediatric literature

    Science.gov (United States)

    Miceli, S; Macchiaiolo, M; Zorzi, G; Tripodi, S

    2004-01-01

    Aims: To evaluate the clinical efficacy of sublingual immunotherapy (SLIT) in respiratory allergy in children. Methods: A systematic literature review was conducted. The search was focused on all the double blind (and double dummy if necessary) studies. Search strategy: Medline, Embase, Cochrane Controlled Trial Register, Abstract of Cochrane Airways Group, hand search, and archives of some SLIT producers. All the selected studies were assessed and evaluated for quality in a standardised independent way. Results: Eight randomised, double blind, placebo controlled studies on SLIT were selected. Five studies were run with house dust mite (HDM), one with olive pollen, one with wall pellitory (Parietaria) pollen, and one with grass pollen. A quantitative evaluation of the studies was not possible because the outcomes and the results of single studies were presented according to different criteria. Therefore only qualitative analysis was performed. No clinically relevant results were shown, independently from statistical significance, in the use of SLIT for respiratory allergies due to seasonal allergens (olive, wall pellitory, and grass pollens) and, on the whole, for rhinoconjunctivitis due to HDM in children. For mild to moderate persistent asthma due to HDM, statistically significant and low to moderate relevant clinical effects were observed. Conclusions: SLIT can be currently considered to have low to moderate clinical efficacy in children of at least 4 years of age, monosensitised to HDM, and suffering from mild to moderate persistent asthma. This benefit seems to be adjunctive with respect to the environmental preventive measures against HDM. PMID:15210490

  6. The Proteomes of Human Parotid and Submandibular/Sublingual Gland Salivas Collected as the Ductal Secretions

    Science.gov (United States)

    Denny, Paul; Hagen, Fred K.; Hardt, Markus; Liao, Lujian; Yan, Weihong; Arellanno, Martha; Bassilian, Sara; Bedi, Gurrinder S.; Boontheung, Pinmannee; Cociorva, Daniel; Delahunty, Claire M.; Denny, Trish; Dunsmore, Jason; Faull, Kym F.; Gilligan, Joyce; Gonzalez-Begne, Mireya; Halgand, Frédéric; Hall, Steven C.; Han, Xuemei; Henson, Bradley; Hewel, Johannes; Hu, Shen; Jeffrey, Sherry; Jiang, Jiang; Loo, Joseph A.; Ogorzalek Loo, Rachel R.; Malamud, Daniel; Melvin, James E.; Miroshnychenko, Olga; Navazesh, Mahvash; Niles, Richard; Park, Sung Kyu; Prakobphol, Akraporn; Ramachandran, Prasanna; Richert, Megan; Robinson, Sarah; Sondej, Melissa; Souda, Puneet; Sullivan, Mark A.; Takashima, Jona; Than, Shawn; Wang, Jianghua; Whitelegge, Julian P.; Witkowska, H. Ewa; Wolinsky, Lawrence; Xie, Yongming; Xu, Tao; Yu, Weixia; Ytterberg, Jimmy; Wong, David T.; Yates, John R.; Fisher, Susan J.

    2009-01-01

    Saliva is a body fluid with important functions in oral and general health. A consortium of three research groups catalogued the proteins in human saliva collected as the ductal secretions: 1166 identifications—914 in parotid and 917 in submandibular/sublingual saliva—were made. The results showed that a high proportion of proteins that are found in plasma and/or tears are also present in saliva along with unique components. The proteins identified are involved in numerous molecular processes ranging from structural functions to enzymatic/catalytic activities. As expected, the majority mapped to the extracellular and secretory compartments. An immunoblot approach was used to validate the presence in saliva of a subset of the proteins identified by mass spectrometric approaches. These experiments focused on novel constituents and proteins for which the peptide evidence was relatively weak. Ultimately, information derived from the work reported here and related published studies can be used to translate blood-based clinical laboratory tests into a format that utilizes saliva. Additionally, a catalogue of the salivary proteome of healthy individuals allows future analyses of salivary samples from individuals with oral and systemic diseases, with the goal of identifying biomarkers with diagnostic and/or prognostic value for these conditions; another possibility is the discovery of therapeutic targets. PMID:18361515

  7. Innovations and Challenges by Applying Sublingual Laser Blood Irradiation in Juvenile Idiopathic Arthritis

    Directory of Open Access Journals (Sweden)

    Laura Marinela Ailioaie

    2014-01-01

    Full Text Available Sublingual laser blood irradiation (SLBI was applied into a randomized, single-blind, placebo-controlled study in juvenile idiopathic arthritis (JIA, aimed at inducing disease remission. 105 children with JIA, without an adequate response to classical treatment, were administrated a disease modifying drug (Methotrexate and were randomly assigned to three groups. Group I (36 patients received SLBI with the Weberneedle Lasershower Mouth Applicator with three wavelengths (635 nm, 536 nm, and 405 nm, 5 mW maximum output power each, in continuous mode, simultaneously, for 20 minutes daily, 7 successive sessions per month, repeated every 7 weeks, for three times. Group II (36 patients received placebo SLBI. Group III (33 patients received only treatment with Methotrexate. Evaluation was performed using American College of Rheumatology Pediatric criteria (ACR Pedi at study enrollment and at 8, 16, 24, and 48 weeks. At the end of study, there was an improvement of the ACR Pedi 30 by 86.11% in SLBI group compared to only 61.11% in Group II, respectively, and 60.6% in Group III (P=0.001, with significant statistical differences. SLBI has reduced the pain, lowered the number of articulations with movement limitation, increased the quality of life, and made it possible to avoid the administration of biological agents.

  8. Sublingual immunotherapy for house dust mite allergy in Southeast Asian children.

    Science.gov (United States)

    Lee, Melissa; Lee, Bee Wah; Vichyanond, Pakit; Wang, Jiu-Yao; Bever, Hugo Van

    2013-09-01

    To determine the use and efficacy of sublingual immunotherapy (SLIT) for house dust mite (HDM) allergies in Southeast Asian children. Aliterature search was performed in Pubmed and the Asian Pacific Journal of Allergy and Immunology. We also evaluated the literature for similar studies performed in Asia. Clinical trials involving children that assess SLIT for HDM allergies in Southeast Asia and Asia. There are no published studies on the use of SLIT for HD Mallergies in Southeast Asian children. However, there are seven studies from Asia which show that there are discrepancies over the benefits of SLIT for HDM allergies in Asian children. Limitations in these studies include small sample sizes and short study periods. We cannot say with certainty what the impact of SLIT is on HDM allergies in Southeast Asian children due to the lack of data. The available studies performed in Asia have their limitations but are suggestive of the potential of SLIT for HDM allergies in Southeast Asian children. This review highlights that good quality clinical research in this area in the Southeast Asian setting is warranted.

  9. The use of sublingual fentanyl for breakthrough pain by using doses proportional to opioid basal regimen.

    Science.gov (United States)

    Mercadante, Sebastiano; Prestia, Giovanna; Casuccio, Alessandra

    2013-11-01

    The aim of this study was to prospectively assess the efficacy and safety of sublingual fentanyl (SLF) in doses proportional to opioid doses used for background analgesia for the treatment of BTP of cancer patients. A sample of patients admitted to an acute palliative care unit, presenting breakthrough pain (BTP) episodes and receiving stable doses of opioids for background pain was selected to assess the efficacy and safety of SLF used in doses proportional to the basal opioid regimen used for the management of BTP. For each patient, data from four consecutive episodes were collected. For each episode, nurses collected changes in pain intensity and adverse effects when pain got severe (T0), and 5, 10, and 15 minutes after SLF was given (T15). Seventy patients were recruited for the study. The mean age was 61.7 (±11.5). Forty-one patients were males. A total of 173 episodes of BTP were recorded (mean 2.5 episodes/patient). In 19 events, documentation regarding changes in pain intensity was incomplete. Of the 154 evaluable episodes, 143 were successfully treated (92%). Mean doses of SLF were 637 µg (SD 786), and 51 patients (72.8%) received SLF doses ≥800 µg. When compared to younger adult patients, older patients received significantly lower doses of SLF (p opioid regimen. Pain intensity significantly decreased at T5, 10 and T15 (p opioid regimen for the management of BTP is safe and effective in clinical practice.

  10. Sublingual-oral rush desensitization to mixed cow and sheep milk: a case report.

    Science.gov (United States)

    Nucera, E; Schiavino, D; Buonomo, A; Pollastrini, E; Altomonte, G; Pecora, V; Decinti, M; Lombardo, C; Patriarca, G

    2008-01-01

    We attempted an oral rush desensitization with mixed cow and sheep milk in a 6-year-old boy who had had adverse reactions to cow and goat milks. Skin prick tests and specific immunoglobulin (Ig) E to cow, sheep and goat milks were positive. The double-blind, placebo-controlled food challenge with cow milk was positive too. He underwent a 12-day sublingual-oral desensitization treatment with mixed cow and sheep milk. Specific IgE and IgG4 were measured. Open oral challenges with cow milk, sheep milk and sheep cheeses were also performed after the desensitization. At the end of the desensitizing treatment our patient could tolerate 120 mL of mixed milk. Specific IgE levels did not vary, whereas an increase of specific IgG4 concentrations was observed. Open oral challenges with cow and sheep milks and sheep cheeses were negative. Oral rush desensitization may represent an alternative approach to the treatment of food allergy in children.

  11. Ranking in importance of allergen extract characteristics for sublingual immunotherapy by Italian specialists.

    Science.gov (United States)

    Canonica, Giorgio Walter; Passalacqua, Giovanni; Incorvaia, Cristoforo; Cadario, Gianni; Fiocchi, Alessandro; Senna, Gianenrico; Rossi, Oliviero; Romano, Antonino; Scala, Enrico; Romano, Catello; Ingrassia, Antonino; Zambito, Marcello; Dell'Albani, Ilaria; Frati, Franco

    2014-01-01

    The efficacy of allergen immunotherapy (AIT) is well supported by evidence from trials and meta-analyses. However, its actual performance in daily practice may be diminished by several pitfalls, including inappropriate patient selection, and, especially, the use of allergen extracts of insufficient quality. We performed a survey, the Allergen Immunotherapy Decision Analysis, to evaluate which criteria specialists use to choose products for sublingual immunotherapy (SLIT) in adult patients suffering from allergic respiratory disease. We surveyed a total of 169 Italian allergists randomly chosen from a database belonging to a market research company (Lexis Ricerche, Milan, Italy). The survey was performed between October and November 2012 under the aegis of the European Center for Allergy Research Foundation and consisted of a questionnaire-based electronic survey prepared by a scientific board of 12 AIT experts. The questionnaire comprised two parts, the first of which contained 14 items to be ranked by each participant according to the importance assigned to each when choosing SLIT products. The physicians' rankings assigned major importance to the level of evidence-based validation of efficacy and safety, standardization of the product, efficacy based on personal experience, and defined content(s) of the major allergen(s) in micrograms. The results of this survey show that Italian allergists rank the quality-related characteristics of allergen extracts as highly important when choosing products for AIT. The allergists' preference for high-quality products should be addressed by regulatory agencies and by producers.

  12. New developments in the management of opioid dependence: focus on sublingual buprenorphine–naloxone

    Directory of Open Access Journals (Sweden)

    Soyka M

    2015-01-01

    Full Text Available Michael Soyka1,21Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-Universität, Munich, Germany; 2Private Hospital Meiringen, Meiringen, SwitzerlandAbstract: Opioid maintenance therapy is a well-established first-line treatment approach in opioid dependence. Buprenorphine, a partial opioid agonist, has been found by numerous studies to be an effective and safe medication in the treatment of opioid dependence. At present, buprenorphine is available as a monodrug or in a fixed 4:1 ratio combination with naloxone. A diminished risk of diversion and abuse for the buprenorphine–naloxone combination is likely but not firmly established. Conventional formulations are given sublingually to avoid the hepatic first-pass effect. A novel film tablet is available only in the US and Australia. Other novel, sustained-release formulations (implant, depot are currently being developed and tested. Recent studies, including a Cochrane meta-analysis, suggest that the retention with buprenorphine is lower than for methadone, but that buprenorphine may be associated with less drug use. Higher doses of buprenorphine are associated with better retention rates. Buprenorphine has a ceiling effect at the opioid receptor with regard to respiratory depression, and may cause fewer fatal intoxications than methadone. Possible antidepressant effects of buprenorphine and its use in comorbid psychiatric patients has not been studied in much detail. Clinical implications are discussed.Keywords: buprenorphine, methadone, naloxone, opioids, opioid dependence, therapy

  13. [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.

  14. 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.

  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. Sublingual grass pollen immunotherapy is associated with increases in sublingual Foxp3-expressing cells and elevated allergen-specific immunoglobulin G4, immunoglobulin A and serum inhibitory activity for immunoglobulin E-facilitated allergen binding to B cells.

    Science.gov (United States)

    Scadding, G W; Shamji, M H; Jacobson, M R; Lee, D I; Wilson, D; Lima, M T; Pitkin, L; Pilette, C; Nouri-Aria, K; Durham, S R

    2010-04-01

    The mechanisms of sublingual immunotherapy (SLIT) are less well understood than those of subcutaneous immunotherapy (SCIT). To determine the effects of grass-pollen SLIT on oral mucosal immune cells, local regulatory cytokines, serum allergen-specific antibody subclasses and B cell IgE-facilitated allergen binding (IgE-FAB). Biopsies from the sublingual mucosa of up to 14 SLIT-treated atopics, nine placebo-treated atopics and eight normal controls were examined for myeloid dendritic cells (mDCs) (CD1c), plasmacytoid dendritic cells (CD303), mast cells (AA1), T cells (CD3) and Foxp3 using immunofluorescence microscopy. IL-10 and TGF-beta mRNA expression were identified by in situ hybridization. Allergen-specific IgG and IgA subclasses and serum inhibitory activity for binding of allergen-IgE complexes to B cells (IgE-FAB) were measured before, during and on the completion of SLIT. Foxp3(+) cells were increased in the oral epithelium of SLIT- vs. placebo-treated atopics (P=0.04). Greater numbers of subepithelial mDCs were present in placebo-treated, but not in SLIT-treated, atopics compared with normal controls (P=0.05). There were fewer subepithelial mast cells and greater epithelial T cells in SLIT- compared with placebo-treated atopics (P=0.1 for both). IgG(1) and IgG(4) were increased following SLIT (Ppollen extract is associated with increased Foxp3(+) cells in the sublingual epithelium and systemic humoral changes as observed previously for SCIT.

  17. α-SNAP Prevents Docking of the Acrosome during Sperm Exocytosis because It Sequesters Monomeric Syntaxin

    Science.gov (United States)

    Rodríguez, Facundo; Bustos, Matías A.; Zanetti, María N.; Ruete, María C.; Mayorga, Luis S.; Tomes, Claudia N.

    2011-01-01

    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 complexes is

  18. Confocal laser scanning microscopic analysis of ectopic sublingual gland-like tissue inside the hamster submandibular gland.

    Science.gov (United States)

    Moriguchi, Keiichi; Utsumi, Michiya; Ohno, Norikazu

    2013-12-01

    Based on its histochemical properties, the secretory portion of the hamster submandibular gland has been classified as seromucous cells. The presence of endogenous peroxidase (PO) reaction was shown in the nuclear envelope, cisternae of endoplasmic reticulum and Golgi apparatus. The 3,3'-diaminobenzidene, tetrahydrochloride (DAB) method revealed bipartite secretory granules containing a PO-positive dense core surrounded by a less dense halo in these cells. In the present investigation, serous and mucous-like cells were found in resin-embedded semi-thin sections of the DAB-reacted hamster submandibular gland. These sections were already on glass slides for routine light microscopic observations, therefore electron microscopic analysis could be unrealizable. We then used reflectance-mode confocal laser scanning microscopy to visualize additional sites of PO activity as detected in these sections. Using this approach, we found mucous cells with PO activity-negative secretory granules and seromucous cells with PO activity-positive spot-like secretory granules of the regular sublingual gland most frequently adjacent to the serous cells with typical electron-dense secretory granules. These cells clearly differ from the seromucous cells with bipartite secretory granules and the granular duct cells with typical electron-dense secretory granules of the hamster submandibular gland. Additionally, secretory endpieces of the ectopic sublingual gland-like tissue empty into the duct of the hamster submandibular gland lobule. Thus, our findings suggest that a mass of sublingual gland tissue extends into the hamster submandibular gland during its development, and PO may be synthesized and secreted into the same duct. Copyright © 2013 Wiley Periodicals, Inc.

  19. Fast Dissolving Sublingual Films Containing Sumatriptan Alone and Combined with Methoclopramide: Evaluation in Vitro Drug Release and Mucosal Permeation

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    Maryam Maghsoodi, Mahdieh Rahmani, Hamed Ghavimi, Seyed Hassan Montazam, Saieede Soltani, Mitra Alami, Sara Salatin, Mitra Jelvehgari

    2016-10-01

    Full Text Available ackground: Sumatriptan succinate is a 5-HT1 receptor agonist which is used in the treatment of migraine. It shows low bioavailability (15% due to high hepatic first pass metabolism. The present work intended to formulate mucoadhesive sublingual films of sumatriptan combined with metoclopramide and sumatriptan alone with the objective of improving the therapeutic efficacy, patient compliance, and bioavailability. Methods: The sublingual films were formulated by solvent casting technique using mucoadhesive polymer of hydroxypropyl methylcellulose and propylene glycol as plasticizers. This study was also designed to evaluate the physicochemical and mucoadhesive characteristics of the films. The films were evaluated for their mechanical strength, folding endurance, drug content uniformity, swelling, in vitro residence time, in vitro release, in vitro bioadhesion, and in vivo mucoadhesion. Results: They showed good appearance and elasticity. The best drugs of polymer ratio were S3 (1:2 and SM2 (2.7:1:8. The film of S3 and SM2 showed 10.6 and 11.01 mg weight, 2.2 and 22.5 µm thickness, 300 folding endurance, 55.9 and 100% content uniformity, respectively. The Differential Scanning Calorimetry (DSC showed no stable sample of sumatriptan and metoclopramide in the drug loaded films and revealed amorphous form and transition of hydrate to anhydrous form for metoclopramide. The results showed that the films prepared were fast dissolving. The films (sumatriptan combined with metoclopramide and sumatriptan alone exhibited very good mucoadhesive properties and shorter retention time (15-30 s. Conclusion: The formulations were found to be suitable candidates for the development of sublingual films for therapeutic uses.

  20. Crushed sublingual versus oral ticagrelor administration strategies in patients with unstable angina. A pharmacokinetic/pharmacodynamic study.

    Science.gov (United States)

    Niezgoda, Piotr; Sikora, Joanna; Barańska, Malwina; Sikora, Adam; Buszko, Katarzyna; Siemińska, Emilia; Marszałł, Michał Piotr; Siller-Matula, Jolanta M; Jilma, Bernd; Alexopoulos, Dimitrios; Fabiszak, Tomasz; Kubica, Jacek

    2017-04-03

    Oral administration of crushed ticagrelor tablets turned out to be an efficacious method that improves its pharmacokinetics and pharmacodynamics. This strategy, however, is unlikely to eliminate the drug-drug interaction in patients receiving intravenous morphine, as the impairment of the P2Y12 inhibitor absorption related to decreased propulsive motility of the gastro-intestinal tract is the most likely mechanism of interaction. Thus, we designed a pharmacokinetic and pharmacodynamic study setting the feasibility of platelet inhibition with a loading dose of ticagrelor given as crushed tablets sublingually compared with two other ticagrelor loading dose administration strategies: integral tablet given orally and crushed tablet given orally in patients with unstable angina. Ticagrelor and its metabolite AR-C124900XX plasma concentration was evaluated in nine time points (time frame of 6 hours) using liquid chromatography coupled with mass spectrometry; platelet reactivity was evaluated using multiple electrode aggregometry. The area under the plasma concentration-time curve for ticagrelor and AR-C124900XX was significantly higher in patients treated with crushed tablets given orally compared with crushed tablets given sublingually only within the first hour after loading dose (936.9 ± 898.0 vs 368.0 ± 422.4, p=0.042 and 103.4 ± 120.8 vs 31.3 ± 43.9, p=0.031, respectively). Moreover, we showed significantly stronger platelet inhibition in patients receiving crushed ticagrelor orally vs. sublingually at 30 and 45 min after the loading dose (p=0.024 and p=0.016, respectively). Therefore, the administration strategy of ticagrelor determines the pharmacokinetic and pharmacodynamic profile of both ticagrelor and its active metabolite AR-C124900XX.

  1. Sublingual vitamin B12 compared to intramuscular injection in patients with type 2 diabetes treated with metformin: a randomised trial.

    Science.gov (United States)

    Parry-Strong, Amber; Langdana, Fali; Haeusler, Sylvan; Weatherall, Mark; Krebs, Jeremy

    2016-06-10

    MAIM: To compare a single 1mg intramuscular hydroxocobalamin injection with a 3-month course of 1mg/day sublingual methylcobalamin supplements on serum vitamin B12 concentrations in participants withtype 2 diabetes treated with metformin. Participants on metformin treatment with vitamin B12 concentrations below 220pmol/L were recruited through hospital diabetes clinics and primary care practices. They were randomised to receive either the injection or sublingual treatment. The primary outcome was serum vitamin B12 level after 3 months adjusted for baseline assessed by analysis of covariance (ANCOVA). The trial was registered on the Australia New Zealand Clinical Trial registry (ACTRN12612001108808). A total of 34 participants were randomised; 19 to the tablet, and 15 to the injection. The mean (SD) age, duration of diabetes, and duration of metformin use were, 64.2 (7.3) years, 13.7 (6.4) years, and 11.6 (5.0) years, respectively. After 3 months, the mean (SD) vitamin B12 was 372.1 (103.3) pmol/L in the tablet group (n=19) compared to 251.7 (106.8) pmol/L in the injection group (n=15), ANCOVA estimated difference -119.4 (95% CI -191.2 to -47.6), p=0.002. After 6 months, the mean (SD) serum B12 was 258.8 (58.7) pmol/L in the tablet group (n=17) and 241.9 (40.1) pmol/L in the injection group (n=15); ANCOVA estimated difference -15.2 (95% CI -50.3 to 19.8), p=0.38. Higher metformin dose was associated with lower serum B12 at 3 months, but not at baseline or 6 months. Decreased serum vitamin B12 level in patients with type 2 diabetes who are treated with metformin can be corrected through treatment with either hydroxocobalamin injections or methylcobalamin sublingual supplements.

  2. 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

    2017-07-06

    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.

  3. 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

    We report the discovery of a new monomeric peptide that reduces body weight and diabetic complications in rodent models of obesity by acting as an agonist at three key metabolically-related peptide hormone receptors: glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP...... demonstrate that these individual constituent activities harmonize to govern the overall metabolic efficacy, which predominantly results from synergistic glucagon action to increase energy expenditure, GLP-1 action to reduce caloric intake and improve glucose control, and GIP action to potentiate the incretin...... effect and buffer against the diabetogenic effect of inherent glucagon activity. These preclinical studies suggest that, so far, this unimolecular, polypharmaceutical strategy has potential to be the most effective pharmacological approach to reversing obesity and related metabolic disorders....

  4. Polyhydroxylated [60]fullerene binds specifically to functional recognition sites on a monomeric and a dimeric ubiquitin

    Science.gov (United States)

    Zanzoni, Serena; Ceccon, Alberto; Assfalg, Michael; Singh, Rajesh K.; Fushman, David; D'Onofrio, Mariapina

    2015-04-01

    The use of nanoparticles (NPs) in biomedical applications requires an in-depth understanding of the mechanisms by which NPs interact with biomolecules. NPs associating with proteins may interfere with protein-protein interactions and affect cellular communication pathways, however the impact of NPs on biomolecular recognition remains poorly characterized. In this respect, particularly relevant is the study of NP-induced functional perturbations of proteins implicated in the regulation of key biochemical pathways. Ubiquitin (Ub) is a prototypical protein post-translational modifier playing a central role in numerous essential biological processes. To contribute to the understanding of the interactions between this universally distributed biomacromolecule and NPs, we investigated the adsorption of polyhydroxylated [60]fullerene on monomeric Ub and on a minimal polyubiquitin chain in vitro at atomic resolution. Site-resolved chemical shift and intensity perturbations of Ub's NMR signals, together with 15N spin relaxation rate changes, exchange saturation transfer effects, and fluorescence quenching data were consistent with the reversible formation of soluble aggregates incorporating fullerenol clusters. The specific interaction epitopes were identified, coincident with functional recognition sites in a monomeric and lysine48-linked dimeric Ub. Fullerenol appeared to target the open state of the dynamic structure of a dimeric Ub according to a conformational selection mechanism. Importantly, the protein-NP association prevented the enzyme-catalyzed synthesis of polyubiquitin chains. Our findings provide an experiment-based insight into protein/fullerenol recognition, with implications in functional biomolecular communication, including regulatory protein turnover, and for the opportunity of therapeutic intervention in Ub-dependent cellular pathways.The use of nanoparticles (NPs) in biomedical applications requires an in-depth understanding of the mechanisms by which

  5. Soy polysaccharide as a novel superdisintegrant in sildenafil citrate sublingual tablets: preparation, characterization, and in vivo evaluation

    Directory of Open Access Journals (Sweden)

    Hosny KM

    2015-01-01

    Full Text Available Khaled Mohamed Hosny,1,2 Hisham Ahmed Mosli,3 Ali Habiballah Hassan4 1Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia; 2Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Beni Suef University, Beni Suef, Egypt; 3Department of Urology, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia; 4Department of Orthodontics, Faculty of Dentistry, King Abdulaziz University, Jeddah, Saudi Arabia Abstract: Sildenafil citrate (SC, a drug used to treat erectile dysfunction, is available in tablet form but has three major problems. First, the drug displays inadequate aqueous solubility, which delays the onset of its action. Second, the drug undergoes extensive first-pass metabolism, resulting in a low (40% bioavailability. Third, the gastrointestinal effects of SC include dyspepsia and a burning sensation. The aim of this research was to prepare SC as a sublingual tablet utilizing soy polysaccharide as novel superdisintegrant to mitigate the abovementioned problems. The solubility of SC in various hydrophilic carrier solutions was estimated in order to prepare the drug as a coprecipitate. Sublingual tablets were prepared and evaluated for hardness, friability, drug content, wetting time, water absorption ratio, in vitro dispersion time, dissolution rate, and stability study. The pharmacokinetic study of the tablets was carried out on healthy volunteers. The results indicated that the co-precipitation of SC with polyvinylpyrollidone K30 enhanced the solubility of SC by more than eight folds. The tablet contained 8% soy polysaccharide as a superdisintegrant and provided a wetting time of 25 seconds, and in vitro dispersion times of 55 seconds. The drug release was found to be 95.6%. The prepared SC sublingual tablet also exhibited a rapid onset of action, and its bioavailability was enhanced 1.68-fold compared with that of the marketed tablets. It

  6. Induction of labour in term premature rupture of membranes; oxytocin versus sublingual misoprostol; a randomised clinical trial.

    Science.gov (United States)

    Pouralil, Leila; Saghafi, Nafiseh; Eslami Hasan Abadi, Saeed; Tara, Fatemeh; Vatanchi, Atieh Mohamadzadeh; Motamedi, Elham

    2017-08-08

    Premature rupture of the membranes (PROM) occurs in about 8-10% of pregnancies and its most important complication is chorioamnionitis, so labour induction has an important role in this situation. This study was performed to compare oxytocin and sublingual Misoprostol for labour induction in PROM cases with term pregnancy. A total of 270 pregnant women who had spontaneous rupture of membrane and unripe cervix were enrolled. The first group underwent Oxytocin infusion according to low-dose standard protocol and the second group received 25 μg sublingual Misoprostol every 4 h. Time interval from induction to the beginning of active phase of labour was similar in both groups. Second stage of labour was significantly shorter in misoprostol group (p induction in PROM cases. Impact statement What is already known on this subject: PROM occurs in about 8-10% of pregnancies; about 60% of these cases are term pregnancies. Most experts recommend early induction of labour in term PROM cases with an eye towards avoiding increased morbidity and mortality. Oxytocin is the most frequently used agent that is administered intravenously for the purpose of labour induction. Misoprostol is an alternative to oxytocin and is simpler to use, as it is administered via the oral, buccal, sublingual, rectal and vaginal routes rather than intravenously. What do the results of this study add: Time interval from induction to the beginning of active phase of labour was similar in both groups. Second stage of labour was significantly shorter in the misoprostol group. Although, some maternal side-effects were significantly higher in misoprostol group, the 5 minute Apgar score was significantly better in this group. What are the implications of these finding for clinical practice and/or further research: Sublingual misoprostol for induction of labour in PROM cases is more effective than oxytocin and its neonatal outcomes are better. Due to its easy prescription and better labour outcomes

  7. 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

  8. Pharmacokinetics of a novel sublingual spray formulation of the antimalarial drug artemether in African children with malaria.

    Science.gov (United States)

    Salman, Sam; Bendel, Daryl; Lee, Toong C; Templeton, David; Davis, Timothy M E

    2015-01-01

    The pharmacokinetics of sublingual artemether (ArTiMist) was investigated in 91 young African children with severe malaria or who could not tolerate oral antimalarial therapy. Each received 3.0 mg/kg of body weight of artemether at 0, 8, 24, 36, 48, and 60 h or until the initiation of oral treatment. Few blood samples were drawn postdose. Plasma artemether and dihydroartemisinin (DHA) levels were measured using liquid chromatography-mass spectrometry, and the data were analyzed using established population compartmental pharmacokinetic models. Parasite clearance was prompt (median parasite clearance time, 24 h), and there were no serious adverse events. Consistent with studies in healthy adults (S. Salman, D. Bendel, T. C. Lee, D. Templeton, and T. M. E. Davis, Antimicrob Agents Chemother 59:3197-3207, 2015, http://dx.doi.org/10.1128/AAC.05013-14), the absorption of sublingual artemether was biphasic, and multiple dosing was associated with the autoinduction of the metabolism of artemether to DHA (which itself has potent antimalarial activity). In contrast to studies using healthy volunteers, pharmacokinetic modeling indicated that the first absorption phase did not avoid first-pass metabolism, suggesting that the drug is transferred to the upper intestine through postdose fluid/food intake. Simulations using the present data and those from an earlier study in older Melanesian children with uncomplicated malaria treated with artemether-lumefantrine tablets suggested that the bioavailability of sublingual artemether was at least equivalent to that after conventional oral artemether-lumefantrine (median [interquartile range] areas under the concentration-time curve for artemether, 3,403 [2,471 to 4,771] versus 3,063 [2,358 to 4,514] μg · h/liter, respectively; and for DHA, 2,958 [2,146 to 4,278] versus 2,839 [1,812 to 3,488] μg · h/liter, respectively; P ≥ 0.42). These findings suggest that sublingual artemether could be used as prereferral treatment for sick

  9. Sublingual immunization with adenovirus F protein-based vaccines stimulates protective immunity against botulinum neurotoxin A intoxication

    OpenAIRE

    Jun, SangMu; Clapp, Beata; Zlotkowska, Dagmara; Hoyt, Teri; Holderness, Kathryn; Maddaloni, Massimo; Pascual, David W.

    2011-01-01

    Sublingual (s.l.) vaccination is an efficient way to induce elevated levels of systemic and mucosal immune responses. To mediate mucosal uptake, ovalbumin (OVA) was genetically fused to adenovirus 2 fiber protein (OVA-Ad2F) to assess whether s.l. immunization was as effective as an alternative route of vaccination. Ad2F-delivered vaccines were efficiently taken up by dendritic cells and migrated mostly to submaxillary gland lymph nodes, which could readily stimulate OVA-specific CD4+ T cells....

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

    Directory of Open Access Journals (Sweden)

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

    Science.gov (United States)

    Herr, Uta-Mareike; Strecker, Paul; Storck, Steffen E.; Thomas, Carolin; Rabiej, Verena; Junker, Anne; Schilling, Sandra; Schmidt, Nadine; Dowds, C. Marie; Eggert, Simone; Pietrzik, Claus U.; Kins, Stefan

    2017-01-01

    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. PMID:28496400

  12. Clinical evaluation for sublingual immunotherapy with Dermatophagoides farinae drops in adult patients with allergic asthma.

    Science.gov (United States)

    Zhong, C; Yang, W; Li, Y; Zou, L; Deng, Z; Liu, M; Huang, X

    2017-10-14

    The efficacy and safety of sublingual immunotherapy (SLIT) in house dust mite-induced allergic asthma (AA) have yet to be firmly established, especially in adult patients. Our objective is to evaluate the efficacy of SLIT with Dermatophagoides farinae drops in adult patients with AA. One hundred and thirty-four adult patient data with house dust mite (HDM)-induced AA who had been treated for 2 years were collected. These patient data that we collected were divided into the SLIT group (n = 85) and control group (n = 49). All patients were treated with low to moderate dose of inhaled glucocorticoid and long-acting β2 agonists. Patients in the SLIT group were further treated with D. farinae drops. Clinical scores including the total asthma symptom score (TASS), total asthma medicine score (TAMS), asthma control test (ACT), and peak flow percentage (PEF%) were assessed before treatment and at yearly visits. The presence of adverse events (AEs) were recorded once a month. Before treatment, the PEF% in the SLIT group was significantly lower than that in the control group (p < 0.05). After 2 years, both treatments were effective in the clinical scores when compared with baseline values (all p < 0.001). Meanwhile, the SLIT group showed significantly lower TASS and TAMS (all p < 0.001) and higher ACT (p < 0.001) and PEF% (p < 0.05) when compared with the control group. No severe systemic AEs were reported. SLIT with D. farinae drops plus pharmacotherapy is more effective than routine drug treatment in adult patients with AA.

  13. The efficacy of sublingual immunotherapy with Dermatophagoides farinae vaccine in a murine atopic dermatitis model.

    Science.gov (United States)

    Liu, L; Guo, D; Liang, Q; Ding, S; Wu, B; Zhang, L; Li, Q

    2015-04-01

    Sublingual immunotherapy (SLIT) is a potential treatment for house dust mite-induced atopic dermatitis (AD). However, the mechanisms of action are not clear. To establish a mouse model of AD in order to study the effect and mechanisms of SLIT. Mice were sensitized and subsequently challenged by repeated cutaneous application of Der f allergen extract. Sensitized mice were SLIT-treated with a Der f vaccine and analyzed for AD symptoms, histopathological and immunological parameters. This experiment was carried in the Laboratory Animal Center, Shanghai University of TCM. Repeated application of Der f extract caused rapid increase in dermatitis scores. Clinical findings (scratching behaviour, dermatitis and oedema) and histological symptoms (inflammatory cell infiltration) in this model were very similar to those in human AD. Serum total and Der f-specific IgE and IgG levels, and the expression level of T helper (Th)2 cytokine IL-5, IL-13; and Th1 cytokine IL-12 and IFN-γ were elevated compared with the control mice. SLIT treatment of sensitized mice markedly reduced the clinical and histopathological symptoms and decreased both Th1 and Th2 cytokine levels. The mouse model induced by Der f allergen extract reflected the typical hallmarks of human AD. In the Der f allergens-sensitized mice, SLIT treatment with Der f vaccine was shown to significantly inhibit AD symptoms through correction of Th2 and Th1 cytokine predominance. Our study suggested that SLIT could be considered as an attractive treatment for patients with extrinsic AD. © 2014 John Wiley & Sons Ltd.

  14. 3D printing of rat salivary glands: The submandibular-sublingual complex.

    Science.gov (United States)

    Cecchini, M P; Parnigotto, M; Merigo, F; Marzola, P; Daducci, A; Tambalo, S; Boschi, F; Colombo, L; Sbarbati, A

    2014-06-01

    The morphology and the functionality of the murid glandular complex, composed of the submandibular and sublingual salivary glands (SSC), were the object of several studies conducted mainly using magnetic resonance imaging (MRI). Using a 4.7 T scanner and a manganese-based contrast agent, we improved the signal-to-noise ratio of the SSC relating to the surrounding anatomical structures allowing to obtain high-contrast 3D images of the SSC. In the last few years, the large development in resin melting techniques opened the way for printing 3D objects starting from a 3D stack of images. Here, we demonstrate the feasibility of the 3D printing technique of soft tissues such as the SSC in the rat with the aim to improve the visualization of the organs. This approach is useful to preserve the real in vivo morphology of the SCC in living animals avoiding the anatomical shape changes due to the lack of relationships with the surrounding organs in case of extraction. It is also harmless, repeatable and can be applied to explore volumetric changes occurring during body growth, excretory duct obstruction, tumorigenesis and regeneration processes. 3D printing allows to obtain a solid object with the same shape of the organ of interest, which can be observed, freely rotated and manipulated. To increase the visibility of the details, it is possible to print the organs with a selected zoom factor, useful as in case of tiny organs in small mammalia. An immediate application of this technique is represented by educational classes. © 2013 Blackwell Verlag GmbH.

  15. Safety of ragweed sublingual allergy immunotherapy tablets in adults with allergic rhinoconjunctivitis.

    Science.gov (United States)

    Nayak, Anjuli S; Atiee, George J; Dige, Ea; Maloney, Jennifer; Nolte, Hendrik

    2012-01-01

    A sublingually administered allergy immunotherapy tablet (AIT) is under development to treat ragweed (Ambrosia artemisiifolia)-induced allergic rhinoconjunctivitis (ARC). This study investigates the optimal tolerable dose of once daily ragweed pollen AIT.Subjects 18-50 years old with ragweed-induced ARC were enrolled at two U.S. centers in a double-blind, placebo-controlled,dose-escalation study outside ragweed season. Groups (12 subjects each) were to be randomized 3:1 to 28 days of active treatment (groups assigned in sequence to 3, 6, 12, 24, 50, or 100 units of Ambrosia artemislifolia major allergen 1 [Amb a 1 U],without dose buildup at any level) or matching placebo. Recruitment to 50 Amb a 1-U was discontinued because of adverse events (AEs) after four AIT subjects were enrolled; 100 Amb a 1-U was not initiated. Fifty-three subjects were randomized (AIT,n = 40; placebo, n = 13); four discontinued, all because of AEs (AIT, n = 3; placebo, n = 1). Treatment-related AEs (TRAEs) were more frequent with AIT (73%) than placebo (31%), increasing with dose level. AIT TRAEs were mostly mild (94%) or moderate(5%). No serious TRAEs or anaphylactic shock occurred. The most common TRAEs with AIT were localized pruritus, nasal irritation, and throat irritation. Median onset for common AIT application site reactions was 24 ≤ hours after first treatment (median duration, 15-50 minutes). AIT increased immunoglobulin (Ig) significantly more than placebo (ragweed-specific IgE [6, 12, and 24 Amb a 1-U]; IgG4 [all doses]; p < 0.05). Three subjects in dose groups ≥ 24 Amb a 1-U experienced symptoms suggestive of systemic reaction. Of tested doses, ragweed AIT 24

  16. 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.

  17. Development of a Report Card for Identifying Local Sublingual Immunotherapy Events in Clinical Trials.

    Science.gov (United States)

    Norquist, Josephine; Flood, Emuella; Tanzosh, Tiffany; Li, Haojie; Iskold, Beata; Ganser, Thelma Rose; Marson-Smith, Helen

    2017-08-01

    The sublingual immunotherapy (SLIT) Report Card was developed to capture patient-reported local reactions from the administration of SLIT, based on the World Allergy Organization side-effect grading system. The objective was to evaluate understandability, usability, and translatability of the paper and electronic versions of the SLIT Report Card. Adults (aged 18+ years), adolescents (aged 12-17 years), and parents/caregivers and their children (aged 5-11 years) participated in two rounds of interviews, testing the paper version in Round 1, and both the paper and electronic versions in Round 2. Interviews assessed comprehension and usability by subjects. Translatability identified potential issues related to translation or cultural relevance. Ten adults, ten adolescents, and ten parent/child dyads were interviewed. In general, subjects demonstrated a clear understanding of the instrument's content. However, some subjects were uncertain of or suggested clarifying the meaning of certain terms, including tablet, ulcer, taste alteration, uvula, nausea, and itching in the ear. The translatability assessment also identified uvula and nausea as potentially problematic for translation. Subjects could use the electronic device and found navigation 'easy', with only a few minor suggestions made to improve usability. Some wording and formatting changes were made based on subjects' feedback and the translatability assessment. The SLIT Report Card was refined following best practices for instrument development, including cognitive interviewing, usability, and translatability assessment. The refined SLIT Report Card is appropriate for comprehensively and systematically collecting SLIT-related local reactions directly from subjects in a clinical trial setting, taking into account the World Allergy Organization grading system.

  18. Mapping the ADF/cofilin binding site on monomeric actin by competitive cross-linking and peptide array: evidence for a second binding site on monomeric actin.

    Science.gov (United States)

    Mannherz, Hans Georg; Ballweber, Edda; Galla, Marco; Villard, Sylvie; Granier, Claude; Steegborn, Clemens; Schmidtmann, Anja; Jaquet, Kornelia; Pope, Brian; Weeds, Alan G

    2007-02-23

    The binding sites for actin depolymerising factor (ADF) and cofilin on G-actin have been mapped by competitive chemical cross-linking using deoxyribonuclease I (DNase I), gelsolin segment 1 (G1), thymosin beta4 (Tbeta4), and vitamin D-binding protein (DbP). To reduce ADF/cofilin induced actin oligomerisation we used ADP-ribosylated actin. Both vitamin D-binding protein and thymosin beta4 inhibit binding by ADF or cofilin, while cofilin or ADF and DNase I bind simultaneously. Competition was observed between ADF or cofilin and G1, supporting the hypothesis that cofilin preferentially binds in the cleft between sub-domains 1 and 3, similar to or overlapping the binding site of G1. Because the affinity of G1 is much higher than that of ADF or cofilin, even at a 20-fold excess of the latter, the complexes contained predominantly G1. Nevertheless, cross-linking studies using actin:G1 complexes and ADF or cofilin showed the presence of low concentrations of ternary complexes containing both ADF or cofilin and G1. Thus, even with monomeric actin, it is shown for the first time that binding sites for both G1 and ADF or cofilin can be occupied simultaneously, confirming the existence of two separate binding sites. Employing a peptide array with overlapping sequences of actin overlaid by cofilin, we have identified five sequence stretches of actin able to bind cofilin. These sequences are located within the regions of F-actin predicted to bind cofilin in the model derived from image reconstructions of electron microscopical images of cofilin-decorated filaments. Three of the peptides map to the cleft region between sub-domains 1 and 3 of the upper actin along the two-start long-pitch helix, while the other two are in the DNase I loop corresponding to the site of the lower actin in the helix. In the absence of any crystal structures of ADF or cofilin in complex with actin, these studies provide further information about the binding sites on F-actin for these important actin

  19. 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 (<10%) lysosomal colocalization and minimal (≤15%) degradation. In the absence of ligands, ICAM-1 also underwent amiloride-sensitive endocytosis with peripheral distribution, suggesting that monomeric (not multimeric) anti-ICAM follows the route of this receptor. In conclusion, ICAM-1 can mediate different intracellular itineraries, revealing new insight into this biological pathway and alternative avenues for drug delivery.

  20. 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

  1. 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

  2. Sublingual immunotherapy: a double-blind, placebo-controlled trial with Parietaria judaica extract standardized in mass units in patients with rhinoconjunctivitis, asthma, or both.

    Science.gov (United States)

    Purello-D'Ambrosio, F; Gangemi, S; Isola, S; La Motta, N; Puccinelli, P; Parmiani, S; Savi, E; Ricciardi, L

    1999-09-01

    New routes of administering immunotherapy in respiratory allergy are being studied as an alternative to conventional injective immunotherapy. We carried out a study to evaluate the clinical efficacy and effects of sublingual immunotherapy in patients with Parietaria judaica-induced respiratory allergy. A double-blind, placebo-controlled design was followed. Thirty patients with P. judaica rhinoconjunctivitis, mild asthma, or both were randomly chosen for sublingual immunotherapy (14 patients) or placebo treatment (16 patients). The patients underwent preseasonal rush induction treatment followed by coseasonal maintenance treatment during the Parietaria pollen season. Symptom and drug scores, as well as specific IgE and specific IgG4, were recorded. Significantly lower symptom and drug scores were found (P=0.04), especially during the Parietaria pollination period, in the immunotherapy group. No significant difference in specific IgE and specific IgG4 was detected between the active and placebo groups; a statistically significant increase of specific IgE was detected in both groups (P=0.05). No patient undergoing active sublingual immunotherapy reported local or systemic side-effects. Our data suggest that sublingual immunotherapy is both clinically effective and safe in treating patients with Parietaria-induced rhinoconjunctivitis and mild asthma.

  3. Study Design of the Microcirculatory Shock Occurrence in Acutely Ill Patients (microSOAP): an International Multicenter Observational Study of Sublingual Microcirculatory Alterations in Intensive Care Patients

    Science.gov (United States)

    Vellinga, Namkje A. R.; Boerma, E. Christiaan; Koopmans, Matty; Donati, Abele; Dubin, Arnaldo; Shapiro, Nathan I.; Pearse, Rupert M.; Bakker, Jan; Ince, Can

    2012-01-01

    Objective. Sublingual microcirculatory alterations are associated with an adverse prognosis in several critical illness subgroups. Up to now, single-center studies have reported on sublingual microcirculatory alterations in ICU patient subgroups, but an extensive evaluation of the prevalence of these alterations is lacking. We present the study design of an international multicenter observational study to investigate the prevalence of microcirculatory alterations in critically ill: the Microcirculatory Shock Occurrence in Acutely ill Patients (microSOAP). Methods. 36 ICU's worldwide have participated in this study aiming for inclusion of over 500 evaluable patients. To enable communication and data collection, a website, an Open Clinica 3.0 database, and image uploading software have been designed. A one-session assessment of the sublingual microcirculation using Sidestream Dark Field imaging and data collection on patient characteristics has been performed in every ICU patient >18 years, regardless of underlying disease. Statistical analysis will provide insight in the prevalence and severity of sublingual alterations, its relation to systemic hemodynamic variables, disease, therapy, and outcome. Conclusion. This study will be the largest microcirculation study ever performed. It is expected that this study will also establish a basis for future studies related to the microcirculation in critically ill. PMID:22666566

  4. Study Design of the Microcirculatory Shock Occurrence in Acutely Ill Patients (microSOAP: an International Multicenter Observational Study of Sublingual Microcirculatory Alterations in Intensive Care Patients

    Directory of Open Access Journals (Sweden)

    Namkje A. R. Vellinga

    2012-01-01

    Full Text Available Objective. Sublingual microcirculatory alterations are associated with an adverse prognosis in several critical illness subgroups. Up to now, single-center studies have reported on sublingual microcirculatory alterations in ICU patient subgroups, but an extensive evaluation of the prevalence of these alterations is lacking. We present the study design of an international multicenter observational study to investigate the prevalence of microcirculatory alterations in critically ill: the Microcirculatory Shock Occurrence in Acutely ill Patients (microSOAP. Methods. 36 ICU’s worldwide have participated in this study aiming for inclusion of over 500 evaluable patients. To enable communication and data collection, a website, an Open Clinica 3.0 database, and image uploading software have been designed. A one-session assessment of the sublingual microcirculation using Sidestream Dark Field imaging and data collection on patient characteristics has been performed in every ICU patient >18 years, regardless of underlying disease. Statistical analysis will provide insight in the prevalence and severity of sublingual alterations, its relation to systemic hemodynamic variables, disease, therapy, and outcome. Conclusion. This study will be the largest microcirculation study ever performed. It is expected that this study will also establish a basis for future studies related to the microcirculation in critically ill.

  5. 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

  6. Network meta-analysis shows commercialized subcutaneous and sublingual grass products have comparable efficacy.

    Science.gov (United States)

    Nelson, Harold; Cartier, Shannon; Allen-Ramey, Felicia; Lawton, Simon; Calderon, Moises A

    2015-01-01

    Subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT) have been shown to effectively treat grass pollen allergies, although direct comparisons are sparse. To estimate the relative efficacy of SLIT tablets compared with SCIT and SLIT drops in commercially available products though network meta-analysis. A literature search of MEDLINE, Embase, and Cochrane Library publications. Randomized, double-blind clinical trials of SCIT, SLIT drops, and SLIT tablets for grass pollen were included. Bayesian network meta-analyses estimated the standardized mean difference (SMD) across 3 immunotherapy modalities on allergic rhinoconjunctivitis symptom and medication score data from publications or received from authors. Both fixed and random effects models were investigated. Thirty-seven studies were included in meta-analyses for symptom scores and 31 studies for medication scores. In the random effects model, SCIT and SLIT tablets were significantly different from placebo for symptom scores: SMDs (95% CI) of -0.32 (-0.45 to -0.18) and -0.32 (-0.41 to -0.23), respectively. No significant difference was identified for SLIT drops compared with placebo (SMD, -0.17; -0.37 to 0.04). For medication scores, significant differences compared with placebo were observed for SCIT (SMD, -0.33; 95% CI, -0.52 to -0.13), SLIT tablets (SMD, -0.23; 95% CI, -0.29 to -0.17), and SLIT drops (SMD, -0.44; 95% CI, -0.83 to -0.06). Network meta-analysis revealed no significant differences in SMDs (95% credible interval) for symptom scores (0.0145 [-0.19 to 0.23]) or medication scores (0.133 [-0.31 to 0.57]) between SLIT tablets and SCIT, or for symptom scores (-0.175 [-0.37 to 0.02]) and medication scores (0.188 [-0.18 to 0.56]) between SLIT tablets and SLIT drops. The comparisons for grass pollen immunotherapy products commercialized in at least 1 country indicate comparable reductions in allergic rhinoconjunctivitis symptoms and supplemental medication use for SLIT tablets

  7. Treatment effect of sublingual immunotherapy tablets and pharmacotherapies for seasonal and perennial allergic rhinitis: Pooled analyses.

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    Durham, Stephen R; Creticos, Peter S; Nelson, Harold S; Li, Ziliang; Kaur, Amarjot; Meltzer, Eli O; Nolte, Hendrik

    2016-10-01

    Data comparing the treatment effect of allergy immunotherapy and pharmacotherapy are lacking. We sought to indirectly compare the treatment effect of sublingual immunotherapy (SLIT)-tablets with pharmacotherapy for seasonal allergic rhinitis (SAR) and perennial allergic rhinitis (PAR). Pooled data from randomized, double-blind, placebo-controlled trials for the clinical development programs of selected allergic rhinitis treatments were evaluated. Total nasal symptom scores (TNSSs) relative to placebo were compared. Subjects scored symptoms daily during entire pollen seasons in 6 timothy grass SLIT-tablet trials (n = 3094) and 2 ragweed SLIT-tablet trials (n = 658) and during the last 8 weeks of treatment in 2 house dust mite (HDM) SLIT-tablet trials (n = 1768). Subjects scored symptoms daily in 7 montelukast (10 mg, n = 6799), 9 desloratadine (5 mg, n = 4455), and 8 mometasone furoate nasal spray (MFNS; 200 μg daily, n = 2140) SAR or PAR trials. SLIT-tablet trials allowed rescue medication use, whereas most pharmacotherapy trials did not. A fixed-effect meta-analysis method estimated differences in on-treatment average TNSSs. In grass and ragweed SLIT-tablet trials, overall improvement in TNSSs relative to placebo was 16.3% and 17.1%, respectively. In HDM SLIT-tablet trials, TNSS overall improvement relative to placebo was 16.1%. In the montelukast, desloratadine, and MFNS trials, TNSS overall improvement relative to placebo was 5.4%, 8.5%, and 22.2%, respectively, for SAR trials, and 3.7%, 4.8%, and 11.2%, respectively, for PAR trials. Although comparisons were limited by study design heterogeneity and use of rescue medications in SLIT-tablet trials, effects on nasal symptoms with timothy grass and ragweed SLIT-tablets were nearly as great as with MFNS and numerically greater than with montelukast and desloratadine for SAR. HDM SLIT-tablet effects were numerically greater than all pharmacotherapies for PAR. SLIT-tablets offer the additional

  8. Intravenous and sublingual buprenorphine in horses: pharmacokinetics and influence of sampling site.

    Science.gov (United States)

    Messenger, Kristen M; Davis, Jennifer L; LaFevers, Douglas H; Barlow, Beth M; Posner, Lysa P

    2011-07-01

    To describe the pharmacokinetics and adverse effects of intravenous (IV) and sublingual (SL) buprenorphine in horses, and to determine the effect of sampling site on plasma concentrations after SL administration. Randomized crossover experiment; prospective study. Eleven healthy adult horses between 6 and 20 years of age and weighing 487-592 kg. In the first phase; buprenorphine was administered as a single IV or SL dose (0.006 mg kg(-1)) and pharmacokinetic parameters were determined for each route of administration using a noncompartmental model. In the second phase; the jugular and lateral thoracic veins were catheterized for simultaneous venous blood sampling, following a dose of 0.006 mg kg(-1) SL buprenorphine. For both phases, plasma buprenorphine concentrations were measured using ultra-performance liquid chromatography with mass spectrometry. At each sampling period, horses were assessed for behavioral excitement and gastrointestinal motility. Following IV administration, buprenorphine mean ± SD half-life was 5.79 ± 1.09 hours. Systemic clearance (Cl) following IV administration was 6.13 ± 0.86 mL kg(-1) minute(-1) and volume of distribution at steady-state was 3.16 ± 0.65 L kg(-1). Following IV administration, horses showed signs of excitement. Gastrointestinal sounds were decreased following both routes of administration; however, none of the horses exhibited signs of colic. There was a significant discrepancy between plasma buprenorphine concentrations measured in the jugular vein versus the lateral thoracic vein following phase 2, thus pharmacokinetic parameters following SL buprenorphine are not reported. Buprenorphine has a long plasma half-life and results in plasma concentrations that are consistent with analgesia in other species for up to 4 hours following IV administration of this dose in horses. While buprenorphine is absorbed into the circulation following SL administration, jugular venous sampling gave a false measurement of the quantity

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

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    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

  10. Randomized double-blind placebo-controlled trial of sublingual immunotherapy in children with house dust mite allergy in primary care: study design and recruitment

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    de Jongste Johan C

    2008-10-01

    Full Text Available Abstract Background For respiratory allergic disorders in children, sublingual immunotherapy has been developed as an alternative to subcutaneous immunotherapy. Sublingual immunotherapy is more convenient, has a good safety profile and might be an attractive option for use in primary care. A randomized double-blind placebo-controlled study was designed to establish the efficacy of sublingual immunotherapy with house dust mite allergen compared to placebo treatment in 6 to18-year-old children with allergic rhinitis and a proven house dust mite allergy in primary care. Described here are the methodology, recruitment phases, and main characteristics of the recruited children. Methods Recruitment took place in September to December of 2005 and 2006. General practitioners (in south-west Netherlands selected children who had ever been diagnosed with allergic rhinitis. Children and parents could respond to a postal invitation. Children who responded positively were screened by telephone using a nasal symptom score. After this screening, an inclusion visit took place during which a blood sample was taken for the RAST test. Results A total of 226 general practitioners invited almost 6000 children: of these, 51% was male and 40% Conclusion Our study was designed in accordance with recent recommendations for research on establishing the efficacy of sublingual immunotherapy; 98% of the target sample size was achieved. This study is expected to provide useful information on sublingual immunotherapy with house dust mite allergen in primary care. The results on efficacy and safety are expected to be available by 2010. Trial registration the trial is registered as ISRCTN91141483 (Dutch Trial Register

  11. Intraoperative temperature monitoring with zero heat flux technology (3M SpotOn sensor) in comparison with sublingual and nasopharyngeal temperature: An observational study.

    Science.gov (United States)

    Iden, Timo; Horn, Ernst-Peter; Bein, Berthold; Böhm, Ruwen; Beese, Janne; Höcker, Jan

    2015-06-01

    Perioperative hypothermia is common in patients undergoing general anaesthesia and is associated with important adverse events. The 'gold standard' for monitoring body core temperature - the pulmonary artery catheter - is invasive and unsuitable for most patients. For routine clinical practice, other sites and methods of temperature monitoring are commonly used. The aim of this study was to evaluate a new temperature sensor (3M SpotOn) using the 'zero heat flux' method attached to the forehead, and compare it to sublingual and nasopharyngeal sensors in terms of correlation, accuracy and precision. An observational study. University Medical Center Schleswig Holstein, Campus Kiel, Germany from October 2013 to January 2014. One hundred and twenty patients scheduled for elective gynaecological or trauma surgery undergoing general anaesthesia were enrolled into this study. Data of 83 patients were finally analysed. Patients with unexpected blood loss, haemodynamic instability determined by the need for continuous norepinephrine infusion and/or need for postoperative ventilation were excluded from this study. Temperature monitoring was established after induction of anaesthesia with sublingual and nasopharyngeal probes, and the SpotOn sensor. Body temperature was measured 15, 45 and 75 min after induction of anaesthesia from sublingual and nasopharyngeal probes and the 3M SpotOn sensor at precisely the same moment. Analysis of 83 data sets revealed that 3M SpotOn temperatures were almost identical with nasopharyngeal temperatures (mean difference 0.07 °C; P = 0.1424) and slightly lower than sublingual temperatures by 0.35 °C (P sensor provides a good measurement of body temperature in comparison to the nasopharyngeal probe and an acceptable measurement in comparison with sublingual thermometry. It is adequate for clinical use. Clinicaltrials.gov identifier: NCT02031159.

  12. Efficacy and safety of sublingual fentanyl orally disintegrating tablet at doses determined from oral morphine rescue doses in the treatment of breakthrough cancer pain.

    Science.gov (United States)

    Shimoyama, Naohito; Gomyo, Ikuo; Teramoto, Osamu; Kojima, Keisuke; Higuchi, Hitomi; Yukitoshi, Nobuyuki; Ohta, Eri; Shimoyama, Megumi

    2015-02-01

    A randomized, crossover, double-blinded placebo-controlled and non-blinded active drug-controlled, comparative clinical trial was conducted to evaluate the efficacy and safety of sublingual fentanyl tablet. Subjects were patients treated with strong opioids at fixed intervals for chronic cancer pain and with oral morphine as rescue medication for breakthrough pain. Sublingual fentanyl was administered at doses that were 1/25th (high dose) and 1/50th (low dose) of the dose of rescue morphine and was compared with placebo and oral morphine. The primary endpoint was pain intensity difference at 30 min after administration. (Clinical Trials Government; NCT00684632). Fifty-one patients were enrolled in the investigation. Their mean pain intensity in visual analog scale before rescue medication prior to the investigation was 60.96 (16.44, standard deviation) mm. Compared with placebo, the low and high doses of sublingual fentanyl showed significant analgesic effects (least squares mean difference, 4.54 and 8.49 mm; P = 0.014, P pain and with oral morphine at doses up to 20 mg as rescue medication were investigated. The doses of sublingual fentanyl to treat breakthrough pain were determined from rescue morphine doses by use of conversion ratios. In these patients, administration of sublingual fentanyl at doses determined by a conversion ratio of 1/50 was effective and safe. Further studies are needed to validate the use of this conversion method. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  13. Photoswitching of monomeric and dimeric DNA-intercalating cyanine dyes for super-resolution microscopy applications.

    Science.gov (United States)

    Flors, Cristina

    2010-05-01

    A growing trend in far-field super resolution fluorescence microscopy based on single molecule photoswitching involves the replacement of photoactivatable fluorophores by common organic dyes in which photoswitching reactions or blinking can be induced. This alternative strategy can greatly simplify the sample preparation and imaging scheme in some cases, and enables its application to a wider range of biological systems. This methodology has been applied successfully to unveil the nanoscale organisation of proteins, but little progress has been seen to date in DNA super-resolution imaging. Previous results have shown that blinking can be induced in the DNA-intercalating dimeric dye YOYO-1 in combination with a reducing buffer, and in turn super-resolution images of DNA can be reconstructed. However, monomeric intercalating dyes like YO-PRO-1 are more advantageous for biological applications. This paper shows that both YO-PRO-1 and YOYO-1 can be used in super-resolution imaging, and different sample preparation strategies are compared in terms of spatial resolution and homogeneity of the reconstructed super-resolution images. Moreover, ensemble and single-molecule experiments provide insight into the switching mechanism. The dyes YOYO-1 and YO-PRO-1 hold great potential for their use in nanoscale imaging of DNA topology in biology and nanoscience.

  14. Monomeric fullerenes in lipid membranes: effects of molecular shape and polarity.

    Science.gov (United States)

    Bortolus, Marco; Parisio, Giulia; Maniero, Anna Lisa; Ferrarini, Alberta

    2011-10-18

    We report a combined theoretical and experimental study on the single-molecule interaction of fullerenes with phospholipid membranes. We studied pristine C(60) (1) and two N-substituted fulleropyrrolidines (2 and 3), one of which (3) bore a paramagnetic nitroxide group. Theoretical predictions of fullerene distribution and permeability across lipid bilayers were combined with electron paramagnetic resonance (EPR) experiments in aligned DMPC/DHPC bicelles containing the paramagnetic fulleropyrrolidine 3 or either one of the diamagnetic fullerenes together with spin-labeled lipids. We found that, at low concentrations, fullerenes are present in the bilayer as single molecules. Their preferred location in the membrane is only slightly influenced by the derivatization: all derivatives were confined just below the hydrophilic/hydrophobic interface, because of the key role played by dispersion interactions between the highly polarizable fullerene cage and the hydrocarbon chains, which are especially tight within this region. However, the deviation from spherical shape is sufficient to induce a preferential orientation of 2 and 3 in the membrane. We predict that monomeric fullerenes spontaneously penetrate the bilayer, in agreement with the results of molecular dynamics simulations, but we point out the limits of the currently used permeability model when applied to hydrophobic solutes. © 2011 American Chemical Society

  15. Renin inhibition by substituted piperidines: a novel paradigm for the inhibition of monomeric aspartic proteinases?

    Science.gov (United States)

    Oefner, C; Binggeli, A; Breu, V; Bur, D; Clozel, J P; D'Arcy, A; Dorn, A; Fischli, W; Grüninger, F; Güller, R; Hirth, G; Märki, H; Mathews, S; M ller, M; Ridley, R G; Stadler, H; Vieira, E; Wilhelm, M; Winkler, F; Wostl, W

    1999-03-01

    The aspartic proteinase renin catalyses the first and rate-limiting step in the conversion of angiotensinogen to the hormone angiotensin II, and therefore plays an important physiological role in the regulation of blood pressure. Numerous potent peptidomimetic inhibitors of this important drug target have been developed, but none of these compounds have progressed past clinical phase II trials. Limited oral bioavailability or excessive production costs have prevented these inhibitors from becoming new antihypertensive drugs. We were interested in developing new nonpeptidomimetic renin inhibitors. High-throughput screening of the Roche compound library identified a simple 3, 4-disubstituted piperidine lead compound. We determined the crystal structures of recombinant human renin complexed with two representatives of this new class. Binding of these substituted piperidine derivatives is accompanied by major induced-fit adaptations around the enzyme's active site. The efficient optimisation of the piperidine inhibitors was facilitated by structural analysis of the renin active site in two renin-inhibitor complexes (some of the piperidine derivatives have picomolar affinities for renin). These structural changes provide the basis for a novel paradigm for inhibition of monomeric aspartic proteinases.

  16. Photoinactivation of multidrug resistant bacteria by monomeric methylene blue conjugated gold nanoparticles.

    Science.gov (United States)

    Khan, Shakir; Khan, Shahper N; Meena, Ramovatar; Dar, Ayaz M; Pal, Ruchita; Khan, Asad U

    2017-09-01

    Multidrug resistant (MDR) bacterial infections have become a severe threat to the community health due to a progressive rise in antibiotic resistance. Nanoparticle-based photodynamic therapy (PDT) is increasingly been adopted as a potential antimicrobial option, yet the cytotoxicity associated with PDT is quite unspecific. Herein, we show Concanavalin-A (ConA) directed dextran capped gold nanoparticles (GNPDEX-ConA) enhanced the efficacy and selectivity of methylene blue (MB) induced killing of multidrug resistant clinical isolates. Here, we show that our complex MB@GNPDEX-ConA is effective against range of MDR clinical isolates, including Escherichia coli, Klebsiella pneumoniae and Enterobacter cloacae. In our treatment modality negligible dark toxicity suggests photochemically driven process with 97% killing of MDR bacteria. GNPDEX-ConA with monomeric form of MB departs maximum fluorescence decay time (τf: 1.7ns in HSA) and singlet oxygen (ΔΦ; 0.84) for improved activity in albumin rich infection sites. Further, the complex show least toxicity when tested against HEK293 mammalian cells. The principle component analysis (PCA) and confocal microscopy illustrates cytosolic (1)O2 mediated type-II PDT as mechanism of action. Hence, MB@GNPDEX-ConA mediated PDT is potential therapeutic approach against MDR infections and can be tailored to fight other infectious diseases. Copyright © 2017 Elsevier B.V. All rights reserved.

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

    Directory of Open Access Journals (Sweden)

    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. Monomeric ephrinB2 binding induces allosteric changes in Nipah virus G that precede its full activation.

    Science.gov (United States)

    Wong, Joyce J W; Young, Tracy A; Zhang, Jiayan; Liu, Shiheng; Leser, George P; Komives, Elizabeth A; Lamb, Robert A; Zhou, Z Hong; Salafsky, Joshua; Jardetzky, Theodore S

    2017-10-03

    Nipah virus is an emergent paramyxovirus that causes deadly encephalitis and respiratory infections in humans. Two glycoproteins coordinate the infection of host cells, an attachment protein (G), which binds to cell surface receptors, and a fusion (F) protein, which carries out the process of virus-cell membrane fusion. The G protein binds to ephrin B2/3 receptors, inducing G conformational changes that trigger F protein refolding. Using an optical approach based on second harmonic generation, we show that monomeric and dimeric receptors activate distinct conformational changes in G. The monomeric receptor-induced changes are not detected by conformation-sensitive monoclonal antibodies or through electron microscopy analysis of G:ephrinB2 complexes. However, hydrogen/deuterium exchange experiments confirm the second harmonic generation observations and reveal allosteric changes in the G receptor binding and F-activating stalk domains, providing insights into the pathway of receptor-activated virus entry.Nipah virus causes encephalitis in humans. Here the authors use a multidisciplinary approach to study the binding of the viral attachment protein G to its host receptor ephrinB2 and show that monomeric and dimeric receptors activate distinct conformational changes in G and discuss implications for receptor-activated virus entry.

  19. The role of barrier function of mucous membranes in allergic diseases and sublingual allergen-specific immunotherapy

    Directory of Open Access Journals (Sweden)

    Oksana M. Kurbacheva

    2017-01-01

    Full Text Available Currently one of the factors of allergy predisposition is the increase in barrier permeability of the mucous membranes of the respiratory system and the gastrointestinal tract (GIT. It defines the probability of an emergence of an allergic response. To understand the mechanisms of the interaction of the mucous membranes of different systems that explain their common function is undoubtedly necessary for discussion of this problem. The features of microbiome influence and the changes of the microbiome state during the formation of the immune response to the contact with allergens are of particular interest. The structure of the epithelial barrier of the airwaysand GIT, and mechanisms of allergen transport through barrier systems with the subsequent interaction with the cells (? associated with barrier fabrics have been considered. The possible role of the barrier function of mucous membranes in conducting sublingual allergen-specific immunotherapy (SLIT is discussed. 

  20. 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...... with uncontrolled and severe asthma were excluded from the trials. Frequencies for treatment-emergent AEs (TEAEs), local allergic swelling (mouth or throat), systemic allergic reactions, and asthma-related treatment-related AEs (TRAEs) were calculated. RESULTS: Among adults (n = 3314) and children (n = 881), 24......% and 31%, respectively, had reported asthma. No serious local allergic swellings or serious systemic allergic reactions occurred in subjects with asthma treated with SLIT-tablet. There was no evidence of increased TEAEs, systemic allergic reactions, or severe local allergic swellings in adults or children...

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

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    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

  2. Could Sublingual Immunotherapy Affect Oral Health in Children with Asthma and/or Allergic Rhinitis Sensitized to House Dust Mite?

    Science.gov (United States)

    Kiykim, Ayca; Mumcu, Gonca; Ogulur, Ismail; Karakoc-Aydiner, Elif; Direskeneli, Haner; Baris, Safa; Cagan, Hasret; Ozen, Ahmet

    2017-01-01

    Sublingual immunotherapy (SLIT) has been successfully employed in IgE-mediated respiratory allergies. However, it is not known whether the modulation of immune responses in the sublingual area during SLIT has any deleterious effect on oral health. We sought to determine the oral health prospectively in children receiving SLIT for house dust mite allergy. Eighteen children with allergic asthma and/or rhinitis and 31 age-matched healthy controls (HC) were included in an open-labeled trial. Oral health was evaluated by scoring the decayed, missing, and filled teeth for primary (dmft) and permanent (DMFT) dentition, and the plaque and gingival indices. Moreover, cariogenic food intake and teeth-brushing habits were also noted at baseline and at 19 months. The mean age of the SLIT participants was 9.5 ± 3.1 years and that of the HC was 9.2 ± 3.7 years. The mean duration of SLIT was 19.13 ± 3.81 months. At baseline, the total dmft and DMFT indices were similar in the SLIT and HC groups (p > 0.05), which demonstrated poor hygiene overall. In the within-group comparisons at the examination at 19 months, the SLIT group had a lower number of carious primary teeth and a higher number of filled primary teeth compared to the count at baseline (p = 0.027 and p = 0.058, respectively). Our study showed no detrimental effect of SLIT on oral health during a period of 19 months of follow-up. Parents should be motivated to use dental health services to prevent new caries formation since our cohort had overall poor oral hygiene at the baseline. © 2017 S. Karger AG, Basel.

  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. Disparity between skin perfusion and sublingual microcirculatory alterations in severe sepsis and septic shock: a prospective observational study.

    Science.gov (United States)

    Boerma, E Christiaan; Kuiper, Michael A; Kingma, W Peter; Egbers, Peter H; Gerritsen, Rik T; Ince, Can

    2008-07-01

    Measurement of central-to-toe temperature difference has been advocated as an index of severity of shock and as a guide for circulatory therapy in critically ill patients. However, septic shock, in contrast to other forms of shock, is associated with a distributive malfunction resulting in a disparity between vascular compartments. Although this disparity has been established between systemic and microcirculatory parameters, it is unclear whether such disparity exists between skin perfusion and microcirculation. To test this hypothesis of disparity, we simultaneously measured parameters of the two vascular compartments, in the early phase of sepsis. Prospective observational study in patients with severe sepsis/septic shock in the first 6 h of ICU admission. Simultaneous measurements of central-to-toe temperature difference and sublingual microcirculatory orthogonal polarization spectral imaging, together with parameters of systemic hemodynamics. 22 bed mixed-ICU in a tertiary teaching hospital. 35 consecutive patients in a 12-month period. In 35 septic patients and a median APACHE II score of 20, no correlation between central-to-toe temperature gradient and microvascular flow index was observed (r (s) = -0.08, p =0.65). Also no significant correlation between temperature gradient/microvascular flow index and systemic hemodynamic parameters could be demonstrated. During the early phase of resuscitated severe sepsis and septic shock there appears to be no correlation between sublingual microcirculatory alterations and the central-to-toe temperature difference. This finding adds to the concept of a dispersive nature of blood flow under conditions of sepsis between microcirculatory and systemic hemodynamics.

  5. Disparity between skin perfusion and sublingual microcirculatory alterations in severe sepsis and septic shock: a prospective observational study

    Science.gov (United States)

    Kuiper, Michael A.; Kingma, W. Peter; Egbers, Peter H.; Gerritsen, Rik T.; Ince, Can

    2008-01-01

    Objective Measurement of central-to-toe temperature difference has been advocated as an index of severity of shock and as a guide for circulatory therapy in critically ill patients. However, septic shock, in contrast to other forms of shock, is associated with a distributive malfunction resulting in a disparity between vascular compartments. Although this disparity has been established between systemic and microcirculatory parameters, it is unclear whether such disparity exists between skin perfusion and microcirculation. To test this hypothesis of disparity, we simultaneously measured parameters of the two vascular compartments, in the early phase of sepsis. Design Prospective observational study in patients with severe sepsis/septic shock in the first 6 h of ICU admission. Simultaneous measurements of central-to-toe temperature difference and sublingual microcirculatory orthogonal polarization spectral imaging, together with parameters of systemic hemodynamics. Setting 22 bed mixed-ICU in a tertiary teaching hospital. Patients 35 consecutive patients in a 12-month period. Measurements and results In 35 septic patients and a median APACHE II score of 20, no correlation between central-to-toe temperature gradient and microvascular flow index was observed (rs = −0.08, p = 0.65). Also no significant correlation between temperature gradient/microvascular flow index and systemic hemodynamic parameters could be demonstrated. Conclusions During the early phase of resuscitated severe sepsis and septic shock there appears to be no correlation between sublingual microcirculatory alterations and the central-to-toe temperature difference. This finding adds to the concept of a dispersive nature of blood flow under conditions of sepsis between microcirculatory and systemic hemodynamics. PMID:18317733

  6. Sublingual misoprostol versus intravenous oxytocin in reducing bleeding during and after cesarean delivery: A randomized clinical trial.

    Science.gov (United States)

    Othman, Essam Rashad; Fayez, Margaret Fathy; El Aal, Diaa Eldeen Mohamed Abd; El-Dine Mohamed, Hazem Saad; Abbas, Ahmed Mohammed; Ali, Mohammed Khairy

    2016-12-01

    This study compares the efficacy of sublingual misoprostol versus intravenous oxytocin in reducing bleeding during and after cesarean delivery. A randomized clinical trial conducted on 120 pregnant women at term (37-40 weeks) gestation scheduled for elective cesarean delivery, who were assigned to either sublingual misoprostol 400 μg or intravenous infusion of 20 units of oxytocin after delivery of the neonate. The main outcome measures were blood loss at and 2 hours after cesarean delivery, change in hematocrit value, need for any additional oxytocic drugs, and drug-related side effects. The overall mean blood loss was significantly lower in the misoprostol group compared to the oxytocin group (490.75 ± 159.90 mL vs. 601.08 ± 299.49 mL; p = 0.025). However, changes in hematocrit level (pre- and postpartum) was comparable between both groups. There was a need for additional oxytocic therapy in 16.7% and 23.3% after use of misoprostol and oxytocin, respectively (p = 0.361). Incidence of side effects such as shivering and metallic taste were significantly higher in the misoprostol group compared to the oxytocin group (p effective than intravenous infusion of oxytocin in reducing blood loss during and after cesarean delivery. However, occurrence of temporary side effects such as shivering and metallic taste was more frequent with the use of misoprostol. Copyright © 2016. Published by Elsevier B.V.

  7. Purification and characterization of thermostable monomeric chloroplastic Cu/Zn superoxide dismutase from Chenopodium murale.

    Science.gov (United States)

    Sundaram, Sabarinath; Khanna, Sunil; Khanna-Chopra, Renu

    2009-07-01

    Superoxide dismutase is the first line of defense against oxidative stress and thus helps in maintaining the cellular integrity. Chenopodium murale, a weed species adapted to widely varying climatic conditions faces extremes of temperatures ranging from 4 °C to 45 °C (Tmax) during growth and development. From this plant, we have purified a thermostable chloroplastic Cu/Zn superoxide dismutase (Chl Cu/Zn SOD) to homogeneity using minimal steps. Incubation of lysed chloroplasts at 70 °C for 1h reduced the interference of cytosolic SOD isoforms and reduced the protein content by 75 %. Chloroplastic SOD was purified from the heat stable fraction by gel filtration chromatography. The purified enzyme had a native molecular weight of 24 kDa, a half-life of 47.9 min at 80 °C and showed a single band at 24 kDa on SDS-PAGE. The N-terminus contained the conserved amino acids of chl Cu-Zn SOD. The Chl Cu/Zn SOD protein and its activity were enhanced under very high temperatures, high light intensities and in water stress/recovered C. murale plants under controlled environment conditions. Chl Cu/Zn SOD was also one of the predominant isoforms throughout growing period in field grown plants and declined during senescence. The Chl Cu/Zn SOD activity increased with the increase in ambient temperature and peaked in April with a 45 °C Tmax. These results clearly indicate that the chloroplastic Cu/Zn SOD is stably expressed at extreme environmental conditions. The presence of stable monomeric chloroplastic Cu/Zn SOD might help the plants to maintain the cellular homeostatis against adverse environmental conditions.

  8. Crystal structure of a monomeric thiolase-like protein type 1 (TLP1 from Mycobacterium smegmatis.

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    Neelanjana Janardan

    Full Text Available An analysis of the Mycobacterium smegmatis genome suggests that it codes for several thiolases and thiolase-like proteins. Thiolases are an important family of enzymes that are involved in fatty acid metabolism. They occur as either dimers or tetramers. Thiolases catalyze the Claisen condensation of two acetyl-Coenzyme A molecules in the synthetic direction and the thiolytic cleavage of 3-ketoacyl-Coenzyme A molecules in the degradative direction. Some of the M. smegmatis genes have been annotated as thiolases of the poorly characterized SCP2-thiolase subfamily. The mammalian SCP2-thiolase consists of an N-terminal thiolase domain followed by an additional C-terminal domain called sterol carrier protein-2 or SCP2. The M. smegmatis protein selected in the present study, referred to here as the thiolase-like protein type 1 (MsTLP1, has been biochemically and structurally characterized. Unlike classical thiolases, MsTLP1 is a monomer in solution. Its structure has been determined at 2.7 Å resolution by the single wavelength anomalous dispersion method. The structure of the protomer confirms that the N-terminal domain has the thiolase fold. An extra C-terminal domain is indeed observed. Interestingly, it consists of six β-strands forming an anti-parallel β-barrel which is completely different from the expected SCP2-fold. Detailed sequence and structural comparisons with thiolases show that the residues known to be essential for catalysis are not conserved in MsTLP1. Consistent with this observation, activity measurements show that MsTLP1 does not catalyze the thiolase reaction. This is the first structural report of a monomeric thiolase-like protein from any organism. These studies show that MsTLP1 belongs to a new group of thiolase related proteins of unknown function.

  9. Monomeric and gemini surfactants as antimicrobial agents - influence on environmental and reference strains.

    Science.gov (United States)

    Koziróg, Anna; Brycki, Bogumił

    2015-01-01

    Quaternary ammonium salts (QAS) belong to surfactant commonly used both, in the household and in different branches of industry, primarily in the process of cleaning and disinfection. They have several positive features inter alia effectively limiting the development of microorganisms on many surfaces. In the present work, two compounds were used as biocides: hexamethylene-1,6-bis-(N,N-dimethyl-N-dodecylammonium bromide) that belongs to the gemini surfactant (GS), and its single analogue - dodecyl(trimethyl)ammonium bromide (DTAB). Two fold dilution method was used to determine the minimum concentration of compounds (MIC) which inhibit the growth of bacteria: Staphylococcus aureus (ATCC 6538 and an environmental strain), Pseudomonas aeruginosa (ATCC 85327 and an environmental strain), and yeast Candida albicans (ATCC 11509 and an environmental strain). The viability of cells in liquid cultures with addition of these substances at ¼ MIC, ½ MIC and MIC concentrations were also determined. The obtained results show that DTAB inhibits the growth of bacteria at the concentration of 0.126-1.010 µM/ml, and gemini surfactant is active at 0.036-0.029 µM/ml. Therefore, GS is active at more than 17-70-fold lower concentrations than its monomeric analogue. Strains isolated from natural environment are less sensitive upon testing biocides than the references strains. Both compounds at the MIC value reduced the number of cells of all strains. The use of too low concentration of biocides can limit the growth of microorganisms, but often only for a short period of time in case of special environmental strains. Later on, they can adapt to adverse environmental conditions and begin to evolve defence mechanisms.

  10. Purification and biochemical characterization of a monomeric form of papaya mosaic potexvirus coat protein.

    Science.gov (United States)

    Lecours, Katia; Tremblay, Marie-Hélène; Gagné, Marie-Eve Laliberté; Gagné, Stéphane M; Leclerc, Denis

    2006-05-01

    Papaya mosaic virus (PapMV) is a flexuous rod shape virus made of 1400 subunits that assemble around a plus sense genomic RNA. The structure determination of PapMV and of flexuous viruses in general is a major challenge for both NMR and X-ray crystallography. In this report, we present the characterization of a truncated version of the PapMV coat protein (CP) that is suitable for NMR study. The deletion of the N-terminal 26 amino acids of the PapMV CP (CP27-215) generates a monomer that can be expressed to high level and easily purified for production of an adequate NMR sample. The RNA gel shift assay showed that CP27-215 lost its ability to bind RNA in vitro, suggesting that the multimerization of the subunit is important for this function. The fusion of a 6x His tag at the C-terminus improved the solubility of the monomer and allowed its concentration to 0.2 mM. The CD spectra of the truncated and the wild-type proteins were similar, suggesting that both proteins are well ordered and have a similar secondary structure. CP27-215 was 15N labeled for NMR studies and a 2D 1H-15N-HSQC spectrum confirmed the presence of a well-ordered structure and the monomeric form of the protein. These results show that CP27-215 is amenable to a complete and exhaustive NMR study that should lead to the first three-dimensional structure determination of a flexuous rod shape virus.

  11. 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.

  12. Identification of synaptosomal proteins binding to monomeric and oligomeric α-synuclein.

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    Cristine Betzer

    Full Text Available Monomeric α-synuclein (αSN species are abundant in nerve terminals where they are hypothesized to play a physiological role related to synaptic vesicle turn-over. In Parkinson's disease (PD and dementia with Lewy body (DLB, αSN accumulates as aggregated soluble oligomers in terminals, axons and the somatodendritic compartment and insoluble filaments in Lewy inclusions and Lewy neurites. The autosomal dominant heritability associated to mutations in the αSN gene suggest a gain of function associated to aggregated αSN. We have conducted a proteomic screen to identify the αSN interactome in brain synaptosomes. Porcine brain synaptosomes were fractionated, solubilized in non-denaturing detergent and subjected to co-immunoprecipitation using purified recombinant human αSN monomers or oligomers as bait. The isolated αSN binding proteins were identified with LC-LTQ-orbitrap tandem mass spectrometry and quantified by peak area using Windows client application, Skyline Targeted Proteomic Environment. Data are available via ProteomeXchange with identifier PXD001462. To quantify the preferential binding an average fold increase was calculated by comparing binding to monomer and oligomer. We identified 10 proteins preferentially binding monomer, and 76 binding preferentially to oligomer and a group of 92 proteins not displaying any preferred conformation of αSN. The proteomic data were validated by immunoprecipitation in both human and porcine brain extracts using antibodies against monomer αSN interactors: Abl interactor 1, and myelin proteolipid protein, and oligomer interactors: glutamate decarboxylase 2, synapsin 1, glial fibrillary acidic protein, and VAMP-2. We demonstrate the existence of αSN conformation selective ligands and present lists of proteins, whose identity and functions will be useful for modeling normal and pathological αSN dependent processes.

  13. Determination of Abraham model solute descriptors for the monomeric and dimeric forms of trans-cinnamic acid using measured solubilities from the Open Notebook Science Challenge

    OpenAIRE

    Bradley, Jean-Claude; Abraham, Michael H.; Acree, William E.; Lang, Andrew SID; Beck, Samantha N; Bulger, David A; Clark, Elizabeth A.; Condron, Lacey N; Costa, Stephanie T; Curtin, Evan M; Kurtu, Sozit B; Mangir, Mark I; McBride, Matthew J

    2015-01-01

    Background Calculating Abraham descriptors from solubility values requires that the solute have the same form when dissolved in all solvents. However, carboxylic acids can form dimers when dissolved in non-polar solvents. For such compounds Abraham descriptors can be calculated for both the monomeric and dimeric forms by treating the polar and non-polar systems separately. We illustrate the method of how this can be done by calculating the Abraham descriptors for both the monomeric and dimeri...

  14. 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

    2018-02-02

    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.

  15. Sublingual Misoprostol versus Intramuscular Oxytocin for Prevention of Postpartum Hemorrhage in Uganda: A Double-Blind Randomized Non-Inferiority Trial

    Science.gov (United States)

    Atukunda, Esther C.; Siedner, Mark J.; Obua, Celestino; Mugyenyi, Godfrey R.; Twagirumukiza, Marc; Agaba, Amon G.

    2014-01-01

    Background Postpartum hemorrhage (PPH) is a leading cause of maternal death in sub-Saharan Africa. Although the World Health Organization recommends use of oxytocin for prevention of PPH, misoprostol use is increasingly common owing to advantages in shelf life and potential for sublingual administration. There is a lack of data about the comparative efficacy of oxytocin and sublingual misoprostol, particularly at the recommended dose of 600 µg, for prevention of PPH during active management of labor. Methods and Findings We performed a double-blind, double-dummy randomized controlled non-inferiority trial between 23 September 2012 and 9 September 2013 at Mbarara Regional Referral Hospital in Uganda. We randomized 1,140 women to receive 600 µg of misoprostol sublingually or 10 IU of oxytocin intramuscularly, along with matching placebos for the treatment they did not receive. Our primary outcome of interest was PPH, defined as measured blood loss ≥500 ml within 24 h of delivery. Secondary outcomes included measured blood loss ≥1,000 ml; mean measured blood loss at 1, 2, and 24 h after delivery; death; requirement for blood transfusion; hemoglobin changes; and use of additional uterotonics. At 24 h postpartum, primary PPH occurred in 163 (28.6%) participants in the misoprostol group and 99 (17.4%) participants in the oxytocin group (relative risk [RR] 1.64, 95% CI 1.32 to 2.05, ppostpartum hemoglobin, change in hemoglobin, or use of additional uterotonics between study groups. Further research should focus on clarifying whether and in which sub-populations use of oxytocin would be preferred over sublingual misoprostol. Trial registration ClinicalTrials.gov NCT01866241 Please see later in the article for the Editors' Summary PMID:25369200

  16. Concomitant occurrence of primary hyperparathyroidism (PHPT) due to mediastinal parathyroid adenoma and sublingual thyroid gland: the role of parathyroid technetium-99m-MIBI scintigraphy.

    Science.gov (United States)

    Choukry, Sara; Benouhoud, Jaafar; Cherkaoui Salhi, Ghofrane; Taleb, Sara; Guensi, Amal; Choukry, Karim

    2017-11-01

    The concomitant appearance of a sublingual thyroid and primary hyperparathyroidism due to parathyroid mediastinal adenoma is not common. This co-occurrence can lead to a misdiagnosis by morphological imaging methods alone. This case emphasizes the role of 99mTc-MIBI scintigraphy in the detection of parathyroid ectopic adenoma in a patient with an ectopic thyroid gland. This more accurate location of parathyroid scintigraphy is of great benefit to the surgeon for surgical excision.

  17. 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

  18. The folding unit of phosphofructokinase-2 as defined by the biophysical properties of a monomeric mutant.

    Science.gov (United States)

    Ramírez-Sarmiento, César A; Baez, Mauricio; Zamora, Ricardo A; Balasubramaniam, Deepa; Babul, Jorge; Komives, Elizabeth A; Guixé, Victoria

    2015-05-05

    monomerizing mutations. Copyright © 2015 Biophysical Society. Published by Elsevier Inc. All rights reserved.

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

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    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.

  20. Down-regulation of Th2 immune responses by sublingual administration of poly (lactic-co-glycolic) acid (PLGA)-encapsulated allergen in BALB/c mice.

    Science.gov (United States)

    Salari, Farhad; Varasteh, Abdol-Reza; Vahedi, Fatemeh; Hashemi, Maryam; Sankian, Mojtaba

    2015-12-01

    The goal of this study was to investigate whether poly (lactic-co-glycolic) acid (PLGA) nanoparticles could enhance sublingual immunotherapy (SLIT) efficacy. BALB/c mice sensitized to rChe a 3 were treated sublingually either with soluble rChe a 3 (100μg/dose) or PLGA-encapsulated rChe a 3 (5, 25, or 50μg/dose). SLIT with PLGA-encapsulated rChe a 3 (equivalent to 25 and 50μg rChe a 3 per dose) led to significantly increased antigen-specific IgG2a, along with no effect on allergen-specific IgE and IgG1 antibody levels. In addition, interleukin 4 (IL-4) levels in restimulated splenocytes were significantly less, while interferon-γ (IFN-γ), interleukin-10 (IL-10), and transforming growth factor-β (TGF-β) levels, as well as Foxp3 expression, were significantly greater than in the control groups. Our findings suggest that PLGA nanoparticle-based vaccination may help rational development of sublingual immunotherapy through reduction of the needed allergen doses and also significantly enhanced systemic T regulatory (Treg) and T helper 1 (Th1) immune responses. Copyright © 2015. Published by Elsevier B.V.

  1. 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.

  2. A Lipopolysaccharide from Pantoea Agglomerans Is a Promising Adjuvant for Sublingual Vaccines to Induce Systemic and Mucosal Immune Responses in Mice via TLR4 Pathway.

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    Masahiro Fukasaka

    Full Text Available A lipopolysaccharide from Pantoea agglomerans (LPSpa has been applied to various fields for human use as a Toll-like receptor 4 ligand and its safety has been confirmed. Here, we showed for the first time the application of LPSpa as an effective mucosal adjuvant for activating vaccine-induced antigen specific immune responses. Mice sublingually immunized with influenza vaccine (HA split vaccine with LPSpa induced both HA-specific IgG (systemic and IgA (mucosal antibody responses, which led to a significant increase in survival rate against lethal influenza virus challenge compared with subcutaneous vaccination. After sublingual administration of ovalbumin with LPSpa, ovalbumin-specific mucosal IgA responses were induced at both mucosal surfaces close to the immunized site and at remote mucosal surfaces. Sublingual administration of LPSpa evoked local antigen-uptake by dendritic cells in cervical lymph nodes. LPSpa induced cytokine production and the maturation and proliferation of innate immune cells via Toll-like receptor 4 in dendritic cells. Collectively, these results suggest that LPSpa can be used as an effective mucosal adjuvant to stimulate and activate local innate immune cells to improve and enhance mucosal vaccine potency against various pathogens.

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

    Directory of Open Access Journals (Sweden)

    Viviana De Caro

    2017-06-01

    Full Text Available 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. 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.

  5. Randomized double-blind placebo-controlled trial of sublingual immunotherapy in children with house dust mite allergy in primary care: study design and recruitment.

    Science.gov (United States)

    de Bot, Cindy M A; Moed, Heleen; Berger, Marjolein Y; Röder, Esther; de Groot, Hans; de Jongste, Johan C; van Wijk, Roy Gerth; van der Wouden, Johannes C

    2008-10-20

    For respiratory allergic disorders in children, sublingual immunotherapy has been developed as an alternative to subcutaneous immunotherapy. Sublingual immunotherapy is more convenient, has a good safety profile and might be an attractive option for use in primary care. A randomized double-blind placebo-controlled study was designed to establish the efficacy of sublingual immunotherapy with house dust mite allergen compared to placebo treatment in 6 to 18-year-old children with allergic rhinitis and a proven house dust mite allergy in primary care. Described here are the methodology, recruitment phases, and main characteristics of the recruited children. Recruitment took place in September to December of 2005 and 2006. General practitioners (in south-west Netherlands) selected children who had ever been diagnosed with allergic rhinitis. Children and parents could respond to a postal invitation. Children who responded positively were screened by telephone using a nasal symptom score. After this screening, an inclusion visit took place during which a blood sample was taken for the RAST test. A total of 226 general practitioners invited almost 6000 children: of these, 51% was male and 40% <12 years of age. The target sample size was 256 children; 251 patients were finally included. The most frequent reasons given for not participating were: absence or mildness of symptoms, absence of house dust mite allergy, and being allergic to grass pollen or tree pollen only. Asthma symptoms were reported by 37% of the children. Of the enrolled children, 71% was sensitized to both house dust mite and grass pollen. Roughly similar proportions of children were diagnosed as being sensitized to one, two, three or four common inhalant allergens. Our study was designed in accordance with recent recommendations for research on establishing the efficacy of sublingual immunotherapy; 98% of the target sample size was achieved. This study is expected to provide useful information on

  6. 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

  7. Inhalant allergy compounding the chronic vaginitis syndrome: characterization of sensitization patterns, comorbidities and responses to sublingual immunotherapy.

    Science.gov (United States)

    Theodoropoulos, Demetrios S; Stockdale, Colleen K; Duquette, Daniel R; Morris, Mary S

    2016-09-01

    To characterize sensitization patterns, diagnoses and comorbidities, and to assess the response of lower genital tract symptoms to sublingual immunotherapy for airborne allergens in a select population of patients with chronic vaginitis. Fifty-two patients referred for allergy evaluation over a 44 month period were studied. Charts were retrospectively reviewed to establish: (1) gynecological diagnoses, (2) allergic-immunological diagnoses, and (3) IgE-mediated sensitivity to airborne allergens on presentation. Patients were contacted at 9-50 months of treatment to assess response to sublingual immunotherapy based on a questionnaire addressing frequency and severity of symptoms and use of medication to control symptoms. Recurrent vulvovaginal candidiasis was identified in 34 (65 %); vulvar vestibulitis syndrome in 12 (23 %); and contact dermatitis in 10 (19 %) patients. Comorbidities included: non-reflux gastrointestinal complaints in 11 (21 %), gastroesophageal reflux in 5 (9 %), migraines in 9 (17 %), chronic non-migrainous headaches in 8 (17 %), and chronic sinusitis in 6 patients (11 %). Asthma was diagnosed in 8 patients (15 %). Oral allergy syndrome was present in 6 (11 %). Most frequent sensitivities were to: ragweed in 33 (63 %), molds in 26 (50 %), dust mites in 23 (44 %), and grass in 12 (23 %) patients. Mono-sensitization was demonstrated for ragweed in 7 (13 %), and for molds, dust mites and grass for 3 (5 %) patients each. Candida sensitization was identified in 15 patients with chronic vaginitis (28 %). Eleven patients with recurrent vulvovaginal diagnosis (32 %) showed Candida sensitization. Response to immunotherapy was generally favorable with pruritus/irritation being more responsive than visceral pain. In a Midwestern referral population, chronic vaginitis compounded by inhalant allergy showed: (1) high incidence rate of recurrent vulvo-vaginal candidiasis, (2) Candida IgE-mediated sensitization in less than one-third of

  8. Three-dimensional structure of the 3'X-tail of hepatitis C virus RNA in monomeric and dimeric states.

    Science.gov (United States)

    Cantero-Camacho, Ángel; Fan, Lixin; Wang, Yun-Xing; Gallego, José

    2017-09-01

    The 3'X domain is a 98-nt region located at the 3' end of hepatitis C virus genomic RNA that plays essential functions in the viral life cycle. It contains an absolutely conserved, 16-base palindromic sequence that promotes viral RNA dimerization, overlapped with a 7-nt tract implicated in a distal contact with a nearby functional sequence. Using small angle X-ray scattering measurements combined with model building guided by NMR spectroscopy, we have studied the stoichiometry, structure, and flexibility of domain 3'X and two smaller subdomain sequences as a function of ionic strength, and obtained a three-dimensional view of the full-length domain in its monomeric and dimeric states. In the monomeric form, the 3'X domain adopted an elongated conformation containing two SL1' and SL2' double-helical stems stabilized by coaxial stacking. This structure was significantly less flexible than that of isolated subdomain SL2' monomers. At higher ionic strength, the 3'X scattering envelope nearly doubled its size, reflecting the formation of extended homodimers containing an antiparallel SL2' duplex flanked by coaxially stacked SL1' helices. Formation of these dimers could initialize and/or regulate the packaging of viral RNA genomes into virions. © 2017 Cantero-Camacho et al.; Published by Cold Spring Harbor Laboratory Press for the RNA Society.

  9. Structural analysis of the bright monomeric yellow-green fluorescent protein mNeonGreen obtained by directed evolution.

    Science.gov (United States)

    Clavel, Damien; Gotthard, Guillaume; von Stetten, David; De Sanctis, Daniele; Pasquier, Hélène; Lambert, Gerard G; Shaner, Nathan C; Royant, Antoine

    2016-12-01

    Until recently, genes coding for homologues of the autofluorescent protein GFP had only been identified in marine organisms from the phyla Cnidaria and Arthropoda. New fluorescent-protein genes have now been found in the phylum Chordata, coding for particularly bright oligomeric fluorescent proteins such as the tetrameric yellow fluorescent protein lanYFP from Branchiostoma lanceolatum. A successful monomerization attempt led to the development of the bright yellow-green fluorescent protein mNeonGreen. The structures of lanYFP and mNeonGreen have been determined and compared in order to rationalize the directed evolution process leading from a bright, tetrameric to a still bright, monomeric fluorescent protein. An unusual discolouration of crystals of mNeonGreen was observed after X-ray data collection, which was investigated using a combination of X-ray crystallography and UV-visible absorption and Raman spectroscopies, revealing the effects of specific radiation damage in the chromophore cavity. It is shown that X-rays rapidly lead to the protonation of the phenolate O atom of the chromophore and to the loss of its planarity at the methylene bridge.

  10. Quantitative analysis and parametric imaging of 18F-labeled monomeric and dimeric RGD peptides using compartment model.

    Science.gov (United States)

    Guo, Ning; Lang, Lixin; Gao, Haokao; Niu, Gang; Kiesewetter, Dale O; Xie, Qingguo; Chen, Xiaoyuan

    2012-12-01

    Non-invasive PET imaging with radiolabeled RGD peptides for α(v)β(3) integrin targeting has become an important tool for tumor diagnosis and treatment monitoring in both pre-clinical and clinical studies. To better understand the molecular process and tracer pharmacokinetics, we introduced kinetic modeling in the investigation of (18)F-labeled RGD peptide monomer (18)F-FP-c(RGDyK) (denoted as (18)F-FPRGD) and dimer (18)F-FP-PEG3-E[c(RGDyK)](2) (denoted as (18)F-FPPRGD2). MDA-MB-435 tumor-bearing mice underwent 60 min dynamic PET scans following the injection of either (18)F-FPRGD or (18)F-FPPRGD2. Blocking studies with pre-injection of a blocking mass dose were performed for both monomeric and dimeric RGD groups. (18)F-FPRAD (RAD) was used as a negative control. Kinetic parameters (K(1), k(2), k(3), k(4)) of a three-compartment model were fitted to the dynamic data to allow quantitative comparisons between the monomeric and dimeric RGD peptides. Dimeric RGD peptide tracer showed significantly higher binding potential (Bp(ND) = k(3)/k(4), 5.87 ± 0.31) than that of the monomeric analog (2.75 ± 0.48, p = 0.0022, n = 4/group). The Bp(ND) values showed a significantly greater ratio (dimer/monomer ~2.1) than the difference in %ID/g uptake measured from static images (dimer/monomer ~1.5, p = 0.0045). Significant decrease in Bp(ND) was found in the blocked groups compared with the unblocked ones (dimer p = 0.00024, monomer p = 0.005, n = 4/group). Similarly, the RAD control group showed the lowest Bp(ND) value among all the test groups, as the RAD peptide does not bind to integrin α(v)β(3). Volume of distribution (V(T) = K(1)/k (2)(1 + k (3)/k (4))) could be separated into non-specific (V (ND) = K (1)/k (2)) and specific (V (S) = K (1) k (3)/(k (2) k (4))) components. Specific distribution volume (V(S)) was the dominant component of V(T) in the unblocked groups and decreased in the blocked groups. Unblocked RGD dimer also showed higher V(S) than that of the monomer

  11. Efficacy and safety of sublingual immunotherapy for allergic rhinitis in pediatric patients: A meta-analysis of randomized controlled trials.

    Science.gov (United States)

    Feng, Bohai; Wu, Jueting; Chen, Bobei; Xiang, Haijie; Chen, Ruru; Li, Bangliang; Chen, Si

    2017-01-01

    Allergic rhinitis (AR) has become a global health problem that constantly affects a large part of the general population, especially children. Sublingual allergen immunotherapy (SLIT) has been used extensively for pediatric AR, although its efficacy and safety are often questioned. In this meta-analysis of randomized controlled trials (RCT), we evaluated the use of SLIT for pediatric AR. A number of medical literature data bases were searched through January 2016 to identify RCTs that examined the use of SLIT for pediatric AR and that assessed clinical outcomes related to efficacy. Descriptive and quantitative information was abstracted. Standardized mean differences (SMD) were calculated by using fixed- and random-effects models. Subgroup analyses were performed. Heterogeneity was assessed by using the I2 metric. A network meta-analysis was used to estimate SMDs between two SLIT protocols for pediatric seasonal AR. All data were extracted from publications or received from the authors. Twenty-six studies were eligible for inclusion in the meta-analysis of rhinitis or rhinoconjunctivitis symptom scores, and 19 studies were eligible for the meta-analysis of medication scores. Descriptive and quantitative data were extracted. SLIT differed significantly from placebo in terms of symptom scores (SMD -0.55 [95% confidence interval {CI}, -0.86 to -0.25]; p = 0.0003, I2 = 90%) and medication scores (SMD -0.67 [95% CI, -0.96 to -0.38]; p pediatric patients. Moreover, the safety of SLIT needs to be confirmed in RCTs with larger samples.

  12. Correlation between early sublingual small vessel density and late blood lactate level in critically ill surgical patients.

    Science.gov (United States)

    Yeh, Yu-Chang; Wang, Ming-Jiuh; Chao, Anne; Ko, Wen-Je; Chan, Wing-Sum; Fan, Shou-Zen; Tsai, Jui-Chang; Sun, Wei-Zen

    2013-04-01

    Surgical stress may cause excessive inflammation and lead to microcirculatory dysfunction. The hypothesis of this study was that early microcirculatory dysfunction may result in anaerobic glycolysis and lead to elevated blood lactate levels in patients admitted to surgical intensive care units. This prospective observational study enrolled adult patients admitted to surgical intensive care units after general surgery or thoracic surgery. We measured blood lactate levels before the operation and at 1 h and 24 h after the operation. We obtained images of sublingual microcirculation using a sidestream dark field video microscope and analyzed them employing automated analysis software. A total of 31 patients completed the study. Perioperative total and perfused small vessel densities were lower in patients with a blood lactate level ≥3 mmol/L. We observed a significant correlation between the total small vessel density at 1 h and the blood lactate level at 24 h (r = -0.573; P = 0.001). In addition, we saw a significant correlation between the perfused small vessel density at 1 h and the blood lactate level at 24 h (r = -0.476; P = 0.008). Early total and perfused small vessel density may be used as an early predictor or therapeutic goal for critically ill surgical patients in further studies. Copyright © 2013 Elsevier Inc. All rights reserved.

  13. [Efficacy of individualized sublingual immunotherapy with dermatophagoides farinae drops on patients with allergic rhinitis of different age groups].

    Science.gov (United States)

    Liu, Jiping; Hu, Xiaoxun; Fu, Shucai; Wu, Chunxuan; Chen, Heling; Zhang, Min

    2014-03-01

    To evaluate the efficacy of personal sublingual immunotherapy (SLIT) with dermatophagoides to study the efficacy of dermatophagoides farinae drops for allergic rhinitis (AR) of different age groups. The current study had analyzed the efficacy of SLIT in 150 patients with AR who were sensitized to house dust mites. All patients were treated with dermatophagoides farinae drops and combined with symptomatic treatment. The patients were divided into groups 1-5, group 1:17 patients (4-7 years old), group 2: 38 patients (> 7-12 years old), group 3:31 patients (> 12-18 years old), group 4: 38 patients (> 18 - 40 years old), group 5: 26 patients (> 40-63 years old). The total nasal symptom scores (TNSS) and total medicine scores (TMS) were recorded at each visit. Before and after SLIT for 0.5 year, 1 year and 1.5 to 2.0 years, the TNSS and TMS of each patient were evaluated. The dosage adjustment of immunotherapy according to the patient's symptoms were performed. The TNSS and TMS had continuously improved significantly after SLIT for half year, 1 year and 1.5 to 2.0 years in all groups as compared with baseline (P differences in the different age groups for TNSS and TMS during all time points. Individualized SLIT with dermatophagoides farinae drops for 1.5-2.0 years is the most effective in the patients with allergic rhinitis of different age groups. And equivalent efficacy could be achieved for different age groups.

  14. Breakthrough Pain Management with Sublingual Fentanyl Tablets in Patients with Cancer: Age Subgroup Analysis of a Multicenter Prospective Study.

    Science.gov (United States)

    Guitart, Jordi; Vargas, María Isabel; De Sanctis, Vicente; Folch, Jordi; Salazar, Rafael; Fuentes, José; Coma, Joan; Ferreras, Julia; Moya, Jordi; Tomás, Albert; Estivill, Pere; Rodelas, Francisco; Jiménez, Antonio Javier; Sanz, Almudena

    2017-09-01

    Breakthrough pain (BTP) management in patients with cancer is challenging, especially in the elderly. However, no studies examining the influence of age on BTP medication have been conducted. The aim of this work was to investigate the effect of sublingual fentanyl tablets (SFTs) in terms of efficacy, safety, and quality of life in two age categories. We performed age subgroup analyses (Pain intensity (PI), onset of pain relief, frequency and duration of BTP episodes, and adverse events (AEs) were assessed at 3, 7, 15, and 30 days. Health-status instruments used were the Short Form 12, version 2 (SF-12v2) questionnaire, and the Hospital Anxiety and Depression Scale (HADS-A and HADS-D). Twenty-six patients were aged 65 years. Most patients experienced one to five daily episodes after 30 days, and <5% needed a treatment change. AEs were less frequently reported in older individuals (20.5 vs. 36.4%). Age subgroup analyses suggest that SFTs are an effective and safe treatment for the management of BTP in cancer patients of all ages. SFTs may offer a well-tolerated and efficient option to control cancer BTP in the elderly.

  15. 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.

  16. Single Enzyme Studies Reveal the Existence of Discrete Functional States for Monomeric Enzymes and How They Are “Selected” upon Allosteric Regulation

    DEFF Research Database (Denmark)

    Hatzakis, Nikos S.; Wei, Li; Jørgensen, Sune Klamer

    2012-01-01

    Allosteric regulation of enzymatic activity forms the basis for controlling a plethora of vital cellular processes. While the mechanism underlying regulation of multimeric enzymes is generally well understood and proposed to primarily operate via conformational selection, the mechanism underlying...... with the enzyme’s major conformational states and are redistributed in the presence of the regulatory effector. Thus, our data support allosteric regulation of monomeric enzymes to operate via selection of preexisting functional states and not via induction of ones.......Allosteric regulation of enzymatic activity forms the basis for controlling a plethora of vital cellular processes. While the mechanism underlying regulation of multimeric enzymes is generally well understood and proposed to primarily operate via conformational selection, the mechanism underlying...... allosteric regulation of monomeric enzymes is poorly understood. Here we monitored for the first time allosteric regulation of enzymatic activity at the single molecule level. We measured single stochastic catalytic turnovers of a monomeric metabolic enzyme (Thermomyces lanuginosus Lipase) while titrating...

  17. Impacto do sildenafil sublingual na hipertensão pulmonar de pacientes com insuficiência cardíaca Impacto del sildenafil sublingual en la hipertensión pulmonar de pacientes con insuficiencia cardiaca Impact of sublingual sildenafil on pulmonary hypertension in patients with heart failure

    Directory of Open Access Journals (Sweden)

    Aguinaldo Figueiredo de Freitas Jr.

    2009-02-01

    Full Text Available FUNDAMENTO: A hipertensão pulmonar (HP é fator de mau prognóstico no pós-operatório de transplante cardíaco (TC e, desta forma, o estudo do grau de reversibilidade a vasodilatadores é obrigatório durante avaliação pré-operatória. OBJETIVO: Avaliar os efeitos hemodinâmicos pulmonares e sistêmicos do sildenafil como droga vasodilatadora durante o teste de reversibilidade da HP em candidatos a transplante cardíaco. MÉTODOS: Pacientes em fila para TC foram submetidos à medida de variáveis hemodinâmicas sistêmicas e pulmonares antes e após a administração de 100mg dose única e sublingual de sildenafil, durante cateterização cardíaca direita. RESULTADOS: Quatorze pacientes (idade: 47±12 anos, 71,4% homens com insuficiência cardíaca avançada, Fração de Ejeção (FE 25 ± 7%, Classe Funcional (CF- NYHA CF III - 6 e CF IV - 8, foram avaliados neste estudo. A administração aguda de sildenafil mostrou ser eficaz na redução das pressões sistólica (62,4 ± 12,1 vs. 51,5 ± 9,6 mmHg, IC=95%, pFUNDAMENTO: La hipertensión pulmonar (HP se muestra factor de mal pronóstico en el postoperatorio de transplante cardiaco (TC y, de esta forma, el estudio del grado de reversibilidad a vasodilatadores se vuelve obligatorio durante evaluación preoperatoria. OBJETIVO: Evaluar los efectos hemodinámicos pulmonares y sistémicos del Sildenafil como droga vasodilatadora durante la prueba de reversibilidad de la HP en candidatos a transplante cardiaco. MÉTODOS: Pacientes en fila para TC fueron sometidos a la medición de variables hemodinámicas sistémicas y pulmonares, antes y luego de la administración de 100mg en dosificación única y sublingual de Sildenafil, durante cateterización cardiaca derecha. RESULTADOS: Se evaluaron en este estudio a 14 pacientes (edad: 47±12 años, el 71,4% varones con insuficiencia cardiaca avanzada, fracción de eyección (FE 25 ± 7%, clase funcional (CF-NYHA CF III - 6 y CF IV - 8. La

  18. Mixed oligomers and monomeric amyloid-β disrupts endothelial cells integrity and reduces monomeric amyloid-β transport across hCMEC/D3 cell line as an in vitro blood-brain barrier model.

    Science.gov (United States)

    Qosa, Hisham; LeVine, Harry; Keller, Jeffrey N; Kaddoumi, Amal

    2014-09-01

    Senile amyloid plaques are one of the diagnostic hallmarks of Alzheimer's disease (AD). However, the severity of clinical symptoms of AD is weakly correlated with the plaque load. AD symptoms severity is reported to be more strongly correlated with the level of soluble amyloid-β (Aβ) assemblies. Formation of soluble Aβ assemblies is stimulated by monomeric Aβ accumulation in the brain, which has been related to its faulty cerebral clearance. Studies tend to focus on the neurotoxicity of specific Aβ species. There are relatively few studies investigating toxic effects of Aβ on the endothelial cells of the blood-brain barrier (BBB). We hypothesized that a soluble Aβ pool more closely resembling the in vivo situation composed of a mixture of Aβ40 monomer and Aβ42 oligomer would exert higher toxicity against hCMEC/D3 cells as an in vitro BBB model than either component alone. We observed that, in addition to a disruptive effect on the endothelial cells integrity due to enhancement of the paracellular permeability of the hCMEC/D3 monolayer, the Aβ mixture significantly decreased monomeric Aβ transport across the cell culture model. Consistent with its effect on Aβ transport, Aβ mixture treatment for 24h resulted in LRP1 down-regulation and RAGE up-regulation in hCMEC/D3 cells. The individual Aβ species separately failed to alter Aβ clearance or the cell-based BBB model integrity. Our study offers, for the first time, evidence that a mixture of soluble Aβ species, at nanomolar concentrations, disrupts endothelial cells integrity and its own transport across an in vitro model of the BBB. Copyright © 2014 Elsevier B.V. All rights reserved.

  19. Assessment of the ventilation function and serum biochemical indexes after sublingual dermatophagoides farinae drops combined with loratadine treatment of children with asthma and allergic rhinitis

    Directory of Open Access Journals (Sweden)

    Ruo-Qing Qiu

    2017-06-01

    Full Text Available Objective: To study the ventilation function after sublingual dermatophagoides farinae drops combined with loratadine treatment of children with asthma and allergic rhinitis and the influence on serum biochemical indexes. Methods: A total of 40 children with asthma and allergic rhinitis treated in our hospital between September 2013 and March 2015 were collected and divided into the control group (n=22 who accepted loratadine therapy alone and the observation group (n=18 who accepted sublingual dermatophagoides farinae drops combined with loratadine therapy after the treatment was reviewed. Before treatment and after 6 months and 1 year of treatment, spirometer was used to test ventilation function indexes; ELISA method was used to determine the contents of inflammatory mediators; RIA method was used to determine the contents of airway remodeling indicators. Results: Before treatment, differences in ventilation function index levels as well as inflammatory mediator and airway remodeling index contents were not statistically significant between two groups of children. After 6 months and 1 year of treatment, FEV1, FVC and PEF levels of observation group were higher than those of control group; serum IL-2 content was higher than that of control group while IL-5, IL-17 and IL-33 contents were lower than those of control group; serum PDGFBB, TGF-β1 and NF-κB contents were lower than those of control group. Conclusion: Sublingual dermatophagoides farinae drops combined with loratadine therapy can optimize the ventilation function, reduce the systemic inflammatory response and inhibit airway remodeling in children with asthma and allergic rhinitis.

  20. Effect of Two Years of Treatment with Sublingual Grass Pollen Immunotherapy on Nasal Response to Allergen Challenge at Three Years among Patients with Moderate to Severe Seasonal Allergic Rhinitis: A Randomized Clinical Trial

    Science.gov (United States)

    Scadding, Guy W.; Calderon, Moises A.; Shamji, Mohamed H.; Eifan, Aarif O.; Penagos, Martin; Dumitru, Florentina; Sever, Michelle L.; Bahnson, Henry T; Lawson, Kaitie; Harris, Kristina M.; Plough, Audrey G.; Panza, Joy Laurienzo; Qin, Tielin; Lim, Noha; Tchao, Nadia K.; Togias, Alkis; Durham, Stephen R.

    2017-01-01

    Importance Sublingual immunotherapy and subcutaneous immunotherapy are effective in seasonal allergic rhinitis. Three years of continuous treatment with subcutaneous immunotherapy and sublingual immunotherapy has been shown to improve symptoms for at least two years following discontinuation of treatment. Objective To assess whether 2 years of treatment with grass pollen sublingual immunotherapy compared with placebo provides improved nasal response to allergen challenge at 3 year follow-up. Design, Setting, Participants A randomized double-blind, placebo-controlled, 3-parallel group study performed in a single academic centre, Imperial College London, including adult patients with moderate-to-severe seasonal allergic rhinitis (interfering with usual daily activities or sleep). First enrolment was March 2011, last follow-up February 2015. Intervention Thirty-six participants received 2 years sublingual immunotherapy (daily tablets containing 15 microgram of major allergen Phleum p 5 and monthly placebo injections), 36 received subcutaneous immunotherapy (monthly injections containing 20 micrograms of Phleum p 5 and daily placebo tablets) and 34 received matched double-placebo. Nasal allergen challenge was performed before treatment, at 1 and 2 years and at 3 years (1 year after treatment discontinuation). Main outcomes and measures Total nasal symptom scores (TNSS, range 0 (best) to 12 (worst) were recorded during 0–10 hours after challenge. The minimum clinically important difference for change in TNSS within an individual is 1.08. The primary outcome was TNSS comparing sublingual immunotherapy to placebo at year 3. Subcutaneous immunotherapy was included as a positive control. The study was not powered to compare sublingual immunotherapy with subcutaneous immunotherapy. Results Among 106 participants who were randomized (mean age 33.5 years, 32.1% female), 92 completed the study at 3 years. Imputed TNSS scores [mean (95% confidence intervals)] pre-treatment and

  1. Effect of 2 Years of Treatment With Sublingual Grass Pollen Immunotherapy on Nasal Response to Allergen Challenge at 3 Years Among Patients With Moderate to Severe Seasonal Allergic Rhinitis: The GRASS Randomized Clinical Trial.

    Science.gov (United States)

    Scadding, Guy W; Calderon, Moises A; Shamji, Mohamed H; Eifan, Aarif O; Penagos, Martin; Dumitru, Florentina; Sever, Michelle L; Bahnson, Henry T; Lawson, Kaitie; Harris, Kristina M; Plough, Audrey G; Panza, Joy Laurienzo; Qin, Tielin; Lim, Noha; Tchao, Nadia K; Togias, Alkis; Durham, Stephen R

    2017-02-14

    Sublingual immunotherapy and subcutaneous immunotherapy are effective in seasonal allergic rhinitis. Three years of continuous treatment with subcutaneous immunotherapy and sublingual immunotherapy has been shown to improve symptoms for at least 2 years following discontinuation of treatment. To assess whether 2 years of treatment with grass pollen sublingual immunotherapy, compared with placebo, provides improved nasal response to allergen challenge at 3-year follow-up. A randomized double-blind, placebo-controlled, 3-parallel-group study performed in a single academic center, Imperial College London, of adult patients with moderate to severe seasonal allergic rhinitis (interfering with usual daily activities or sleep). First enrollment was March 2011, last follow-up was February 2015. Thirty-six participants received 2 years of sublingual immunotherapy (daily tablets containing 15 µg of major allergen Phleum p 5 and monthly placebo injections), 36 received subcutaneous immunotherapy (monthly injections containing 20 µg of Phleum p 5 and daily placebo tablets) and 34 received matched double-placebo. Nasal allergen challenge was performed before treatment, at 1 and 2 years of treatment, and at 3 years (1 year after treatment discontinuation). Total nasal symptom scores (TNSS; range; 0 [best] to 12 [worst]) were recorded between 0 and 10 hours after challenge. The minimum clinically important difference for change in TNSS within an individual is 1.08. The primary outcome was TNSS comparing sublingual immunotherapy vs placebo at year 3. Subcutaneous immunotherapy was included as a positive control. The study was not powered to compare sublingual immunotherapy with subcutaneous immunotherapy. Among 106 randomized participants (mean age, 33.5 years; 34 women [32.1%]), 92 completed the study at 3 years. In the intent-to-treat population, mean TNSS score for the sublingual immunotherapy group was 6.36 (95% CI, 5.76 to 6.96) at pretreatment and 4.73 (95% CI, 3.97 to 5

  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. 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

    to elicit antibodies preferentially neutralizing mutant variants of HIV-BRU lacking the N306 glycan. Therefore, two guinea pigs were immunized with monomeric wild-type HIV-BRU gp120 possessing the N306 glycan and immune sera were tested for neutralization against target viruses HIV-BRU, -A308, and -A308T321....... HIV-A308 and HIV-A308T321 lack the N306 glycan; HIV-A308T321 contains an additional mutation at the tip of V3 rendering it resistant to MAb binding at this epitope. Both immune sera preferentially neutralized the two mutant virus variants lacking the N306 glycan, with a 10- to 20-fold increase...

  4. Antigenic determinants of influenza virus haemagglutinin. X. A comparison of the physical and antigenic properties of monomeric and trimeric forms.

    Science.gov (United States)

    Nestorowicz, A; Laver, G; Jackson, D C

    1985-08-01

    Haemagglutinin prepared from influenza virus A/Memphis/1/71 by bromelain digestion was centrifuged through continuous sucrose gradients buffered at pH 7.4 or pH 4.9. From these gradients were isolated two forms of the protein which displayed different equilibrium sedimentation properties. One species behaved as a molecule with a mol. wt. of 190 000, the other with a mol. wt. of 70 000. These results are consistent with the separation of trimeric and monomeric haemagglutinin. A comparison of their antigenic properties, using monoclonal antibodies raised against intact virus, showed that major antigenic differences occur between the two forms of haemagglutinin. None of the monoclonal antibodies reacted with haemagglutinin denatured by reduction and alkylation.

  5. 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 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.

  6. Sublingual immunotherapy abrogates seasonal bronchial hyperresponsiveness in children with Parietaria-induced respiratory allergy: a randomized controlled trial.

    Science.gov (United States)

    Pajno, G B; Passalacqua, G; Vita, D; Caminiti, L; Parmiani, S; Barberio, G

    2004-08-01

    The use of immunotherapy in asthmatic children is still controversial. Sublingual immunotherapy (SLIT) may represent an advance, due to the good safety profile, but little is known about its effects on lung function and nonspecific bronchial responsiveness. The aim of this study was to assess the effects of SLIT on these parameters, in children with Parietaria pollen-induced asthma. Thirty children with asthma solely due to Parietaria who participated in a previous randomized, placebo-controlled trial with SLIT were studied: pulmonary function test and methacholine challenge were carried out at baseline in winter 1999 (out season), during the 1999 season (before randomization), and during the 2001 season. Before randomization, there was a significant fall in methacholine provocation concentration during the pollen season vs baseline in both groups (SLIT group 9.78 +/- 5.95 mg/ml vs 3.37 +/- 2.99 mg/ml; placebo 8.70 +/- 6.25 mg/ml vs 2.44 +/- 2.25 mg/ml; P =.005). In the second pollen season, the response to methacholine returned to baseline values in the active group (9.10 +/- 7.7 mg/ml; P = NS vs baseline), whereas in the placebo group a significant increase in reactivity was still present (2.46 +/- 2.26; P = 0.008 vs baseline). No significant difference in FEV(1) and FEF(25-75) between the two groups was observed at all times. Our data show that SLIT abrogates the seasonal bronchial hyperreactivity in children with asthma due to Parietaria. This may be regarded as an indirect evidence of the effect on bronchial inflammation.

  7. Changes in cytokine profiles following treatment with food allergen-specific sublingual immunotherapy in dogs with adverse food reactions.

    Science.gov (United States)

    Maina, Elisa; Devriendt, Bert; Cox, Eric

    2017-12-01

    Food allergen-specific sublingual immunotherapy (FA-SLIT) is considered to be a novel, safe and effective approach in dogs with adverse food reactions (AFR). To investigate changes in key cytokines associated with FA-SLIT. Eleven dogs with confirmed AFR. Participants received either dose escalation of FA-SLIT or placebo over a six month period. Oral food challenge was performed at the beginning and end of the study, along with clinical examinations and collection of skin surface bacterial cytology and blood. Peripheral blood mononuclear cells were stimulated with the culprit food antigen. ELISA methods were used to quantify Interleukin (IL)-10, IFN-γ, IL-4 and IL-17A in the supernatant of stimulated cells. IL-10 and IFN-γ levels were significantly increased at the end of the study in the treatment group (T), compared with the placebo group (P), whereas no changes were found in IL-4 levels. IL-17A levels were decreased in both groups (but more profoundly in T). Bacterial scores on the skin were positively correlated with IL-17A and inversely correlated with IL-10 concentrations. Interleukins were not correlated with clinical scores. FA-SLIT may modulate the allergic response toward Th1 and Treg cell phenotypes, and induction of tolerance in dogs with AFR. Therefore, FA-SLIT may be a tool to desensitize dogs with AFR. However, more data on a larger number of cases and a broader panel of cytokines are needed to corroborate these findings, and to elucidate the mechanism of action for responses to FA-SLIT by dogs with AFR. © 2017 ESVD and ACVD.

  8. Sublingual Fentanyl Tablets for Relief of Breakthrough Pain in Cancer Patients and Association with Quality-of-Life Outcomes.

    Science.gov (United States)

    Guitart, Jordi; Vargas, María Isabel; De Sanctis, Vicente; Folch, Jordi; Salazar, Rafael; Fuentes, José; Coma, Jordi; Ferreras, Julia; Moya, Jordi; Tomás, Albert; Estivill, Pere; Rodelas, Francisco; Jiménez, Antonio Javier

    2015-12-01

    Breakthrough pain (BTP) is highly prevalent in patients with cancer and is strongly associated with adverse outcomes related to health status, mood, anxiety and depression. However, studies on the effect of BTP medication on quality of life (QOL) are lacking. The purpose of this study was to provide a qualitative evaluation of the effect of sublingual fentanyl tablets (SFT), a therapy specifically developed for BTP, on the QOL of cancer pain patients. We conducted a multicentre, prospective observation post-authorisation, open-label study between March and December 2013. The study consisted of a screening visit and four assessment points at 3, 7, 15 and 30 days. Pain intensity (PI), frequency of BTP, onset of pain relief and adverse events (AEs) were assessed at each visit. Anxiety and depression were evaluated using the validated Hospital Anxiety and Depression Scale (HADS) and health status using the Short Form 12, version 2 (SF-12v2) Health Survey. Of the 102 patients considered eligible, 81 (79.4 %) were enrolled; of these, 69 (85.1 %) completed the study. Significant pain reduction was achieved for average PI (p < 0.001) compared with baseline. At the end of the observational period, HADS scores showed significant improvement in the depression subscale (p = 0.005) and the anxiety subscale (p < 0.001). Similarly, SF-12 scores showed significant improvement, both in the mental component score (p < 0.001) and the physical component score (p = 0.002). SFT was well-tolerated and only one patient withdrew from the study due to drug-related AEs. SFT represents an effective, well-tolerated treatment for cancer BTP. Results provide consistent evidence for the positive impact of SFT on health-related QOL and physical functioning as well as other co-morbidities of cancer BTP such as anxiety and depression.

  9. Efficacy of Sublingual Immunotherapy for House Dust Mite-Induced Allergic Rhinitis: A Meta-Analysis of Randomized Controlled Trials

    Science.gov (United States)

    Feng, Bohai; Xiang, Haijie; Jin, Haiyong; Gao, Jinjian; Huang, Saiyu; Shi, Yunbin; Chen, Ruru

    2017-01-01

    Purpose Allergic rhinitis (AR) has become a global issue for a large part of the general population. Sublingual immunotherapy (SLIT) has been used extensively to treat persistent allergic rhinitis (PAR). Although systematic reviews have confirmed the effectiveness of SLIT for the treatment of AR, a considerable number of studies using extracts of house dust mites (HDMs) for immunotherapy found no consensus on basic treatment parameters and questioned the efficacy of SLIT. Methods In this study, we evaluated SLIT for PAR by a meta-analysis of randomized controlled trials (RCTs). Medline, Embase, and Cochrane Library database searches were performed for RCTs on the treatment of PAR by SLIT that assessed clinical outcomes related to efficacy through May 2016. Descriptive and quantitative information was abstracted. An analysis was performed with standardized mean differences (SMDs) under a fixed or random effects model. Subgroup analyses were performed. Heterogeneity was assessed using the I2 metric. Results In total, 25 studies were eligible for inclusion in the meta-analysis for symptom scores and 15 studies for medication scores. SLIT was significantly different from the controls for symptom scores (SMD=1.23; 95% confidence interval [CI]=1.74 to 0.73; P<0.001). For medication scores, significant differences for SLIT were also observed versus the controls (SMD=-1.39; 95% CI=-1.90 to -0.88; P<0.001). Conclusions Our meta-analysis indicates that SLIT provided significant symptom relief and reduced the need for medications in PAR. In this study, significant evidence was obtained despite heterogeneity with regard to the use of mite extract. Specifically, the mite extract used was provided by the patients with PAR. Furthermore, to confirm both the objective outcomes and the effective doses of HDM allergen extracts, experimental data should be obtained from large high-quality population-based studies. PMID:28293928

  10. Major allergen content consistency of SQ house dust mite sublingual immunotherapy tablets and relevance across geographic regions.

    Science.gov (United States)

    Nolte, Hendrik; Plunkett, Greg; Grosch, Karin; Larsen, Jorgen Nedergaard; Lund, Kaare; Bollen, Mirko

    2016-09-01

    Consistency in composition and potency, particularly regarding major allergens, is crucial for the quality of extracts for allergen immunotherapy. To characterize the major allergen composition of house dust mite (HDM) extracts commercially available in the United States and the SQ HDM sublingual immunotherapy (SLIT) tablet, and to relate the composition to patient sensitization patterns. Der 1/Der 2 ratios were determined in 10,000- and 30,000-AU/mL HDM extracts from 5 US companies and the SQ HDM SLIT-tablet. Allergen content was analyzed by enzyme-linked immunosorbent assay and compared with an in-house reference. Sensitivity toward Der p 1, Der p 2, and Der p 10 was determined in serum from randomly selected subgroups of 220 individuals from North American and European SQ HDM SLIT-tablet trials. Mean Der 1/Der 2 ratios in US HDM extracts ranged from 0.4 to 20.5. For the SQ HDM SLIT-tablet (20 batches), variability did not exceed 12% regarding content of Der f 1 (SD, 11.9%; 95% confidence interval [CI], 0.94-1.06), Der p 1 (SD, 6.1%; 95% CI, 0.97-1.03), and combined Der 2 allergen (SD, 6.4%; 95% CI, 0.97-1.03), indicating a consistent Der 1/Der 2 ratio. High allergen sensitivity frequencies toward Der p 1 and Der p 2 were observed regardless of geographic region. Efficacy of the SQ HDM SLIT-tablet has been demonstrated in 5 clinical trials. The SQ HDM SLIT-tablet has efficacy potential for a broad range of patients because it includes a consistent 1:1 ratio of the 2 major HDM allergens to which individuals were most frequently sensitized across geographic regions. Efficacy has been demonstrated. Copyright © 2016 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  11. The efficacy of sublingual immunotherapy for house dust mites respiratory allergy: results of a GA2LEN meta-analysis.

    Science.gov (United States)

    Compalati, E; Passalacqua, G; Bonini, M; Canonica, G W

    2009-11-01

    Recent meta-analyses documented the efficacy and safety of sublingual immunotherapy (SLIT) in patients with allergic rhinitis (AR) and asthma (AA). Although SLIT appeared globally effective, the sub-analyses for single allergens provided uncertain results. This study is aimed to investigate the efficacy of SLIT with house dust mite (HDM) extracts in AR and AA through an updated reassessment of randomized controlled trials. Electronic databases were searched up to March 31, 2008, for randomized DBPC trials, assessing the efficacy of SLIT in AR and AA due to HDM sensitization. Outcomes were symptom scores and rescue medications use. For AR, eight studies fulfilled the selection criteria. A significant reduction in symptoms of AR (SMD -0.95; CI 95%-1.77 to -0.14 P = 0.02) was found in 194 patients (adults and children) receiving SLIT compared to 188 receiving placebo. For AA, with nine studies, similar results were found for symptoms (SMD -0.95; CI 95%-1.74 to -0.15 P = 0.02) in 243 patients (adults and children) receiving SLIT compared to 209 receiving placebo. A reduction in rescue medication use was found for AR (SMD -1.88; CI 95%-3.65 to -0.12 P = 0.04) in 89 patients, and AA (SMD -1.48; CI 95%-2.70 to -0.26 P = 0.02) in 202 patients. A relevant inter-study heterogeneity was detected. Promising evidence of efficacy for SLIT, using mite extract in allergic patients suffering from AR and AA, are herein shown. These findings suggest that more data are needed, derived from large-population-based high quality studies, and corroborated by objective outcomes, mainly for AA.

  12. 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.

  13. 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.

  14. Cost-minimization analysis of sublingual immunotherapy versus subcutaneous immunotherapy for house dust mite respiratory allergic disease in Denmark.

    Science.gov (United States)

    Rønborg, Steen; Johnsen, Claus R; Theilgaard, Sune; Winther, Anders; Hahn-Pedersen, Julie; Andreasen, Jakob Nørgaard; Olsen, Jens

    2016-08-01

    Objectives Currently, patients with persistent moderate-to-severe house dust mite (HDM) allergic rhinitis despite use of symptom-relieving medication can be offered subcutaneously administered allergy immunotherapy (SQ SCIT; Alutard SQ) as standard care of treatment in Denmark. Recently, a HDM sublingually administered allergy immunotherapy tablet (SQ SLIT-tablet; ACARIZAX) has been developed for at-home treatment. The purpose of this analysis is to compare the costs related to treatment and administration of SQ SLIT-tablet and SQ SCIT. Methods Assuming equal efficacy between ther SQ SLIT-tablet and SQ SCIT, the cost-minimization analysis was the most appropriate for the comparison. According to guidelines and Summary of Product Characteristics, the treatment duration of SQ SLIT-tablet is 3 years and 3-5 years for SQ SCIT. The courses of treatment vary among patients and, therefore, the costs of treatment have been calculated for an average patient with HDM respiratory allergic disease (RAD) receiving either SQ SLIT-tablet or SQ SCIT. All costs associated with allergy immunotherapy were collected, i.e., cost of medication, administration and treatment setting, and discounted according to Danish guidelines. Comprehensive univariate sensitivity analyses were carried out. Results The treatment costs for an average patient with HDM RAD are €3094 for SQ SLIT-tablet and €3799 for SQ SCIT; however, when adding indirect costs to the calculations the total costs of the treatments are €3697 and €6717 for SQ SLIT-tablet and SQ SCIT, respectively. Therefore, if 2500 patients with HDM RAD were treated with SQ SLIT-tablet instead of SQ SCIT, it would elicit a saving to the healthcare system of ∼€1.8 million. The conclusion was robust to any changes in the sensitivity analysis. Conclusion With regards to the cost of treating Danish patients with HDM RAD, it is clearly cost-saving to treat patients with SQ SLIT-tablet compared to SQ SCIT.

  15. Efficacy and safety of house dust mite sublingual immunotherapy in monosensitized and polysensitized children with respiratory allergic diseases.

    Science.gov (United States)

    Li, Peng; Li, Qi; Huang, Zhenghua; Chen, Wenbo; Lu, Yueqian; Tian, Man

    2014-10-01

    The efficacy of single-allergen-specific immunotherapy in polysensitized subjects is a matter of debate. This study aimed to investigate the efficacy of house dust mite (HDM) sublingual immunotherapy (SLIT) in monosensitized and polysensitized children. A total of 112 children, aged 4 to 13 years old, with HDM-induced respiratory allergic diseases were allocated to a monosensitized group (n = 56) or a polysensitized group (n = 56). Both groups were treated by standard pharmacotherapy and SLIT with Dermatophagoides farinae (American HDM) extracts for 52 weeks. Symptoms, medications, visual analogue scale (VAS), and presence of adverse events (AEs) were assessed once a month. Skin-prick test (SPT) was done before and after treatment. After treatment, subjects in the polysensitized group who completed the study were further analyzed as subgroup 1 (n = 20) and subgroup 2 (n = 15) according to the number of coexisting allergens. Forty-one subjects in the monosensitized group and 35 subjects in the polysensitized group completed the study. The global clinical parameters had significantly improved after treatment, with no significant difference between the monosensitized and polysensitized group throughout this period (all p > 0.05). The comparison among the monosensitized group, subgroup 1, and subgroup 2 indicated that there was no significant difference in symptoms scores and VAS at each scheduled follow-up visit. There was also no significant difference in total medications score (TMS) in the monosensitized group, subgroup 1, and subgroup 2 after week 24 (all p > 0.05). No severe systemic AEs were reported. No significant difference was observed in the clinical effects of HDM SLIT between polysensitized and monosensitized children with respiratory allergic diseases. © 2014 ARS-AAOA, LLC.

  16. Analysis of by-product formation and sugar monomerization in sugarcane bagasse pretreated at pilot plant scale: Differences between autohydrolysis, alkaline and acid pretreatment

    NARCIS (Netherlands)

    Pol, van der E.C.; Bakker, R.; Zeeland, van A.N.T.; Sanchez Garcia, D.; Punt, A.M.; Eggink, G.

    2015-01-01

    Sugarcane bagasse is an interesting feedstock for the biobased economy since a large fraction is polymerized sugars. Autohydrolysis, alkaline and acid pretreatment conditions combined with enzyme hydrolysis were used on lignocellulose rich bagasse to acquire monomeric. By-products found after

  17. C-nitroso compounds. Part XIII: monomeric nitroso compounds by photochemical nitrosation of branched-chain hydrocarbons with tert-butyl nitrite

    NARCIS (Netherlands)

    Mackor, A.; Boer, T.J. de

    1970-01-01

    The photochemical nitrosation with t‐butyl nitrite of some branched‐chain hydrocarbons, containing tertiary hydrogen atoms leads to the formation of monomeric nitroso compounds in yields up to 78%, when a special Soxhlet technique is employed. The use of wavelengths around 400 nm is essential for

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

    Energy Technology Data Exchange (ETDEWEB)

    Supangat [Division of Applied Life Science (BK21 Program), Gyeongsang National University, Jinju 660-701 (Korea, Republic of); Environmental Biotechnology National Core Research Center, Gyeongsang National University, Jinju 660-701 (Korea, Republic of); Seo, Kyung Hye; Furqoni, Ahmad [Division of Applied Life Science (BK21 Program), Gyeongsang National University, Jinju 660-701 (Korea, Republic of); Environmental Biotechnology National Core Research Center, Gyeongsang National University, Jinju 660-701 (Korea, Republic of); Plant Molecular Biology and Biotechnology Research Center, Gyeongsang National University, Jinju 660-701 (Korea, Republic of); Kwon, Young-Chul; Cho, Myung-Je; Rhee, Kwang-Ho [Department of Microbiology, School of Medicine, Gyeongsang National University, Jinju 660-701 (Korea, Republic of); Lee, Sang Yeol; Lee, Kon Ho, E-mail: lkh@gsnu.ac.kr [Division of Applied Life Science (BK21 Program), Gyeongsang National University, Jinju 660-701 (Korea, Republic of); Environmental Biotechnology National Core Research Center, Gyeongsang National University, Jinju 660-701 (Korea, Republic of); Plant Molecular Biology and Biotechnology Research Center, Gyeongsang National University, Jinju 660-701 (Korea, Republic of)

    2008-05-01

    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.

  19. Efficacy and safety of sublingual immunotherapy in children aged 6-24 months with rhinitis and bronchial asthma sensitized to house dust mites

    Directory of Open Access Journals (Sweden)

    Olimpio Rodríguez-Santos

    2015-11-01

    Full Text Available Serv The efficacy and safety of sublingual immunotherapy (SLIT was assessed in patients from Previsora Camagüey Clinic, who were diagnosed with allergic rhinitis and asthma. A retrospective case-control study was carried out. Cases and controls were selected in 62 children from 6 to 24 months of age: 34 children had used ITSL (cases; the other 28 children received only environmental prevention (controls. All children used medicines in the crisis stage. Quality of life questionnaires for rhinitis (RQLQm and asthma (AQLQm were applied. Medicine consumption and frequency of crises were analyzed. A subjective assessment of children health before and after the treatment was performed to relatives and physicians. Local and systemic reactions to SLIT were evaluated. An increase in the score of life quality questionnaires was detected (p=0.033. The medicine consumption was more reduced in cases than in controls (p=0.003. The frequency of respiratory symptomatology decreased (p=0.029. The score of subjective assessment was negative before treatment. After the treatment 85% of cases got 5 points, while the remaining 15% of cases obtained between 3 and 4 points. In the control group 55% of patients obtained 5 points, 10% of evaluated children between 3 and 4, and 5% between 0 and 2 points (p=0.011. Two mild adverse reactions to the SLIT were reported. Results showed that the sublingual immunotherapy with mites in children under 2 years old with rhinitis and asthma is effective and safe

  20. Multi-layered nanofibrous mucoadhesive films for buccal and sublingual administration of drug-delivery and vaccination nanoparticles - important step towards effective mucosal vaccines.

    Science.gov (United States)

    Mašek, Josef; Lubasová, Daniela; Lukáč, Róbert; Turánek-Knotigová, Pavlína; Kulich, Pavel; Plocková, Jana; Mašková, Eliška; Procházka, Lubomír; Koudelka, Štěpán; Sasithorn, Nongnut; Gombos, Jozsef; Bartheldyová, Eliška; Hubatka, František; Raška, Milan; Miller, Andrew D; Turánek, Jaroslav

    2017-03-10

    Nanofibre-based mucoadhesive films were invented for oromucosal administration of nanocarriers used for delivery of drugs and vaccines. The mucoadhesive film consists of an electrospun nanofibrous reservoir layer, a mucoadhesive film layer and a protective backing layer. The mucoadhesive layer is responsible for tight adhesion of the whole system to the oral mucosa after application. The electrospun nanofibrous reservoir layer is intended to act as a reservoir for polymeric and lipid-based nanoparticles, liposomes, virosomes, virus-like particles, dendrimers and the like, plus macromolecular drugs, antigens and/or allergens. The extremely large surface area of nanofibrous reservoir layers allows high levels of nanoparticle loading. Nanoparticles can either be reversibly adsorbed to the surface of nanofibres or they can be deposited in the pores between the nanofibres. After mucosal application, nanofibrous reservoir layers are intended to promote prolonged release of nanoparticles into the submucosal tissue. Reversible adsorption of model nanoparticles as well as sufficient mucoadhesive properties were demonstrated. This novel system appears appropriate for the use in oral mucosa, especially for sublingual and buccal tissues. To prove this concept, trans-/intramucosal and lymph-node delivery of PLGA-PEG nanoparticles was demonstrated in a porcine model. This system can mainly be used for sublingual immunization and the development of "printed vaccine technology". Copyright © 2017 Elsevier B.V. All rights reserved.

  1. Once-daily sublingual allergen-specific immunotherapy improves quality of life in patients with grass pollen-induced allergic rhinoconjunctivitis: a double-blind, randomised study.

    Science.gov (United States)

    Rak, Sabina; Yang, William H; Pedersen, Martin R; Durham, Stephen R

    2007-03-01

    The effect of sublingual immunotherapy on quality of life (QoL) was examined in patients with grass pollen-induced rhinoconjunctivitis. Patients (n = 855) were randomised to once-daily grass allergen tablets (2,500; 25,000; or 75,000 SQ-T Phleum pratense extract; GRAZAX or placebo. Treatment was initiated 8 weeks before the start of the grass pollen season and continued throughout. If symptoms were present, patients received loratadine or placebo rescue medication. There were three major findings: in patients using loratadine, grass allergen tablets provided QOL benefits over placebo; Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) score was 17% (p = 0.006) and 20% (p = 0.020) greater with 75,000 SQ-T tablet than with placebo at first and second seasonal visit, respectively; in patients not using loratadine, grass allergen tablets improved QoL more than placebo; RQLQ score was 21% greater (p = 0.021) with 75,000 SQ-T tablet at second seasonal visit; grass tablets (without loratadine) had a greater effect on QoL than loratadine alone. RQLQ score was 26% (p = 0.014) greater with 75,000 SQ-T tablets than loratadine at second seasonal visit. These data show that sublingual immunotherapy with grass allergen tablets improves QOL in allergic rhinoconjunctivitis, reduces symptoms, and that this effect is greater than rescue antihistamine alone.

  2. 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

  3. A meta-analysis of sublingual allergen immunotherapy and pharmacotherapy in pollen-induced seasonal allergic rhinoconjunctivitis.

    Science.gov (United States)

    Devillier, Philippe; Dreyfus, Jean-François; Demoly, Pascal; Calderón, Moisés A

    2014-05-01

    The capacity of sublingual allergen immunotherapy (SLIT) to provide effective symptom relief in pollen-induced seasonal allergic rhinitis is often questioned, despite evidence of clinical efficacy from meta-analyses and well-powered, double-blind, placebo-controlled randomized clinical trials. In the absence of direct, head-to-head, comparative trials of SLIT and symptomatic medication, only indirect comparisons are possible. We performed a meta-analysis of classes of products (second-generation H1-antihistamines, nasal corticosteroids and grass pollen SLIT tablet formulations) and single products (the azelastine-fluticasone combination MP29-02, and the leukotriene receptor antagonist montelukast) for the treatment of seasonal allergic rhinitis in adults, adolescents and/or children. We searched the literature for large (n >100 in the smallest treatment arm) double-blind, placebo-controlled randomized clinical trials. For each drug or drug class, we performed a meta-analysis of the effect on symptom scores. For each selected trial, we calculated the relative clinical impact (according to a previously published method) on the basis of the reported post-treatment or season-long nasal or total symptom scores: 100 × (scorePlacebo - scoreActive)/scorePlacebo. Twenty-eight publications on symptomatic medication trials and ten on SLIT trials met our selection criteria (total number of patients: n = 21,223). The Hedges' g values from the meta-analyses confirmed the presence of a treatment effect for all drug classes. In an indirect comparison, the weighted mean (range) relative clinical impacts were -29.6% (-23% to -37%) for five-grass pollen SLIT tablets, -19.2% (-6% to -29%) for timothy pollen SLIT tablets, -23.5% (-7% to -54%) for nasal corticosteroids, -17.1% (-15% to -20%) for MP29-02, -15.0% (-3% to -26%) for H1-antihistamines and -6.5% (-3% to -10%) for montelukast. In an indirect comparison, grass pollen SLIT tablets had a greater mean relative clinical impact

  4. Qualitative real-time analysis by nurses of sublingual microcirculation in intensive care unit: the MICRONURSE study.

    Science.gov (United States)

    Tanaka, Sébastien; Harrois, Anatole; Nicolaï, Camille; Flores, Mélanie; Hamada, Sophie; Vicaut, Eric; Duranteau, Jacques

    2015-11-06

    We aimed to determine i) the feasibility of nurses taking bedside measurements of microcirculatory parameters in real time in intensive care patients; and ii) whether such measurements would be comparable to those obtained by the classical delayed semi quantitative analysis made by a physician. This prospective observational study was conducted in a university hospital and was approved by our local Institutional Review Board (IRB 00006477). After ICU admission and study inclusion, a set of measurements of macrocirculatory and microcirculatory parameters was taken by the nurse in charge of the patient every 4 h within the first 12 h after admission and before and after every hemodynamic therapeutic intervention. Seventy-four sublingual microvascular measurements were performed with incident dark field illumination (IDF) microscopy in 20 mechanically ventilated patients hospitalized in the ICU. There were no significant differences between the microvascular flow index (MFI) taken in real time by the nurses and the delayed evaluation by the physician. In fact, the nurses' real-time measurement of MFI demonstrated good agreement with the physician's delayed measurement. The mean difference between the two MFIs was -0.15, SD = 0.28. The nurses' real-time MFI assessment showed 97 % sensitivity (95 % CI: 84-99 %) and 95 % specificity (95 % CI: 84-99 %) at detecting a MFI real-time TVD assessment showed 77 % sensitivity (95 % CI: 46-95 %) and 100 % specificity (95 % CI: 89-100 %) at detecting a TVD real-time qualitative bedside evaluation of MFI by nurses showed good agreement with the conventional delayed analysis by physicians. The bedside evaluations of MFI and TVD were highly sensitive and specific for detecting impaired microvascular flow and low capillary density. These results suggest that this real-time technique could become part of ICU nurse routine surveillance and be implemented in algorithms for hemodynamic resuscitation in future clinical trials and

  5. Sublingual immunization with adenovirus F protein-based vaccines stimulates protective immunity against botulinum neurotoxin A intoxication

    Science.gov (United States)

    Jun, SangMu; Clapp, Beata; Zlotkowska, Dagmara; Hoyt, Teri; Holderness, Kathryn; Maddaloni, Massimo

    2012-01-01

    Sublingual (s.l.) vaccination is an efficient way to induce elevated levels of systemic and mucosal immune responses. To mediate mucosal uptake, ovalbumin (OVA) was genetically fused to adenovirus 2 fiber protein (OVA-Ad2F) to assess whether s.l. immunization was as effective as an alternative route of vaccination. Ad2F-delivered vaccines were efficiently taken up by dendritic cells and migrated mostly to submaxillary gland lymph nodes, which could readily stimulate OVA-specific CD4+ T cells. OVA-Ad2F + cholera toxin (CT)-immunized mice elicited significantly higher OVA-specific serum IgG, IgA and mucosal IgA antibodies among the tested immunization groups. These were supported by elevated OVA-specific IgG and IgA antibody-forming cells. A mixed Th-cell response was induced as evident by the enhanced IL-4, IL-10, IFN-γ and TNF-α-specific cytokine-forming cells. To assess whether this approach can stimulate neutralizing antibodies, immunizations were performed with the protein encumbering the β-trefoil domain of C-terminus heavy chain (Hcβtre) from botulinum neurotoxin A (BoNT/A) as well as when fused to Ad2F. Hcβtre-Ad2F + CT-dosed mice showed the greatest serum IgG, IgA and mucosal IgA titers among the immunization groups. Hcβtre-Ad2F alone also induced elevated antibody production in contrast to Hcβtre alone. Plasma from Hcβtre + CT- and Hcβtre-Ad2F + CT-immunized groups neutralized BoNT/A and protected mice from BoNT/A intoxication. Most importantly, Hcβtre-Ad2F + CT-immunized mice were protected from BoNT/A intoxication relative to Hcβtre + CT-immunized mice, which only showed ∼60% protection. This study shows that s.l. immunization with Ad2F-based vaccines is effective in conferring protective immunity. PMID:22207133

  6. Quantification and Statistical Modeling—Part I: Breathing-Zone Concentrations of Monomeric and Polymeric 1,6-Hexamethylene Diisocyanate

    Science.gov (United States)

    Fent, Kenneth W.; Gaines, Linda G. Trelles; Thomasen, Jennifer M.; Flack, Sheila L.; Ding, Kai; Herring, Amy H.; Whittaker, Stephen G.; Nylander-French, Leena A.

    2009-01-01

    We conducted a repeated exposure-assessment survey for task-based breathing-zone concentrations (BZCs) of monomeric and polymeric 1,6-hexamethylene diisocyanate (HDI) during spray painting on 47 automotive spray painters from North Carolina and Washington State. We report here the use of linear mixed modeling to identify the primary determinants of the measured BZCs. Both one-stage (N = 98 paint tasks) and two-stage (N = 198 paint tasks) filter sampling was used to measure concentrations of HDI, uretidone, biuret, and isocyanurate. The geometric mean (GM) level of isocyanurate (1410 μg m−3) was higher than all other analytes (i.e. GM tests, significantly higher concentrations of HDI (P = 0.0363) and isocyanurate (P = 0.0035) were measured using one-stage samplers. Marginal R2 statistics were calculated for each model; significant fixed effects were able to describe 25, 52, 54, and 20% of the variability in BZCs of HDI, uretidone, biuret, and isocyanurate, respectively. Mixed models developed in this study characterize the processes governing individual polyisocyanate BZCs. In addition, the mixed models identify ways to reduce polyisocyanate BZCs and, hence, protect painters from potential adverse health effects. PMID:19622637

  7. 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.

  8. DNA unwinding by Escherichia coli DNA helicase I (TraI) provides evidence for a processive monomeric molecular motor.

    Science.gov (United States)

    Sikora, Bartek; Eoff, Robert L; Matson, Steven W; Raney, Kevin D

    2006-11-24

    The F plasmid TraI protein (DNA helicase I) plays an essential role in conjugative DNA transfer as both a transesterase and a helicase. Previous work has shown that the 192-kDa TraI protein is a highly processive helicase, catalytically separating >850 bp under steady-state conditions. In this report, we examine the kinetic mechanism describing DNA unwinding of TraI. The kinetic step size of TraI was measured under both single turnover and pre-steady-state conditions. The resulting kinetic step-size estimate was approximately 6-8 bp step(-1). TraI can separate double-stranded DNA at a rate of approximately 1100 bp s(-1), similar to the measured unwinding rate of the RecBCD helicase, and appears to dissociate very slowly from the 3' terminus following translocation and strand-separation events. Analyses of pre-steady-state burst amplitudes indicate that TraI can function as a monomer, similar to the bacteriophage T4 helicase, Dda. However, unlike Dda, TraI is a highly processive monomeric helicase, making it unique among the DNA helicases characterized thus far.

  9. 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.

  10. Application of dimeric and monomeric ortho-palladated complexes as an efficient catalysts for Heck cross-coupling reaction

    Directory of Open Access Journals (Sweden)

    Ali Naghipour

    2013-10-01

    Full Text Available The catalytic acvtivity of dimeric and monomeric ortho-palladated complexes [Pd{C6H2(CH2NH2-(OMe2,3,4}(µ-Cl]22 and [Pd{C6H2(CH2NH2-(OMe2,3,4}Cl(PPh3](3, were investigated in Heck cross-coupling reaction. These complexes are more active and efficient catalysts for Heck cross-coupling reaction. The palladium complexes 2 and 3 are employed in the Heck cross-coupling reaction between styrene and acrylate with several aryl halides. High yields of corresponding C–C products, low catalyst loadings, mild reaction conditions and short reaction times are important features of these homogeneous reactions. The cross-coupled prod-ucts were produced in high yields using catalytic amounts of [Pd{C6H2(CH2NH2-(OMe2,3,4}(µ-Cl]2 or [Pd{C6H2(CH2NH2-(OMe2,3,4}Cl(PPh3] as a thermally stable and oxygen insensitive complexes in NMP at 130 ºC.

  11. A Novel Ultra-Stable, Monomeric Green Fluorescent Protein For Direct Volumetric Imaging of Whole Organs Using CLARITY.

    Science.gov (United States)

    Scott, Daniel J; Gunn, Natalie J; Yong, Kelvin J; Wimmer, Verena C; Veldhuis, Nicholas A; Challis, Leesa M; Haidar, Mouna; Petrou, Steven; Bathgate, Ross A D; Griffin, Michael D W

    2018-01-12

    Recent advances in thick tissue clearing are enabling high resolution, volumetric fluorescence imaging of complex cellular networks. Fluorescent proteins (FPs) such as GFP, however, can be inactivated by the denaturing chemicals used to remove lipids in some tissue clearing methods. Here, we solved the crystal structure of a recently engineered ultra-stable GFP (usGFP) and propose that the two stabilising mutations, Q69L and N164Y, act to improve hydrophobic packing in the core of the protein and facilitate hydrogen bonding networks at the surface, respectively. usGFP was found to dimerise strongly, which is not desirable for some applications. A point mutation at the dimer interface, F223D, generated monomeric usGFP (muGFP). Neurons in whole mouse brains were virally transduced with either EGFP or muGFP and subjected to Clear Lipid-exchanged Acrylamide-hybridized Rigid Imaging/Immunostaining/In situ hybridization-compatible Tissue-hYdrogel (CLARITY) clearing. muGFP fluorescence was retained after CLARITY whereas EGFP fluorescence was highly attenuated, thus demonstrating muGFP is a novel FP suitable for applications where high fluorescence stability and minimal self-association are required.

  12. Efeitos de misoprostol sublingual pré-operatório no tônus uterino durante anestesia com isoflurano para cesariana

    Directory of Open Access Journals (Sweden)

    Mohamed R. El Tahan

    2012-10-01

    Full Text Available JUSTIFICATIVA E OBJETIVOS: Misoprostol reduz o sangramento uterino após o parto cesáreo sem efeitos prejudiciais para a mãe ou o bebê. Nosso objetivo foi avaliar os efeitos de misoprostol pré-operatório no sangramento materno e no tônus uterino e a necessidade de ocitocina após cesariana sob anestesia com isoflurano. MÉTODOS: Depois da aprovação pelo Comitê de Ética, 366 pacientes programadas para cesariana eletiva foram randomicamente designadas para receber 400 µg de misoprostol sublingual (n = 179 ou um comprimido de placebo (n = 187 após intubação. A anestesia foi mantida com CAM de isoflurano a 0,5-0,7 e óxido nitroso. Todas as pacientes receberam infusão de ocitocina (10 UI após expulsão da placenta. A estimativa de perda sanguínea, do tônus uterino, da necessidade de ocitocina complementar, da contagem de hematócrito, dos escores de Apgar no 1º e aos 5 minutos e os efeitos adversos foram registrados. RESULTADOS: Após a indução, as pacientes que receberam misoprostol sublingual tiveram perda sanguínea perioperatória (202 ± 383,1 vs 708 ± 204,3 mL, p < 0,001, necessidade de ocitocina (p < 0,001, níveis mais elevados de hematócrito (p < 0,001 e tônus uterino (p < 0,02 menos significativos. A incidência de tremores foi maior no grupo misoprostol (p = 0,04. Não houve diferenças entre os dois grupos quanto aos índices de Apgar, náusea e vômito, distúrbios gastrointestinais e febre. CONCLUSÃO: A administração pré-operatória de misoprostol sublingual (400 µg é segura e eficaz para atenuar o sangramento materno e o efeito no tônus uterino da anestesia com isoflurano em parto cesário.

  13. Fentanyl Sublingual Tablets Versus Subcutaneous Morphine for the Management of Severe Cancer Pain Episodes in Patients Receiving Opioid Treatment: A Double-Blind, Randomized, Noninferiority Trial.

    Science.gov (United States)

    Zecca, Ernesto; Brunelli, Cinzia; Centurioni, Fabio; Manzoni, Andrea; Pigni, Alessandra; Caraceni, Augusto

    2017-03-01

    Purpose Fentanyl sublingual tablets (FST) are a potentially useful alternative to parenteral opioids such as subcutaneous morphine (SCM) to treat severe cancer pain episodes. No direct comparison between FST and SCM is available. The aim of this study was to test noninferiority of FST versus SCM during the first 30 min postadministration. Methods Patients receiving stable opioid therapy and experiencing a severe pain episode were randomly assigned to either 100 µg FST or 5 mg SCM in a double-blind, double-dummy trial. Average pain intensity (PI) assessed on a 0 to 10 numerical rating scale at 10, 20, and 30 min postadministration was the main end point. Analysis of covariance, adjusted by baseline PI, was the main analysis. The noninferiority margin (NIm) for the between-group difference was set at -0.6, that is, equal to one third of the minimum clinically important PI difference of two points. Results A total of 114 patients were randomly assigned to either FST (n = 58) or SCM (n = 56). One patient (in the FST group) withdrew consent before drug administration and was excluded from analysis. Baseline mean PIs were 7.5 in both groups; mean average PIs assessed at 10, 20, and 30 min postadministration were 5.0 and 4.5 for FST and SCM, respectively, with the 95% CI of the between-group difference including the NIm (-0.49; 95% CI, -1.10 to 0.09). Patients taking FST received a second drug dose after 30 min more frequently than did patients taking SCM (51% v 37%, respectively; risk difference, -13%; 95% CI, -30% to 3%). Both treatments were well tolerated, with average follow-up adverse event scores below the response of "A Little." Ninety-three percent of patients preferred the sublingual administration. Conclusion This trial did not show noninferiority of FST versus SCM within the chosen NIm. Both treatments were safe, and patients preferred the sublingual route of administration. FST provides analgesia with modest to moderate increased risk of lower efficacy

  14. 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...

  15. 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...... 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 muM. 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 was significantly...

  16. Relationship between population of the fibril-prone conformation in the monomeric state and oligomer formation times of peptides: Insights from all-atom simulations

    Science.gov (United States)

    Nam, Hoang Bao; Kouza, Maksim; Zung, Hoang; Li, Mai Suan

    2010-04-01

    Despite much progress in understanding the aggregation process of biomolecules, the factors that govern its rates have not been fully understood. This problem is of particular importance since many conformational diseases such as Alzheimer, Parkinson, and type-II diabetes are associated with the protein oligomerization. Having performed all-atom simulations with explicit water and various force fields for two short peptides KFFE and NNQQ, we show that their oligomer formation times are strongly correlated with the population of the fibril-prone conformation in the monomeric state. The larger the population the faster the aggregation process. Our result not only suggests that this quantity plays a key role in the self-assembly of polypeptide chains but also opens a new way to understand the fibrillogenesis of biomolecules at the monomeric level. The nature of oligomer ordering of NNQQ is studied in detail.

  17. 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

    2017-12-20

    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.

  18. {Ba[Au(SCN2]2}n: a three-dimensional net comprised of monomeric and trimeric gold(I units

    Directory of Open Access Journals (Sweden)

    A. Darren Back

    2010-07-01

    Full Text Available The noteworthy structural feature of the title complex, poly[acetonitriletetra-μ2-thiocyanato-barium(IIdigold(I], {[Au2Ba(SCN4(CH3CN]}n, is that the bis(thiocyanatoaurate(I anion adopts both monomeric and trimeric motifs. The trimer unit has an Au...Au distance of 3.1687 (3 Å. In both the monomeric and trimeric units, the AuI atoms are also bonded to two S atoms. Within the trimeric unit, the AuI atoms exist in differing environments; one Au atom has a T-shaped three-coordinate geometry while the other has a square-planar four-coordinate geometry. The AuI atom of the monomer adopts a linear two-coordinate geometry. The extended structure can be described as a three-dimensional coordination polymer consisting of chains of Ba atoms bridged by thiocyanate N atoms. These chains are cross-linked via the gold monomeric and trimeric units.

  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.

    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 (t1/2 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.

  20. 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...

  1. Comparative analysis of the oral mucosae from rodents and non-rodents: Application to the nonclinical evaluation of sublingual immunotherapy products.

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    Catherine Thirion-Delalande

    Full Text Available A comparative characterization of the oral mucosa in various animals is needed to identify the best animal model(s for nonclinical evaluation of sublingual immunotherapy products. With this aim, we studied the histological characteristics and immune cell infiltrates of oral mucosae from common animal species.Three oral regions (i.e. ventral surface of the tongue, mouth floor and cheek obtained from eight animal species, including rodents (i.e. mice, rats, hamsters, guinea pigs and non-rodents (i.e. rabbits, dogs, minipigs and monkeys were characterized by histology and immunohistology in comparison with a human tongue.Rodents exhibit a thin keratinized epithelium with low epithelial extensions, whereas non-rodents, most particularly minipigs and monkeys, display a non-keratinized epithelium with larger rete ridges, similarly to humans. Glycogen-rich cells in the superficial epithelial layers are observed in samples from both minipigs, monkeys and humans. Comparable immune subpopulations detected in the 3 oral regions from rodent and non-rodent species include MHC-II+ antigen presenting cells, mostly CD163+ macrophages, located in the lamina propria (LP and muscle tissue in the vicinity of resident CD3+CD4+ T cells. Limited numbers of mast cells are also detected in the LP and muscle tissue from all species.The oral mucosae of minipigs and monkeys are closest to that of humans, and the immune networks are quite similar between all rodents and non-rodents. Taking into account the ethical and logistical difficulties of performing research in the latter species, rodents and especially mice, should preferentially be used for pharmacodynamics/efficacy studies. Our data also support the use of minipigs to perform biodistribution and safety studies of sublingual immunotherapy products.

  2. A Cost-Minimisation Analysis Comparing Sublingual Immunotherapy to Subcutaneous Immunotherapy for the Treatment of House Dust Mite Allergy in a Swedish Setting.

    Science.gov (United States)

    Björstad, Åse; Cardell, Lars-Olaf; Hahn-Pedersen, Julie; Svärd, Mikael

    2017-06-01

    In Sweden, approximately 6% of children and 10% of adults suffer from house dust mite (HDM) allergy with symptoms of allergic rhinitis and allergic asthma. Treatment is aimed at reducing HDM exposure and to control the symptoms of allergic rhinitis and allergic asthma by symptom-relieving pharmacotherapy. This pharmacotherapy is often effective, but some patients remain inadequately controlled. For these patients, allergy immunotherapy (AIT, subcutaneous or sublingual) with repeated administration of HDM allergen should be considered. The objective of this study was to compare the costs for sublingual AIT (SLIT; SQ® SLIT-tablet) to the costs for subcutaneous AIT (SCIT; SQ® SCIT) for the treatment of HDM allergy in a cost-minimisation analysis (CMA). The CMA included resources (and costs) for treatment, healthcare visits, travelling and lost productivity. Resource use based on Swedish clinical treatment practice and costs were obtained from medical price lists. Analyses were conducted from the societal, as well as healthcare perspective, by use of a time horizon of 3 years. The results show that SQ® SLIT-tablet is a cost-saving treatment as compared to SQ® SCIT for the treatment of HDM allergy (€6800 over 3 years). The results are mainly driven by the cost of healthcare visits and the frequency of SCIT administrations. In conclusion, cost-savings of €6800 over 3 years are expected from treating HDM allergy with SQ® SLIT-tablet as compared to SQ® SCIT, including costs for treatment, healthcare visits, travelling and lost productivity. The reduced number of healthcare visits compensates for higher medication costs.

  3. Objective approach for fending off the sublingual immunotherapy placebo effect in subjects with pollenosis: double-blinded, placebo-controlled trial.

    Science.gov (United States)

    Kralimarkova, Tanya Z; Popov, Todor A; Staevska, Maria; Mincheva, Roxana; Lazarova, Cvetelina; Racheva, Rumyana; Mustakov, Tihomir B; Filipova, Violina; Koleva, Margarita; Bacheva, Kalina; Dimitrov, Vasil D

    2014-07-01

    Symptom scoring for the assessment of allergen immunotherapy is associated with a substantial placebo effect. To assess the ability of exhaled breath temperature (EBT), a putative marker of airway inflammation, to evaluate objectively the efficacy of grass pollen sublingual immunotherapy in a proof-of-concept study. This was a double-blinded, placebo-controlled clinical trial in 56 subjects (mean ± SD 30 ± 12 years old, 33 men) sensitized to grass pollen. The objective measurements were EBT, spirometry, and periostin and high-sensitivity C-reactive protein in blood. Overall discomfort scored on a visual analog scale was used as a proxy for subjective symptoms. Evaluations were performed before, during, and after the grass pollen season. Fifty-one subjects (25 and 26 in the active treatment and placebo groups, respectively) were assessed before and during the pollen season. The mean pre- vs in-season increase in EBT was significantly smaller (by 59.1%) in the active treatment than in the placebo group (P = .030). Of the other objective markers, only the blood periostin level increased significantly during the pollen season (P = .047), but without intergroup differences. Subjectively, the mean pre- vs in-season increase in the visual analog scale score was 32.3% smaller in the active treatment than in the placebo group, although this difference did not reach statistical significance (P = .116). These results suggest that the efficacy of grass pollen sublingual immunotherapy can be assessed by EBT, a putative quantitative measurement of airway inflammation, which is superior in its power to discriminate between active and placebo treatment than a subjective assessment of symptoms assessed on a visual analog scale. clinicaltrials.gov Identifier: NCT01785394. Copyright © 2014 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  4. Orodispersible sublingual piribedil to abort OFF episodes: a single dose placebo-controlled, randomized, double-blind, cross-over study.

    Science.gov (United States)

    Rascol, Olivier; Azulay, Jean-Philippe; Blin, Olivier; Bonnet, Anne-Marie; Brefel-Courbon, Christine; Césaro, Pierre; Damier, Philippe; Debilly, Bérengère; Durif, Frank; Galitzky, Monique; Grouin, Jean-Marie; Pennaforte, Sylvie; Villafane, Gabriel; Yaici, Sadek; Agid, Yves

    2010-02-15

    S90049, a novel sublingual formulation of the non-ergoline D(2)-D(3) agonist piribedil, has a pharmacokinetic profile promising to provide rapid relief on motor signs in Parkinson's disease (PD). We assessed the efficacy and safety of S90049 in aborting OFF episodes responding to subcutaneous apomorphine in PD patients with motor fluctuations. This was a single-dose double-blind double-placebo 3 x 3 cross-over study. Optimal tested doses were determined during a previous open-label titration phase (S90049 median dose: 60 mg, apomorphine: 5 mg). Primary endpoint was the maximal change versus baseline in UPDRS motor score (Delta UPDRS III) assessed after drug administration following an overnight withdrawal of antiparkinsonian medications. Thirty patients (age: 60 +/- 8 years, PD duration: 12 +/- 6 years, UPDRS III OFF: 37 +/- 15) participated. S90049 was superior to placebo on Delta UPDRS III (-13 +/- 12 versus -7 +/- 9 respectively; estimated difference -5.2, 95% Confidence Interval (CI)[-10.4;0.05], P = 0.05). This was also true for secondary outcomes: number of patients switching from OFF to ON (17 on S90049 vs. 8 on placebo, P = 0.03), time to turn ON (P = 0.013) and duration of the ON phase (P = 0.03). In the 17 patients who switched ON on S90049, Delta UPDRS III was similar on S90049 (-21.2 +/- 10.1) and apomorphine (-23.6 +/- 14.1) (estimated difference: 4.0 95% CI [-2.9;10.9]). S90049 was well tolerated: no serious or unexpected adverse event occurred. A single dose of up to 60 mg of S90049 given sublingually was superior to placebo in improving UPDRS III and aborting a practical OFF in patients with advanced PD. Testing greater doses might improve response rate. (c) 2009 Movement Disorder Society.

  5. Self-Assembling Monomeric Nucleoside Molecular Nanoparticles Loaded with 5-FU Enhancing Therapeutic Efficacy against Oral Cancer.

    Science.gov (United States)

    Zhao, Hang; Feng, Hui; Liu, Dongjuan; Liu, Jiang; Ji, Ning; Chen, Fangman; Luo, Xiaobo; Zhou, Yu; Dan, Hongxia; Zeng, Xin; Li, Jing; Sun, Congkui; Meng, Jinyu; Ju, Xiaojie; Zhou, Min; Yang, Hanshuo; Li, Longjiang; Liang, Xinhua; Chu, Liangyin; Jiang, Lu; He, Yang; Chen, Qianming

    2015-10-27

    Conventional oligonucleotide based drug delivery systems suffer from lengthy synthetic protocols, high cost, and poor chemical or enzymatic stability under certain circumstances. Canonical free individual nucleosides cannot form stable nanostructures in aqueous solution as drug vehicles. Here, we report the development of a monomeric self-assembled nucleoside nanoparticle (SNNP) into an efficient drug delivery system which has currently no parallel in such field. This was achieved using a l-configurational pyrimido[4,5-d]pyrimidine nucleoside building block that can form robust discrete nanoparticles in just one step with water as the sole solvent. Its high biocompatibility and low toxicity was demonstrated in vitro and in vivo. In mouse xenograft model of oral squamous cell carcinoma (OSCC), SNNP loaded with 5-fluoro-uracile (5-FU-SNNP) remarkably retarded the tumor growth compared with free 5-FU, albeit SNNP alone showed no antitumor effect. The stability in blood circulation and the effective concentration of 5-FU in tumor tissue were increased upon the loading with SNNP. TUNEL and immunohistochemistry analyses further indicated that the superior in vivo antitumor efficacy of 5-FU-SNNP compared to free 5-FU was associated with an enhanced degree of inhibition of cell proliferation and stimulation of cell apoptosis. Furthermore, SNNP alleviated the toxic side effects of 5-FU. These findings suggested that when loaded with SNNP, 5-FU has better antitumor efficacy and lower side effects, indicating that SNNP can efficiently act as a readily accessible, robust, biocompatible and low-toxic nanobiomaterial which may find wide therapeutic applications clinically in the future.

  6. Quantification and Statistical Modeling—Part II: Dermal Concentrations of Monomeric and Polymeric 1,6-Hexamethylene Diisocyanate

    Science.gov (United States)

    Fent, Kenneth W.; Trelles Gaines, Linda G.; Thomasen, Jennifer M.; Flack, Sheila L.; Ding, Kai; Herring, Amy H.; Whittaker, Stephen G.; Nylander-French, Leena A.

    2009-01-01

    We conducted a quantitative dermal and inhalation exposure assessment of monomeric and polymeric 1,6-hexamethylene diisocyanates (HDI) in 47 automotive spray painters from North Carolina and Washington State. We report here the use of linear mixed modeling (LMM) to identify the primary determinants of dermal exposure. Dermal concentrations of HDI, uretidone, biuret, and isocyanurate were significantly higher in 15 painters who did not wear coveralls or gloves (N = 51 paint tasks) than in 32 painters who did wear coveralls and gloves (N = 192 paint tasks) during spray painting. Regardless of whether protective clothing was worn, isocyanurate was the predominant species measured in the skin [geometric mean (GM) = 33.8 ng mm−3], with a 95% detection rate. Other polyisocyanates (GM ≤ 0.17 ng mm−3) were detected in skin during <23% of the paint tasks. According to marginal R2 statistics, mixed models generated in this study described no <36% of the variability in dermal concentrations of the different polyisocyanates measured in painters who did not wear protective clothing. These models also described 55% of the variability in dermal concentrations of isocyanurate measured in all painters (N = 288 paint tasks). The product of analyte-specific breathing-zone concentration (BZC) and paint time was the most significant variable in all the models. Through LMM, a better understanding of the exposure pathways governing individual polyisocyanate exposures may be achieved. In particular, we were able to establish a link between BZC and dermal concentration, which may be useful for exposure reconstruction and quantitatively characterizing the protective effect of coveralls and gloves. This information can be used to reduce dermal exposures and better protect automotive spray painters from potential adverse health effects. PMID:19635734

  7. 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

  8. Mechanisms of U87 astrocytoma cell uptake and trafficking of monomeric versus protofibril Alzheimer's disease amyloid-β proteins.

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    Yali Li

    Full Text Available A significant hallmark of Alzheimer's disease is the formation of senile plaques in the brain due to the unbalanced levels of amyloid-beta (Aβ. However, although how Aβ is produced from amyloid precursor proteins is well understood, little is known regarding the clearance and metabolism of various Aβ aggregates from the brain. Similarly, little is known regarding how astrocytes internalize and degrade Aβ, although astrocytes are known to play an important role in plaque maintenance and Aβ clearance. The objective of this study is to investigate the cellular mechanisms that mediate the internalization of soluble monomeric versus oligomeric Aβ by astrocytes. We used a combination of laser confocal microscopy and genetic and pharmacological experiments to dissect the internalization of sAβ42 and oAβ42 and their postendocytic transport by U87 human brain astrocytoma cell line. Both Aβ42 species were internalized by U87 cells through fluid phase macropinocytosis, which required dynamin 2. Depleting LDL receptor-related protein 1 (LRP1 decreased sAβ42 uptake more significantly than that of oAβ42. We finally show that both Aβ42 species were rapidly transported to lysosomes through an endolytic pathway and subjected to proteolysis after internalization, which had no significant toxic effects to the U87 cells under relatively low concentrations. We propose that macropinocytic sAβ42 and oAβ42 uptake and their subsequent proteolytic degradation in astroglial cells is a significant mechanism underlying Aβ clearance from the extracellular milieu. Understanding the molecular events involved in astrocytic Aβ internalization may identify potential therapeutic targets for Alzheimer's disease.

  9. Continuous Perioperative Sublingual Buprenorphine.

    Science.gov (United States)

    Silva, Marcelina Jasmine; Rubinstein, Andrea

    2016-12-01

    Buprenorphine, a semisynthetic thebaine derivative, is a unique opioid, as it has activity at multiple receptors, including mu (partial agonist), kappa (antagonist), OLR-1 (agonist), and delta (antagonist). Because buprenorphine's pharmacology is relatively complex, misconceptions about its actions are common. Most other opioids act solely or predominately as full mu receptor agonists. Common practice at many institutions calls for the cessation of regular buprenorphine use 48-72 hours prior to surgery. This practice is based on three foundational theories that have come from scant data about the properties of buprenorphine: (1) that buprenorphine is only a partial mu agonist and therefore is not a potent analgesic; (2) because buprenorphine has a ceiling effect on respiratory depression, it also has a ceiling effect on analgesia; and (3) that buprenorphine acts as a "blockade" to the analgesic effects of other opiates when coadministered due to its strong binding affinity. However, several recent studies have called this practice into question. At our institution, we continue buprenorphine perioperatively, whenever possible, in order to provide superior pain control, discourage potentially problematic use and the more dangerous side effects of full mu agonist opiates, and avoid putting recovery at risk for those with opiate dependency issues. We present a unique case comparing two different outcomes for the same surgical course performed at two different times on the same chronic pain patient. These differences may be attributable to the variable of buprenorphine being present for one perioperative course and not the other. Pain control was easier to achieve, and functional recovery was greater when buprenorphine was maintained throughout the perioperative period when compared with using a full mu agonist opioid for chronic pain preoperatively. This is an outcome that much of the literature heretofore suggests would be unlikely. We review some aspects of buprenorphine's unique pharmacology that may explain why remaining on buprenorphine perioperatively may be preferable, which contradicts many practice guidelines.

  10. Production of Monomeric Aromatic Compounds from Oil Palm Empty Fruit Bunch Fiber Lignin by Chemical and Enzymatic Methods

    Science.gov (United States)

    Tang, Pei-Ling; Hassan, Osman; Maskat, Mohamad Yusof; Badri, Khairiah

    2015-01-01

    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. PMID:26798644

  11. 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.

  12. Uncoupled responses of Smad4-deficient cancer cells to TNFα result in secretion of monomeric laminin-γ2

    Directory of Open Access Journals (Sweden)

    Schmiegel Wolff

    2010-03-01

    Full Text Available Abstract Background Functional loss of the tumor suppressor Smad4 is involved in pancreatic and colorectal carcinogenesis and has been associated with the acquisition of invasiveness. We have previously demonstrated that the heterotrimeric basement membrane protein laminin-332 is a Smad4 target. Namely, Smad4 functions as a positive transcriptional regulator of all three genes encoding laminin-332; its loss is thus implicated in the reduced or discontinuous deposition of the heterotrimeric basement membrane molecule as evident in carcinomas. Uncoupled expression of laminin genes, on the other hand, namely overexpression of the laminin-γ2 chain is an impressive marker at invasive edges of carcinomas where tumor cells are maximally exposed to signals from stromal cell types like macrophages. As Smad4 is characterized as an integrator of multiple extracellular stimuli in a strongly contextual manner, we asked if loss of Smad4 may also be involved in uncoupled expression of laminin genes in response to altered environmental stimuli. Here, we address Smad4 dependent effects of the prominent inflammatory cytokine TNFα on tumor cells. Results Smad4-reconstituted colon carcinoma cells like adenoma cells respond to TNFα with an increased expression of all three chains encoding laminin-332; coincubation with TGFβ and TNFα leads to synergistic induction and to the secretion of large amounts of the heterotrimer. In contrast, in Smad4-deficient cells TNFα can induce expression of the γ2 and β3 but not the α3 chain. Surprisingly, this uncoupled induction of laminin-332 chains in Smad4-negative cells rather than causing intracellular accumulation is followed by the release of γ2 into the medium, either in a monomeric form or in complexes with as yet unknown proteins. Soluble γ2 is associated with increased cell migration. Conclusions Loss of Smad4 may lead to uncoupled induction of laminin-γ2 in response to TNFα and may therefore represent one of

  13. A Newly Developed Sublingual Tonometric Method for the Evaluation of Tissue Perfusion and Its Validation In Vitro and in Healthy Persons In Vivo and the Results of the Measurements in COPD Patients

    Science.gov (United States)

    2014-01-01

    Introduction. Since its first publication in the medical literature, an extremely large number of references have demonstrated that the tonometric measurement of tissue perfusion is a reliable indicator of the actual condition of critically ill patients. Later a new method was developed by the introduction of sublingual tonometry for the determination of tissue perfusion. In comparison with gastric tonometry, the new method was simpler and could even be used in awake patients. Unfortunately, at present, because of severe failures of manufacturing, the device is withdrawn from commerce. Materials and Methods. In this study, we present a new method using a newly developed tool for the PslCO2 measurement in sublingual tonometry as well as the data for its validation in vitro and in vivo and the results of 25 volunteers and 54 COPD patients belonging to different GOLD groups at their hospitalization due to the acute exacerbation of the disease but already in a stable condition at the time of the examination. Results and Conclusion. The results of the performed examinations showed that the method is suitable for monitoring the actual condition of the patients by mucosal perfusion tonometry in the sublingual region. PMID:25580290

  14. A Newly Developed Sublingual Tonometric Method for the Evaluation of Tissue Perfusion and Its Validation In Vitro and in Healthy Persons In Vivo and the Results of the Measurements in COPD Patients

    Directory of Open Access Journals (Sweden)

    Zoltán Rózsavölgyi

    2014-01-01

    Full Text Available Introduction. Since its first publication in the medical literature, an extremely large number of references have demonstrated that the tonometric measurement of tissue perfusion is a reliable indicator of the actual condition of critically ill patients. Later a new method was developed by the introduction of sublingual tonometry for the determination of tissue perfusion. In comparison with gastric tonometry, the new method was simpler and could even be used in awake patients. Unfortunately, at present, because of severe failures of manufacturing, the device is withdrawn from commerce. Materials and Methods. In this study, we present a new method using a newly developed tool for the PslCO2 measurement in sublingual tonometry as well as the data for its validation in vitro and in vivo and the results of 25 volunteers and 54 COPD patients belonging to different GOLD groups at their hospitalization due to the acute exacerbation of the disease but already in a stable condition at the time of the examination. Results and Conclusion. The results of the performed examinations showed that the method is suitable for monitoring the actual condition of the patients by mucosal perfusion tonometry in the sublingual region.

  15. The impact of single nucleotide polymorphism in monomeric alpha-amylase inhibitor genes from wild emmer wheat, primarily from Israel and Golan

    Directory of Open Access Journals (Sweden)

    Yan Ze-Hong

    2010-06-01

    Full Text Available Abstract Background Various enzyme inhibitors act on key insect gut digestive hydrolases, including alpha-amylases and proteinases. Alpha-amylase inhibitors have been widely investigated for their possible use in strengthening a plant's defense against insects that are highly dependent on starch as an energy source. We attempted to unravel the diversity of monomeric alpha-amylase inhibitor genes of Israeli and Golan Heights' wild emmer wheat with different ecological factors (e.g., geography, water, and temperature. Population methods that analyze the nature and frequency of allele diversity within a species and the codon analysis method (comparing patterns of synonymous and non-synonymous changes in protein coding sequences were used to detect natural selection. Results Three hundred and forty-eight sequences encoding monomeric alpha-amylase inhibitors (WMAI were obtained from 14 populations of wild emmer wheat. The frequency of SNPs in WMAI genes was 1 out of 16.3 bases, where 28 SNPs were detected in the coding sequence. The results of purifying and the positive selection hypothesis (p Conclusions Great diversity at the WMAI locus, both between and within populations, was detected in the populations of wild emmer wheat. It was revealed that WMAI were naturally selected for across populations by a ratio of dN/dS as expected. Ecological factors, singly or in combination, explained a significant proportion of the variations in the SNPs. A sharp genetic divergence over very short geographic distances compared to a small genetic divergence between large geographic distances also suggested that the SNPs were subjected to natural selection, and ecological factors had an important evolutionary role in polymorphisms at this locus. According to population and codon analysis, these results suggested that monomeric alpha-amylase inhibitors are adaptively selected under different environmental conditions.

  16. RpaA regulates the accumulation of monomeric photosystem I and PsbA under high light conditions in Synechocystis sp. PCC 6803.

    Directory of Open Access Journals (Sweden)

    Waqar Majeed

    Full Text Available The response regulator RpaA was examined by targeted mutagenesis under high light conditions in Synechocystis sp. PCC 6803. A significant reduction in chlorophyll fluorescence from photosystem I at 77 K was observed in the RpaA mutant cells under high light conditions. Interestingly, the chlorophyll fluorescence emission from the photosystem I trimers at 77 K are similar to that of the wild type, while the chlorophyll fluorescence from the photosystem I monomers was at a much lower level in the mutant than in the wild type under high light conditions. The RpaA inactivation resulted in a dramatic reduction in the monomeric photosystem I and the D1 protein but not the CP47 content. However, there is no significant difference in the transcript levels of psaA or psbA or other genes examined, most of which are involved in photosynthesis, pigment biosynthesis, or stress responses. Under high light conditions, the growth of the mutant was affected, and both the chlorophyll content and the whole-chain oxygen evolution capability of the mutant were found to be significantly lower than those of the wild type, respectively. We propose that RpaA regulates the accumulation of the monomeric photosystem I and the D1 protein under high light conditions. This is the first report demonstrating that inactivation of a stress response regulator has specifically reduced the monomeric photosystem I. It suggests that PS I monomers and PS I trimers can be regulated independently for acclimation of cells to high light stress.

  17. Directed evolution of a monomeric, bright and photostable version of Clavularia cyan fluorescent protein: structural characterization and applications in fluorescence imaging

    Energy Technology Data Exchange (ETDEWEB)

    Al, Hui-wang; Henderson, J. Nathan; Remington, S. James; Campbell, Robert E. (Alberta); (Oregon)

    2008-05-07

    The arsenal of engineered variants of the GFP [green FP (fluorescent protein)] from Aequorea jellyfish provides researchers with a powerful set of tools for use in biochemical and cell biology research. The recent discovery of diverse FPs in Anthozoa coral species has provided protein engineers with an abundance of alternative progenitor FPs from which improved variants that complement or supersede existing Aequorea GFP variants could be derived. Here, we report the engineering of the first monomeric version of the tetrameric CFP (cyan FP) cFP484 from Clavularia coral. Starting from a designed synthetic gene library with mammalian codon preferences, we identified dimeric cFP484 variants with fluorescent brightness significantly greater than the wild-type protein. Following incorporation of dimer-breaking mutations and extensive directed evolution with selection for blue-shifted emission, high fluorescent brightness and photostability, we arrived at an optimized variant that we have named mTFP1 [monomeric TFP1 (teal FP 1)]. The new mTFP1 is one of the brightest and most photostable FPs reported to date. In addition, the fluorescence is insensitive to physiologically relevant pH changes and the fluorescence lifetime decay is best fitted as a single exponential. The 1.19 {angstrom} crystal structure (1 {angstrom}=0.1 nm) of mTFP1 confirms the monomeric structure and reveals an unusually distorted chromophore conformation. As we experimentally demonstrate, the high quantum yield of mTFP1 (0.85) makes it particularly suitable as a replacement for ECFP (enhanced CFP) or Cerulean as a FRET (fluorescence resonance energy transfer) donor to either a yellow or orange FP acceptor.

  18. Wild-Type Monomeric α-Synuclein Can Impair Vesicle Endocytosis and Synaptic Fidelity via Tubulin Polymerization at the Calyx of Held.

    Science.gov (United States)

    Eguchi, Kohgaku; Taoufiq, Zacharie; Thorn-Seshold, Oliver; Trauner, Dirk; Hasegawa, Masato; Takahashi, Tomoyuki

    2017-06-21

    α-Synuclein is a presynaptic protein the function of which has yet to be identified, but its neuronal content increases in patients of synucleinopathies including Parkinson's disease. Chronic overexpression of α-synuclein reportedly expresses various phenotypes of synaptic dysfunction, but the primary target of its toxicity has not been determined. To investigate this, we acutely loaded human recombinant α-synuclein or its pathological mutants in their monomeric forms into the calyces of Held presynaptic terminals in slices from auditorily mature and immature rats of either sex. Membrane capacitance measurements revealed significant and specific inhibitory effects of WT monomeric α-synuclein on vesicle endocytosis throughout development. However, the α-synuclein A53T mutant affected vesicle endocytosis only at immature calyces, whereas the A30P mutant had no effect throughout. The endocytic impairment by WT α-synuclein was rescued by intraterminal coloading of the microtubule (MT) polymerization blocker nocodazole. Furthermore, it was reversibly rescued by presynaptically loaded photostatin-1, a photoswitcheable inhibitor of MT polymerization, in a light-wavelength-dependent manner. In contrast, endocytic inhibition by the A53T mutant at immature calyces was not rescued by nocodazole. Functionally, presynaptically loaded WT α-synuclein had no effect on basal synaptic transmission evoked at a low frequency, but significantly attenuated exocytosis and impaired the fidelity of neurotransmission during prolonged high-frequency stimulation. We conclude that monomeric WT α-synuclein primarily inhibits vesicle endocytosis via MT overassembly, thereby impairing high-frequency neurotransmission. SIGNIFICANCE STATEMENT Abnormal α-synuclein abundance is associated with synucleinopathies including Parkinson's disease, but neither the primary target of α-synuclein toxicity nor its mechanism is identified. Here, we loaded monomeric α-synuclein directly into mammalian

  19. Impact of sublingual immunotherapy on seasonal asthma and skin reactivity in children allergic to Parietaria pollen treated with inhaled fluticasone propionate.

    Science.gov (United States)

    Pajno, G B; Vita, D; Parmiani, S; Caminiti, L; La Grutta, S; Barberio, G

    2003-12-01

    Immunotherapy is a recognized treatment for allergic respiratory diseases. To study the usefulness of immunotherapy in combination with optimal pharmacological therapy. Thirty-eight children (8-14 years) suffering from seasonal asthma+/-rhinoconjunctivitis due to Parietaria poorly controlled by anti-allergic drugs treatment were selected. After randomization according to a double-blind placebo-controlled design they received active sublingual immunotherapy (15 children) or placebo (15 children) for 13 months combined with inhaled fluticasone twice a day during the pollen season. Eight children were taken as control, whereas all patients were instructed to take symptomatic drugs on need. Early and late skin response to the allergen were assessed in all patients before and after treatment. Drug and symptom scores, as well as visual analogue scores (VASs) and Parietaria pollen counts were assessed during the pollen season. Groups were well balanced for age, gender, early and late skin response before treatment. Four children dropped out, in one case in relationship with active sublingual immunotherapy (SLIT) administration. Chest and nose symptoms, as well as drug scores and VASs were significantly better in both the active or placebo SLIT+fluticasone (S+F) as compared to the control group (P between <0.001 and 0.043). Eye symptoms were significantly better in the active S+F group as compared to control (P=0.025). The VASs were significantly better in the active S+F group as compared to the placebo S+F group (P=0.037). The early skin response decreased significantly in the active S+F group (P<0.001), whereas the late skin response changed significantly in all groups, with an increase in the placebo+fluticasone group (P=0.019) and in the control group (P=0.037) and a decrease (P<0.0001) in the active S+F group. The clinical efficacy of S+F is equal to that of fluticasone alone, but the addition of SLIT has effects also on non-bronchial symptoms.

  20. 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

  1. Synthesis, Radical Reactivity, and Thermochemistry of Monomeric Cu(II) Alkoxide Complexes Relevant to Cu/Radical Alcohol Oxidation Catalysis.

    Science.gov (United States)

    Porter, Thomas R; Capitao, Dany; Kaminsky, Werner; Qian, Zhaoshen; Mayer, James M

    2016-06-06

    Two new monomeric Cu(II) alkoxide complexes were prepared and fully characterized as models for intermediates in copper/radical mediated alcohol oxidation catalysis: Tp(tBuR)Cu(II)OCH2CF3 with Tp(tBu) = hydro-tris(3-tert-butyl-pyrazol-1-yl)borate 1 or Tp(tBuMe) = hydro-tris(3-tert-butyl-5-methyl-pyrazol-1-yl)borate 2. These complexes were made as models for potential intermediates in enzymatic and synthetic catalytic cycles for alcohol oxidation. However, the alkoxide ligands are not readily oxidized by loss of H; instead, these complexes were found to be hydrogen atom acceptors. They oxidize the hydroxylamine TEMPOH, 2,4,6-tri-t-butylphenol, and 1,4-cyclohexadiene to the nitroxyl radical, phenoxyl radical, and benzene, with formation of HOCH2CF3 (TFE) and the Cu(I) complexes Tp(tBuR)Cu(I)-MeCN in dichloromethane/1% MeCN or 1/2 [Tp(tBuR)Cu(I)]2 in toluene. On the basis of thermodynamics and kinetics arguments, these reactions likely proceed through concerted proton-electron transfer mechanisms. Thermochemical analyses give lower limits for the "effective bond dissociation free energies (BDFE)" of the O-H bonds in 1/2[Tp(tBuR)Cu(I)]2 + TFE and upper limits for the free energies associated with alkoxide oxidations via hydrogen atom transfer (effective alkoxide α-C-H BDFEs). These values are summations of the free energies of multiple chemical steps, which include the energetically favorable formation of 1/2[Tp(tBuR)Cu(I)]2. The effective alkoxide α-C-H bonds are very weak, BDFE ≤ 38 ± 4 kcal mol(-1) for 1 and ≤44 ± 5 kcal mol(-1) for 2 (gas-phase estimates), because C-H homolysis is thermodynamically coupled to one electron transfer to Cu(II) as well as the favorable formation of the 1/2[Tp(tBuR)Cu(I)]2 dimer. Treating 1 with the H atom acceptor (t)Bu3ArO(•) did not result in the expected alkoxide oxidation to an aldehyde, but rather net 2,2,2-trifluoroethoxyl radical transfer occurred to generate an unusual 2-substituted dienone-ether product. Treating 2

  2. Oxidation of a Cyclometalated Pd(II) Dimer with “CF3+”: Formation and Reactivity of a Catalytically Competent Monomeric Pd(IV) Aquo Complex

    Science.gov (United States)

    Ye, Yingda; Ball, Nicholas D.; Kampf, Jeff W.; Sanford, Melanie S.

    2010-01-01

    The reaction of [(bzq)Pd(OAc)]2 (bzq = benzo[h]quinoline) with “CF3+” reagents to afford the monomeric PdIV aquo complex (bzq)Pd(CF3)(OAc)2(OH2) is demonstrated. Heating this PdIV adduct at 60 °C for 12 h leads to highly chemoselective Aryl–CF3 bond-forming reductive elimination. The rate and yield of this transformation are both significantly enhanced by the addition of Brønsted and Lewis acidic additives. The mechanism of C–CF3 bond-formation from (bzq)Pd(CF3)(OAc)2(OH2) has been studied, and the major pathway is proposed to involve pre-equilibrium acetate dissociation followed by C–CF3 coupling. Finally, this monomeric PdIV complex is shown to be a kinetically competent intermediate for C–H trifluoromethylation with “CF3+” reagents. Collectively, these studies provide valuable insights about the speciation, nuclearity, and reactivity of Pd intermediates in catalytic C–H trifluoromethylation reactions. PMID:20866077

  3. Oxidation of a cyclometalated Pd(II) dimer with "CF3+": formation and reactivity of a catalytically competent monomeric Pd(IV) aquo complex.

    Science.gov (United States)

    Ye, Yingda; Ball, Nicholas D; Kampf, Jeff W; Sanford, Melanie S

    2010-10-20

    The reaction of [(bzq)Pd(OAc)](2) (bzq = benzo[h]quinoline) with "CF(3)(+)" reagents to afford the monomeric Pd(IV) aquo complex (bzq)Pd(CF(3))(OAc)(2)(OH(2)) is demonstrated. Heating this Pd(IV) adduct at 60 °C for 12 h leads to highly chemoselective aryl-CF(3) bond-forming reductive elimination. The rate and yield of this transformation are both significantly enhanced by the addition of Brønsted and Lewis acidic additives. The mechanism of C-CF(3) bond formation from (bzq)Pd(CF(3))(OAc)(2)(OH(2)) has been studied, and the major pathway is proposed to involve pre-equilibrium acetate dissociation followed by C-CF(3) coupling. Finally, this monomeric Pd(IV) complex is shown to be a kinetically competent intermediate for C-H trifluoromethylation with "CF(3)(+)" reagents. Collectively, these studies provide valuable insights about the speciation, nuclearity, and reactivity of Pd intermediates in catalytic C-H trifluoromethylation reactions.

  4. Analysis of by-product formation and sugar monomerization in sugarcane bagasse pretreated at pilot plant scale: differences between autohydrolysis, alkaline and acid pretreatment.

    Science.gov (United States)

    van der Pol, Edwin; Bakker, Rob; van Zeeland, Alniek; Sanchez Garcia, David; Punt, Arjen; Eggink, Gerrit

    2015-04-01

    Sugarcane bagasse is an interesting feedstock for the biobased economy since a large fraction is polymerized sugars. Autohydrolysis, alkaline and acid pretreatment conditions combined with enzyme hydrolysis were used on lignocellulose rich bagasse to acquire monomeric. By-products found after pretreatment included acetic, glycolic and coumaric acid in concentrations up to 40, 21 and 2.5 g/kg dry weight bagasse respectively. Alkaline pretreated material contained up to 45 g/kg bagasse DW of sodium. Acid and autohydrolysis pretreatment results in a furan formation of 14 g/kg and 25 g/kg DW bagasse respectively. Enzyme monomerization efficiencies of pretreated solid material after 72 h were 81% for acid pretreatment, 77% for autohydrolysis and 57% for alkaline pretreatment. Solid material was washed with superheated water to decrease the amount of by-products. Washing decreased organic acid, phenol and furan concentrations in solid material by at least 60%, without a major sugar loss. Copyright © 2015 Elsevier Ltd. All rights reserved.

  5. Sublingual immunotherapy (SLIT for house dust mites does not prevent new allergen sensitization and bronchial hyper-responsiveness in allergic rhinitis children.

    Directory of Open Access Journals (Sweden)

    Jae Hyun Lim

    Full Text Available The aim of this study is to identify the effects of sublingual immunotherapy (SLIT on immunologic parameters and bronchial-hyper-responsiveness in children with allergic rhinitis to house-dust mite (HDM, through long-term follow-up cohort.Among the Allergic Rhinitis Cohort Study for Kids, pediatric patients who visited the hospital for rhinitis symptoms and proven allergy to HDM through skin prick test were studied. In this cohort, 37 patients received SLIT more than 3-years (SLIT group, and 184 patients received only pharmacologic therapy (non-SLIT group were included in this study. The results of skin prick test, eosinophil percent and count, total immunoglobulin E (IgE, and bronchial provocation test at initial and 3-year followed-up were compared in the two groups.After 3 year follow-up, only the serum eosinophil percent decreased more significantly in SLIT group than that in the non-SLIT group. New-sensitization rate other than HDM between SLIT and non-SLIT group did not show any significant differences. The distribution of sensitized allergen other than HDM showed increasing tendency after 3 years in both groups. Older age and a small number of sensitized allergen affected the improvement of bronchial hyper-responsiveness regardless of SLIT.HDM SLIT in allergic rhinitis children for 3 years in Korea does not affect prevention of new sensitization and poly-sensitization rate increment, and improvement of bronchial hyper-responsiveness.

  6. Sublingual immunotherapy (SLIT) for house dust mites does not prevent new allergen sensitization and bronchial hyper-responsiveness in allergic rhinitis children.

    Science.gov (United States)

    Lim, Jae Hyun; Kim, Jin Youp; Han, Doo Hee; Lee, Chul Hee; Hong, Seung-No; Wee, Jee Hye; Park, Sue K; Rhee, Chae-Seo

    2017-01-01

    The aim of this study is to identify the effects of sublingual immunotherapy (SLIT) on immunologic parameters and bronchial-hyper-responsiveness in children with allergic rhinitis to house-dust mite (HDM), through long-term follow-up cohort. Among the Allergic Rhinitis Cohort Study for Kids, pediatric patients who visited the hospital for rhinitis symptoms and proven allergy to HDM through skin prick test were studied. In this cohort, 37 patients received SLIT more than 3-years (SLIT group), and 184 patients received only pharmacologic therapy (non-SLIT group) were included in this study. The results of skin prick test, eosinophil percent and count, total immunoglobulin E (IgE), and bronchial provocation test at initial and 3-year followed-up were compared in the two groups. After 3 year follow-up, only the serum eosinophil percent decreased more significantly in SLIT group than that in the non-SLIT group. New-sensitization rate other than HDM between SLIT and non-SLIT group did not show any significant differences. The distribution of sensitized allergen other than HDM showed increasing tendency after 3 years in both groups. Older age and a small number of sensitized allergen affected the improvement of bronchial hyper-responsiveness regardless of SLIT. HDM SLIT in allergic rhinitis children for 3 years in Korea does not affect prevention of new sensitization and poly-sensitization rate increment, and improvement of bronchial hyper-responsiveness.

  7. A Retrospective Cohort Study of Obstetric Outcomes in Opioid-Dependent Women Treated with Implant Naltrexone, Oral Methadone or Sublingual Buprenorphine, and Non-Dependent Controls.

    Science.gov (United States)

    Kelty, Erin; Hulse, Gary

    2017-07-01

    Opioid pharmacotherapies play an important role in the treatment of opioid-dependent women; however, very little is known about the safety of naltrexone in pregnant patients. This study examined the obstetric health of opioid-dependent women who were treated with implant naltrexone during pregnancy, and compared them with women treated with methadone and/or buprenorphine and a cohort of non-opioid-dependent controls. Women treated with implant naltrexone, oral methadone or sublingual buprenorphine between 2001 and 2010, along with a cohort of age-matched controls, were linked with records from midwives, hospital and emergency departments (EDs) and the death registry to identify pregnancy and health events that occurred during pregnancy and in the post-partum period. Overall rates of pregnancy loss (requiring hospital or ED attendance) were significantly elevated in naltrexone-treated women compared with buprenorphine-treated women (p = 0.018) and controls (p buprenorphine groups, and neither were overall complications during pregnancy and labour. Overall rates of complications during pregnancy were significantly higher in the naltrexone-treated women than in the controls. Opioid-dependent women treated with naltrexone implant had higher rates of birth than the other three groups (methadone- or buprenorphine-treated women, or age-matched controls). Overall rates of complications during pregnancy were elevated in naltrexone-treated women when compared with the control group, but were generally not significantly different to rates in methadone- or buprenorphine-treated women.

  8. Opioid substitution treatment with sublingual buprenorphine in Manipur and Nagaland in Northeast India: what has been established needs to be continued and expanded

    Directory of Open Access Journals (Sweden)

    Sharma Charan

    2009-02-01

    Full Text Available Abstract Manipur and Nagaland in northeast India report an antenatal HIV prevalence of > 1% and the current HIV prevalence among injecting drug users is 24% and 4.5% respectively. Through support from DFID's Challenge Fund, Emmanuel Hospital Association (EHA established thirteen drop-in-centres across the two states to deliver opioid substitution treatment with sublingual buprenorphine for 1200 injecting drug users. Within a short span of time the treatment has been found to be attractive to the clients and currently 1248 injecting opioid users are receiving opioid substitution treatment. The project is acceptable to the drug users, the families, the communities, religious as well as the militant groups. The treatment centres operate all days of the week, have trained staff members, utilize standardized protocols and ensure a strict supervised delivery system to prevent illicit diversion of buprenorphine. The drug users receiving the substitution treatment are referred to HIV voluntary counselling and testing. As this treatment has the potential to change HIV related risk behaviours, what has been established in the two states needs to be continued and expanded with the support from the Government of India.

  9. Sublingual immunotherapy provides long-term relief in allergic rhinitis and reduces the risk of asthma: A retrospective, real-world database analysis.

    Science.gov (United States)

    Zielen, S; Devillier, P; Heinrich, J; Richter, H; Wahn, U

    2018-01-01

    Allergy immunotherapy (AIT) is the only treatment for allergic rhinitis (AR) and/or allergic asthma (AA) with long-term efficacy. However, there are few real-life data on the progression of AR and/or AA in patients receiving AIT. To assess the real-world, long-term efficacy of grass pollen sublingual immunotherapy (SLIT) tablets in AR and their impact on asthma onset and progression. In a retrospective analysis of a German longitudinal prescription database, AR patients treated with grass pollen SLIT tablets were compared with a control group not having received AIT. Multiple regression analysis was used to compare changes over time in rescue symptomatic AR medication use after treatment cessation, asthma medication use, and the time to asthma onset in the two groups. After applying all selection criteria, 2851 SLIT and 71 275 control patients were selected for the study. After treatment cessation, AR medication use was 18.8 percentage points lower (after adjustment for covariates, and relative to the pretreatment period) in SLIT tablet group than in the non-AIT group (PReal-world treatment of AR patients with grass pollen SLIT tablets was associated with slower AR progression, less frequent asthma onset, and slower asthma progression. © 2017 The Authors. Allergy Published by John Wiley & Sons Ltd.

  10. A comparison of the effects of morphine and sublingual desmopressin combination therapy with morphine alone in treatment of renal colic: a controlled clinical trial.

    Science.gov (United States)

    Keshvari Shirvani, Maliheh; Darabi Mahboub, Mohammadreza; Ghazi, Mahdi; Delijani, Alireza

    2015-02-22

    To compare the therapeutic efficacy of combined desmopressin and morphine with morphine and placebo on acute renal colic. In a single blind case-control clinical trial 81 consecutive patients, 54 males and 27 females with the mean age of 30.12 ± 9.88 years, presenting with acute renal colic to the urology emergency unit were studied. The patients were randomly assigned into two groups. The 40 cases were treated with 0.1 mg/kg IM morphine and 60 μg of sublingual desmopressin melt; whereas the 41 controls received the same dose of morphine beside a placebo. There were no significant statistical differences regarding the mean age, gender, stone size, location and affected side between the two groups. Our results showed a significantly higher acuity of pain in the study group in comparison to the controls at 10, 20 and 30 minutes of receiving the medication (P = .06, .017 and P = .008, respectively). No superiority was found in adding desmopressin to morphine compared to the traditional treatments (opioids only) in relieving the pain of acute renal colic cases.

  11. Sublingual administration of bacteria-expressed influenza virus hemagglutinin 1 (HA1) induces protection against infection with 2009 pandemic H1N1 influenza virus.

    Science.gov (United States)

    Shim, Byoung-Shik; Choi, Jung-Ah; Song, Ho-Hyun; Park, Sung-Moo; Cheon, In Su; Jang, Ji-Eun; Woo, Sun Je; Cho, Chung Hwan; Song, Min-Suk; Kim, Hyemi; Song, Kyung Joo; Lee, Jae Myun; Kim, Suhng Wook; Song, Dae Sub; Choi, Young Ki; Kim, Jae-Ouk; Nguyen, Huan Huu; Kim, Dong Wook; Bahk, Young Yil; Yun, Cheol-Heui; Song, Man Ki

    2013-02-01

    Influenza viruses are respiratory pathogens that continue to pose a significantly high risk of morbidity and mortality of humans worldwide. Vaccination is one of the most effective strategies for minimizing damages by influenza outbreaks. In addition, rapid development and production of efficient vaccine with convenient administration is required in case of influenza pandemic. In this study, we generated recombinant influenza virus hemagglutinin protein 1 (sHA1) of 2009 pandemic influenza virus as a vaccine candidate using a well-established bacterial expression system and administered it into mice via sublingual (s.l.) route. We found that s.l. immunization with the recombinant sHA1 plus cholera toxin (CT) induced mucosal antibodies as well as systemic antibodies including neutralizing Abs and provided complete protection against infection with pandemic influenza virus A/CA/04/09 (H1N1) in mice. Indeed, the protection efficacy was comparable with that induced by intramuscular (i.m.) immunization route utilized as general administration route of influenza vaccine. These results suggest that s.l. vaccination with the recombinant non-glycosylated HA1 protein offers an alternative strategy to control influenza outbreaks including pandemics.

  12. First report of angio-oedema subsequent to the administration of allergen specific sublingual immunotherapy for the management of equine hypersensitivity dermatitis.

    Science.gov (United States)

    Scholz, Fiona M; Burrows, Amanda K; Muse, Russell

    2016-10-01

    Sublingual immunotherapy (SLIT) offers an alternative mode of allergen delivery to subcutaneous immunotherapy (SCIT) with the aim of inducing immunological tolerance. Currently, there are no published reports regarding the efficacy or safety of SLIT in horses. To describe the first case of several adverse events occurring in a horse subsequent to the repeat administration of SLIT. A seven-year-old, warmblood mare with a confirmed diagnosis of equine hypersensitivity dermatitis (EHD). Immunotherapy was recommended for management of EHD. Due to the temperament of the horse, the owner elected to proceed with SLIT. Thirty six hours after commencing SLIT, the mare developed scleral oedema, moderate dyspnoea and abdominal discomfort. SLIT was withdrawn for 10 days and re instituted using a ten-fold dilution of the original vaccine. Localized oedema and swelling of the tongue developed within 12 h of administration. At this juncture, SLIT was withdrawn. The horse was rechallenged with the SLIT allergen vehicle, 50% glycerine and no adverse reactions occurred. SCIT was commenced using the same allergens and no adverse events occurred with repeated administration. To the best of the authors' knowledge, this is the first reported case of adverse reactions developing subsequent to the administration of SLIT for the management of EHD. © 2016 ESVD and ACVD.

  13. 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

  14. 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.

  15. Optimization of ultrasound-assisted extraction of total monomeric anthocyanin (TMA) and total phenolic content (TPC) from eggplant (Solanum melongena L.) peel.

    Science.gov (United States)

    Dranca, Florina; Oroian, Mircea

    2016-07-01

    The present study describes the extraction of total monomeric anthocyanin (TMA) and total phenolic content (TPC) from eggplant peel using ultrasonic treatments and methanol and 2-propanol as extraction solvents. The extraction yields were optimized by varying the solvent concentration, ultrasonic frequency, temperature and time of ultrasonic treatment. Box-Behnken design was used to investigate the effect of process variables on the ultrasound-assisted extraction. The results showed that for TPC extraction the optimal condition were obtained with a methanol concentration of 76.6%, 33.88 kHz ultrasonic frequency, a temperature of 69.4 °C and 57.5 min extraction time. For TMA the optimal condition were the following: 54.4% methanol concentration, 37 kHz, 55.1 °C and process time of 44.85 min. Copyright © 2015 Elsevier B.V. All rights reserved.

  16. Oxidation of a Cyclometalated Pd(II) Dimer with “CF3+”: Formation and Reactivity of a Catalytically Competent Monomeric Pd(IV) Aquo Complex

    OpenAIRE

    Ye, Yingda; Ball, Nicholas D.; Kampf, Jeff W.; Sanford, Melanie S.

    2010-01-01

    The reaction of [(bzq)Pd(OAc)]2 (bzq = benzo[h]quinoline) with “CF3+” reagents to afford the monomeric PdIV aquo complex (bzq)Pd(CF3)(OAc)2(OH2) is demonstrated. Heating this PdIV adduct at 60 °C for 12 h leads to highly chemoselective Aryl–CF3 bond-forming reductive elimination. The rate and yield of this transformation are both significantly enhanced by the addition of Brønsted and Lewis acidic additives. The mechanism of C–CF3 bond-formation from (bzq)Pd(CF3)(OAc)2(OH2) has been studied, a...

  17. 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.

  18. PENGARUH PENGOLAHAN PANAS TERHADAP KONSENTRASI ANTOSIANIN MONOMERIK UBI JALAR UNGU (Ipomoea batatas L (Efect of Heat Processing on Monomeric Anthocyanin of Purple Sweet Potato (Ipomoea batatas L

    Directory of Open Access Journals (Sweden)

    Ai Mahmudatussa'adah

    2015-09-01

    content in PSP during heat processing of flakes. The other purpose of this reseach was to observe the order kinetics model of effect temperature and time baking on total anthocyanin monomeric of fresh PSP and rehydration PSP flakes. The experimental applied a completely randomized design with three replications. The color and amount of anthocyanin (L * = 23.38 ± 0.71, C = 9.84 ± 0.98, Hue = 12.25 ± 1.61. Total monomeric anthocyanin in fresh PSP was 1.45 ± 0.00 mg cyanidin equivalent (CyE/g dry basis (db. In general, the color and the amount of PSP anthocyanin changed during the flakes processing. Steamed PSP for 7 minutes turned its color into a bright purple (L * = 25.88 ± 0.47, C = 24.64 ± 0.25, Hue = 348.83 ± 0.33 with the amount of monomeric anthocyanin increased to 3.76 ± 0.01 CyE mg/g db. Flakes PSP was very bright purple (L * = 36.12 ± 0.11, C = 9.97 ± 0.18, Hue = 359.29 ± 0.31 and the amount of monomericanthocyanin was slightly lower than that of steamed sweet potato (3.19 ± 0.12 mg CyE / g db. Total monomeric anthocyanin of fresh PSP and rehydration flakes PSP decrease during baking time. Keywords: Color, anthocyanin, purple sweet potato, flakes, degradation kinetics   ABSTRAK Antosianin merupakan salah satu kelompok zat warna alami yang terdapat pada tanaman, seperti daun, bunga, umbi, buah atau sayur. Salah satu sumber antosianin pada tanaman adalah ubi jalar ungu (UJU yang mengandung lebih dari 98% antosianin terasilasi dari konsentrasi antosianin umbi. Warna antosianin bervariasi mulai dari merah, ungu, biru, sampai kuning. Warna dan konsentrasi antosianin dapat berubah karena pengaruh panas. Penelitian ini bertujuan untuk mempelajari perubahan warna dan konsentrasi antosianin monomerik sebagai akibat proses pengolahan dalam pembuatan  UJU. Penelitian ini mengkaji juga mengenai model kinetika reaksi pengaruh suhu dan waktu panggang terhadap konsentrasi antosianin UJU segar dan  rehidrasi. Penelitian menggunakan rancangan acak lengkap

  19. Ligand Exchange Reactions of a Monomeric Zirconium Carbonate Complex with Carboxylic Acids Studied by Extended X-ray Absorption Fine Structure, UV Absorption and Raman Spectrophotometry.

    Science.gov (United States)

    Takasaki, Fumiyuki; Fujiwara, Kazuhiko; Kikuchi, Tomomi; Tanno, Takenori; Nakajima, Yasushi; Toyoda, Yasunori; Ogawa, Nobuaki

    2017-01-01

    Ligand exchange reactions of a monomeric zirconium carbonate complex with carboxylic acids were studied by means of extended X-ray absorption fine structure (EXAFS), UV absorption spectrophotometry and Raman spectrometry. Three carboxylic acids, gluconic acid, and L-tartaric acid and citric acid, which are mono-, di- and tri-carboxylic acids, respectively, were employed in this study. These three carboxylic acids gave different spectral signatures and concentration dependences, respectively. In the gluconic acid system, the peaks on Fourier transform of EXAFS spectrum and Raman spectrum caused by carbonate ion coordinating to zirconium atom were obviously decreased with increasing gluconic acid concentration compared to the other two carboxylic acid systems. This indicates the high association ability of gluconic acid to zirconium, which was revealed by UV spectrophotometric analysis.

  20. A Novel g.55040074delT in ALAS2 Gene Resulting in a Monomeric Protein and Severe Sideroblastic Anemia Phenotype.

    Science.gov (United States)

    Bhatia, Prateek; Singh, Aditya; Hedge, Avani

    2017-08-01

    Sideroblastic anemias are a rare group of disorders resulting from defective iron incorporation during heme synthesis and hence characterized by anemia and presence of ringed sideroblasts in bone marrow. The most common form is an X-linked disorder caused by mutations in ALAS2 gene. In the current paper, a case of X-linked sideroblastic anemia caused by a novel homozygous deletional mutation in exon 10 of ALAS2 gene is presented. The female infant developed moderately severe anemia at 6 months of age, which did not improve despite adequate nutritional support. The diagnosis was suspected considering a high plasma ferritin of 740.9 μg/L. The protein structure as predicted by SWISS model was a monomeric form rather than wild-type homodimer, resulting in marked loss of function and protein instability.

  1. Purified monomeric ligand.MD-2 complexes reveal molecular and structural requirements for activation and antagonism of TLR4 by Gram-negative bacterial endotoxins.

    Science.gov (United States)

    Gioannini, Theresa L; Teghanemt, Athmane; Zhang, DeSheng; Esparza, Gregory; Yu, Liping; Weiss, Jerrold

    2014-08-01

    A major focus of work in our laboratory concerns the molecular mechanisms and structural bases of Gram-negative bacterial endotoxin recognition by host (e.g., human) endotoxin-recognition proteins that mediate and/or regulate activation of Toll-like receptor (TLR) 4. Here, we review studies of wild-type and variant monomeric endotoxin.MD-2 complexes first produced and characterized in our laboratories. These purified complexes have provided unique experimental reagents, revealing both quantitative and qualitative determinants of TLR4 activation and antagonism. This review is dedicated to the memory of Dr. Theresa L. Gioannini (1949-2014) who played a central role in many of the studies and discoveries that are reviewed.

  2. FAN1 Activity on Asymmetric Repair Intermediates Is Mediated by an Atypical Monomeric Virus-type Replication-Repair Nuclease Domain

    Directory of Open Access Journals (Sweden)

    Simon Pennell

    2014-07-01

    Full Text Available FAN1 is a structure-selective DNA repair nuclease with 5′ flap endonuclease activity, involved in the repair of interstrand DNA crosslinks. It is the only eukaryotic protein with a virus-type replication-repair nuclease (“VRR-Nuc” “module” that commonly occurs as a standalone domain in many bacteria and viruses. Crystal structures of three representatives show that they structurally resemble Holliday junction resolvases (HJRs, are dimeric in solution, and are able to cleave symmetric four-way junctions. In contrast, FAN1 orthologs are monomeric and cleave 5′ flap structures in vitro, but not Holliday junctions. Modeling of the VRR-Nuc domain of FAN1 reveals that it has an insertion, which packs against the dimerization interface observed in the structures of the viral/bacterial VRR-Nuc proteins. We propose that these additional structural elements in FAN1 prevent dimerization and bias specificity toward flap structures.

  3. The influence of monomeric resin and filler characteristics on the performance of experimental resin-based composites (RBCs) derived from a commercial formulation.

    Science.gov (United States)

    Hahnel, Sebastian; Dowling, Adam H; El-Safty, Samy; Fleming, Garry J P

    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. Six experimental RBCs modified from a commercial RBC were tested. The three-point flexure strength (σ(3)) and modulus (E) data was determined for groups of 20 bar-shaped specimens, prepared in a custom-made knife-edge split aluminum mold and irradiated using a modification of the ISO 4049 protocol. The biaxial flexure strength (BFS) and top and bottom Vickers hardness number (VHN) determination was performed on disc-shaped specimens (n=20). Normal distribution of the σ(3), E, BFS and top and bottom VHN data was verified using the Shapiro-Wilk's test. Paired groups were compared using independent samples t-test for the individual tests investigated (σ(3), E, BFS and top and bottom VHN) at a significance level of P<0.05. A significant decrease in the mean σ(3) (P<0.011) and mean E (P<0.001) were identified on increasing the filler fraction (from 71.4 to 74.5 vol%) or increasing the mean filler diameter (from 1.5 to 2.5 μm). Increasing the filler density resulted in a significant increase in the mean σ(3) (P<0.001), mean E (P<0.001) and mean top VHN (P≤0.001). Replacing the monomeric blend with an ormocer blend significantly reduced the mean σ(3), E, BFS and top and bottom VHNs (all P<0.001). For each RBC monomeric resin and filler (type, density and diameter) combination employed, a finite filler volume fraction exists. Operating at the finite filler volume fraction increases the difficulty in improving the mechanical properties of the RBCs tailored from a commercial product. Copyright © 2011 Academy of Dental Materials. Published by Elsevier Ltd. All rights reserved.

  4. Characterization of monomeric and multimeric snake neurotoxins and other bioactive proteins from the venom of the lethal Australian common copperhead (Austrelaps superbus).

    Science.gov (United States)

    Marcon, Francesca; Purtell, Louise; Santos, Jerran; Hains, Peter G; Escoubas, Pierre; Graudins, Andis; Nicholson, Graham M

    2013-05-15

    Envenomation by Australian copperheads results mainly in muscle paralysis largely attributed to the presence of postsynaptic α-neurotoxins. However, poorly reversible neurotoxic effects suggest that these venoms may contain snake presynaptic phospholipase A2 neurotoxins (SPANs) that irreversibly inhibit neurotransmitter release. Using size-exclusion liquid chromatography, the present study isolated the first multimeric SPAN complex from the venom of the Australian common copperhead, Austrelaps superbus. The multimeric SPAN P-elapitoxin-As1a (P-EPTX-As1a) along with two novel monomeric SPANs and a new postsynaptic α-neurotoxin were then pharmacologically characterized using the chick biventer cervicis nerve-muscle preparation. All SPANs inhibited nerve-evoked twitch contractions at the neuromuscular junction without inhibiting contractile responses to cholinergic agonists or KCl. These actions are consistent with a prejunctional action to inhibit neurotransmitter release, without direct myotoxicity. Furthermore, the multimeric P-EPTX-As1a caused tetanic 'fade' in muscle tension under high frequency nerve stimulation, and produced a triphasic alteration to neurotransmitter release. These actions have been previously noted with other multimeric SPAN complexes such as taipoxin. Moreover, the neurotoxic α-subunit of P-EPTX-As1a shows high homology to taipoxin α-chain. Several other coagulopathic and myotoxic high mass proteins including a class PIII snake venom metalloproteinase, C-type lectin, l-amino acid oxidase, acetylcholinesterase and phospholipase B were also identified that may contribute to the overall toxicity of A. superbus venom. In conclusion, clinicians should be aware that early antivenom intervention might be necessary to prevent the onset of irreversible presynaptic neurotoxicity caused by multimeric and monomeric SPANs and that A. superbus venom is potentially capable of producing coagulopathic and myotoxic effects. Copyright © 2013 Elsevier Inc

  5. Zn-bis-glutathionate is the best co-substrate of the monomeric phytochelatin synthase from the photosynthetic heavy metal-hyperaccumulator Euglena gracilis.

    Science.gov (United States)

    García-García, Jorge D; Girard, Lourdes; Hernández, Georgina; Saavedra, Emma; Pardo, Juan P; Rodríguez-Zavala, José S; Encalada, Rusely; Reyes-Prieto, Adrián; Mendoza-Cózatl, David G; Moreno-Sánchez, Rafael

    2014-03-01

    The phytochelatin synthase from photosynthetic Euglena gracilis (EgPCS) was analyzed at the transcriptional, kinetic, functional, and phylogenetic levels. Recombinant EgPCS was a monomeric enzyme able to synthesize, in the presence of Zn(2+) or Cd(2+), phytochelatin2-phytochelatin4 (PC2-PC4) using GSH or S-methyl-GS (S-methyl-glutathione), but not γ-glutamylcysteine or PC2 as a substrate. Kinetic analysis of EgPCS firmly established a two-substrate reaction mechanism for PC2 synthesis with Km values of 14-22 mM for GSH and 1.6-2.5 μM for metal-bis-glutathionate (Me-GS2). EgPCS showed the highest Vmax and catalytic efficiency with Zn-(GS)2, and was inactivated by peroxides. The EgPCS N-terminal domain showed high similarity to that of other PCSases, in which the typical catalytic core (Cys-70, His-179 and Asp-197) was identified. In contrast, the C-terminal domain showed no similarity to other PCSases. An EgPCS mutant comprising only the N-terminal 235 amino acid residues was inactive, suggesting that the C-terminal domain is essential for activity/stability. EgPCS transcription in Euglena cells was not modified by Cd(2+), whereas its heterologous expression in ycf-1 yeast cells provided resistance to Cd(2+) stress. Phylogenetic analysis of the N-terminal domain showed that EgPCS is distant from plants and other photosynthetic organisms, suggesting that it evolved independently. Although EgPCS showed typical features of PCSases (constitutive expression; conserved N-terminal domain; kinetic mechanism), it also exhibited distinct characteristics such as preference for Zn-(GS)2 over Cd-(GS)2 as a co-substrate, a monomeric structure, and ability to solely synthesize short-chain PCs, which may be involved in conferring enhanced heavy-metal resistance.

  6. 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.

  7. Structural mechanism governing the quaternary organization of monocot mannose-binding lectin revealed by the novel monomeric structure of an orchid lectin.

    Science.gov (United States)

    Liu, Wei; Yang, Na; Ding, Jingjin; Huang, Ren-huai; Hu, Zhong; Wang, Da-Cheng

    2005-04-15

    Two isoforms of an antifungal protein, gastrodianin, were isolated from two subspecies of the orchid Gastrodia elata, belonging to the protein superfamily of monocot mannose-specific lectins. In the context that all available structures in this superfamily are oligomers so far, the crystal structures of the orchid lectins, both at 2.0 A, revealed a novel monomeric structure. It resulted from the rearrangement of the C-terminal peptide inclusive of the 12th beta-strand, which changes from the "C-terminal exchange" into a "C-terminal self-assembly" mode. Thus, the overall tertiary scaffold is stabilized with an intramolecular beta-sheet instead of the hybrid observed on subunit/subunit interface in all known homologous dimeric or tetrameric lectins. In contrast to the constrained extended conformation with a cis peptide bond between residues 98 and 99 commonly occurring in oligomers, a beta-hairpin forms from position 97 to 101 with a normal trans peptide bond at the corresponding site in gastrodianin, which determines the topology of the C-terminal peptide and thereby its unique fold pattern. Sequence and structure comparison shows that residue replacement and insertion at the position where the beta-hairpin occurs in association with cis-trans inter-conversion of the specific peptide bond (97-98) are possibly responsible for such a radical structure switch between monomers and oligomers. Moreover, this seems to be a common melody controlling the quaternary states among bulb lectins through studies on sequence alignment. The observations revealed a structural mechanism by which the quaternary organization of monocot mannose binding lectins could be governed. The mutation experiment performed on maltose-binding protein-gastrodianin fusion protein followed by a few biochemical detections provides direct evidence to support this conclusion. Potential carbohydrate recognition sites and biological implications of the orchid lectin based on its monomeric state are also

  8. Effects of irradiation on intracellular protein synthesis in demilune of mouse sublingual gland; Study of electron microscopic autoradiography with [sup 3]H-leucine

    Energy Technology Data Exchange (ETDEWEB)

    Ohki, Ikuko; Nasu, Masanori; Matsunaga, Hajime; Furumoto, Keiichi (Nippon Dental Univ., Tokyo (Japan))

    1994-08-01

    The effects of radiation on amino acid transport in demilune of the sublingual glands were examined in mice. After 10 Gy X-ray irradiation to the submandibular region, [sup 3]H-leucine was administered to these mice. Three days after irradiation, light microscopic autoradiograms and electron microscopic autoradiograms were obtained to determine the silver grain count in demilune and the distribution of silver grain in the organelles of these cells involved in protein synthesis. Both non-irradiated and irradiated groups showed a peak count 30 minutes after the administration of [sup 3]H-leucine and a tendency to decrease in the count thereafter. The magnitude of the chronological change in this parameter was smaller in the irradiated group than in the non-irradiated group. The percentage of silver grain in the rough endoplasmic reticulum also reached a peak 30 minutes after [sup 3]H-leucine administration in both non-irradiated and irradiated groups. Thereafter the percentage tended to decrease with time in the non-irradiated group. In the irradiated group, on the other hand, the percentage showed little change from the peak level at 60, 120, and 180 minutes. In the non-irradiated group, the percentage of silver grain in the Golgi apparatus was relatively high at 30 and 60 minutes. The percentage tended to be low at 120 and 180 minutes in the irradiated group. In the non-irradiated group, the percentage of silver grain in condencing vacuoles reached a peak at 60 minutes and decreased gradually thereafter. This parameter reached a peak at 30 minutes in the irradiated group. The percentage of silver grain in the secretory granules increased with time in both non-irradiated and irradiated groups. At 30 and 60 minutes, the percentage was significantly higher in the irradiated group than in the non-irradiated group. At 180 minutes, however, it was significantly lower in the irradiated group than in the non-irradiated group. (author).

  9. 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.

  10. Sustained 3-year efficacy of pre- and coseasonal 5-grass-pollen sublingual immunotherapy tablets in patients with grass pollen-induced rhinoconjunctivitis.

    Science.gov (United States)

    Didier, Alain; Worm, Margitta; Horak, Friedrich; Sussman, Gordon; de Beaumont, Olivier; Le Gall, Martine; Melac, Michel; Malling, Hans-Jorgen

    2011-09-01

    Seasonal allergic rhinoconjunctivitis affects millions of persons. The efficacy of allergen sublingual immunotherapy (SLIT) was demonstrated in previous short-term studies. We sought to evaluate the sustained efficacy of 2 dosing regimens of a pre- and coseasonal treatment with 300 IR (index of reactivity) 5-grass-pollen SLIT tablets (Oralair) compared with placebo assessed by using the average adjusted symptom score (AAdSS) at season 3 in adults with grass pollen-induced rhinoconjunctivitis. Six hundred thirty-three patients were treated for either 2 or 4 months before and then during the grass pollen season with active or placebo treatment for 3 consecutive seasons. The primary outcome was the AAdSS, a symptom score adjusted for rescue medication use, after 3 consecutive treatment seasons. Secondary outcomes were symptoms and rescue medication score, quality-of-life, and safety assessments. The mean AAdSS was reduced by 36.0% and 34.5% at season 3 in the 2- and 4-month pre- and coseasonal active treatment groups, respectively, compared with that in the placebo group (P ISSs and the medication score, with a marked improvement in quality of life for both active groups compared with the placebo group at season 3. Most treatment-emergent adverse events were local reactions expected with SLIT, decreasing in number and intensity in each treatment season. Sustained efficacy of 2- and 4-month pre- and coseasonal treatment with the 300 IR tablet over 3 pollen seasons was demonstrated, with reduction in symptoms and rescue medication use. The treatment was well tolerated. Adverse events decreased in number and intensity over the 3 seasons. Copyright © 2011 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

  11. 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.

  12. 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.

  13. Acceptability and feasibility of the use of 400 μg of sublingual misoprostol after mifepristone for medical abortion up to 63 days since the last menstrual period: evidence from Uzbekistan.

    Science.gov (United States)

    Raghavan, Sheila; Tsereteli, Tamar; Kamilov, Asamidin; Kurbanbekova, Dilfuza; Yusupov, Dilmurod; Kasimova, Feruza; Jymagylova, Dilbar; Winikoff, Beverly

    2013-04-01

    To examine the efficacy, acceptability and feasibility of early medical abortion, with the option of home administration of misoprostol, in Uzbekistan. A total of 450 women were enrolled at national, municipal and private facilities in Tashkent, Uzbekistan. Women who presented for termination of pregnancy with gestations up to 63 days were recruited to participate in the study. All eligible pregnant women who consented to participate swallowed a 200 mg mifepristone pill in the clinic and were given the option of taking 400 μg misoprostol sublingually either at the clinic or at home 24-48 hours after mifepristone administration. Abortion status was determined two weeks later. Almost all women (99.5%) chose home administration of misoprostol. The sublingual route of misoprostol administration was acceptable or very acceptable to 89% of participants. Ninety-five percent of women had complete abortions after mifepristone and misoprostol. Almost all participants preferred a medical abortion to surgery for a future procedure (95%). Mifepristone medical abortion with home administration of misoprostol is an acceptable and feasible option for women in Uzbekistan. The method worked well at all three facility types.

  14. 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

  15. The First Archaeal ATP-Dependent Glucokinase, from the Hyperthermophilic Crenarchaeon Aeropyrum pernix, Represents a Monomeric, Extremely Thermophilic ROK Glucokinase with Broad Hexose Specificity

    Science.gov (United States)

    Hansen, Thomas; Reichstein, Bianca; Schmid, Roland; Schönheit, Peter

    2002-01-01

    An ATP-dependent glucokinase of the hyperthermophilic aerobic crenarchaeon Aeropyrum pernix was purified 230-fold to homogeneity. The enzyme is a monomeric protein with an apparent molecular mass of about 36 kDa. The apparent Km values for ATP and glucose (at 90°C and pH 6.2) were 0.42 and 0.044 mM, respectively; the apparent Vmax was about 35 U/mg. The enzyme was specific for ATP as a phosphoryl donor, but showed a broad spectrum for phosphoryl acceptors: in addition to glucose, which showed the highest catalytic efficiency (kcat/Km), the enzyme also phosphorylates glucosamin, fructose, mannose, and 2-deoxyglucose. Divalent cations were required for maximal activity: Mg2+, which was most effective, could partially be replaced with Co2+, Mn2+, and Ni2+. The enzyme had a temperature optimum of at least 100°C and showed significant thermostability up to 100°C. The coding function of open reading frame (ORF) APE2091 (Y. Kawarabayasi, Y. Hino, H. Horikawa, S. Yamazaki, Y. Haikawa, K. Jin-no, M. Takahashi, M. Sekine, S. Baba, A. Ankai, H. Kosugi, A. Hosoyama, S. Fukui, Y. Nagai, K. Nishijima, H. Nakazawa, M. Takamiya, S. Masuda, T. Funahashi, T. Tanaka, Y. Kudoh, J. Yamazaki, N. Kushida, A. Oguchi, and H. Kikuchi, DNA Res. 6:83-101, 145-152, 1999), previously annotated as gene glk, coding for ATP-glucokinase of A. pernix, was proved by functional expression in Escherichia coli. The purified recombinant ATP-dependent glucokinase showed a 5-kDa higher molecular mass on sodium dodecyl sulfate-polyacrylamide gel electrophoresis, but almost identical kinetic and thermostability properties in comparison to the native enzyme purified from A. pernix. N-terminal amino acid sequence of the native enzyme revealed that the translation start codon is a GTG 171 bp downstream of the annotated start codon of ORF APE2091. The amino acid sequence deduced from the truncated ORF APE2091 revealed sequence similarity to members of the ROK family, which comprise bacterial sugar kinases and

  16. Unfolding events in the water-soluble monomeric Cry1Ab toxin during transition to oligomeric pre-pore and membrane-inserted pore channel.

    Science.gov (United States)

    Rausell, Carolina; Pardo-López, Liliana; Sánchez, Jorge; Muñoz-Garay, Carlos; Morera, Claudia; Soberón, Mario; Bravo, Alejandra

    2004-12-31

    The insecticidal crystal (Cry) proteins produced by Bacillus thuringiensis undergo several conformational changes from crystal inclusion protoxins to membrane-inserted channels in the midgut epithelial cells of the target insect. Here we analyzed the stability of the different forms of Cry1Ab toxin, monomeric toxin, pre-pore complex, and membrane-inserted channel, after urea and thermal denaturation by monitoring intrinsic tryptophan fluorescence of the protein and 1-anilinonaphthalene-8-sulfonic acid binding to partially unfolded proteins. Our results showed that flexibility of the monomeric toxin was dramatically enhanced upon oligomerization and was even further increased by insertion of the pre-pore into the membrane as shown by the lower concentration of chaotropic agents needed to achieve unfolding of the oligomeric species. The flexibility of the toxin structures is further increased by alkaline pH. We found that the monomer-monomer interaction in the pre-pore is highly stable because urea promotes oligomer denaturation without disassembly. Partial unfolding and limited proteolysis studies demonstrated that domains II and III were less stable and unfold first, followed by unfolding of the most stable domain I, and also that domain I is involved in monomer-monomer interaction. The thermal-induced unfolding and analysis of energy transfer from Trp residues to bound 1-anilinonaphthalene-8-sulfonic acid dye showed that in the membrane-inserted pore domains II and III are particularly sensitive to heat denaturation, in contrast to domain I, suggesting that only domain I may be inserted into the membrane. Finally, the insertion into the membrane of the oligomeric pre-pore structure was not affected by pH. However, a looser conformation of the membrane-inserted domain I induced by neutral or alkaline pH correlates with active channel formation. Our studies suggest for the first time that a more flexible conformation of Cry toxin could be necessary for membrane

  17. Efficacy and safety of a sublingual buprenorphine/naloxone rapidly dissolving tablet for the treatment of adults with opioid dependence: A randomized trial.

    Science.gov (United States)

    Webster, Lynn; Hjelmström, Peter; Sumner, Michael; Gunderson, Erik W

    2016-01-01

    This prospective, randomized, active-controlled, non-inferiority study evaluated the efficacy and safety of a sublingual buprenorphine/naloxone rapidly dissolving tablet (Zubsolv ® ; buprenorphine/naloxone rapidly dissolving tablet) versus generic buprenorphine for induction of opioid maintenance among dependent adults. The study, conducted at 13 sites from June 2013 to January 2014, included a 2-day blinded induction phase and a 27-day open-label stabilization/maintenance phase. During the blinded induction, patients received fixed doses of buprenorphine/naloxone rapidly dissolving tablets or generic buprenorphine. During open-label stabilization/early maintenance, all patients received buprenorphine/naloxone rapidly dissolving tablets. The primary efficacy assessment was treatment retention at day 3; buprenorphine/naloxone rapidly dissolving tablets were considered non-inferior to generic buprenorphine if the lower limit of the 95% confidence interval for the difference between the treatments was ≥-10% in patients retained on day 3. Secondary assessments included opioid withdrawal symptoms and cravings as measured using the Clinical Opiate Withdrawal Scale, the Subjective Opiate Withdrawal Scale, and the opioid cravings visual analogue scale. Safety was also assessed. A total of 313 patients were randomly assigned to induction with generic buprenorphine or buprenorphine/naloxone rapidly dissolving tablets. The mean age was 38.4 years, and the mean duration of opioid dependence was 12.4 years. For the primary efficacy assessment, 235 of 256 patients (91.8%) were retained at day 3 and continued to the maintenance phase. The lower limit of the 95% confidence interval was -13.7; thus, buprenorphine/naloxone rapidly dissolving tablets did not demonstrate non-inferiority to generic buprenorphine, and significantly more patients who received induction with generic buprenorphine (122/128 [95.3%]) were retained at day 3 compared with those who received induction with

  18. Efficacy of sublingual specific immunotherapy in intermittent and persistent allergic rhinitis in children: an observational case-control study on 171 patients. The EFESO-children multicenter trial.

    Science.gov (United States)

    Acquistapace, Franca; Agostinis, Fabio; Castella, Vincenzo; Kantar, Ahmad; Novembre, Elio; Perrone, Maria Rosaria; Pietrasanta, Michele; Sambugaro, Renato; Milani, Massimo

    2009-11-01

    Sublingual-specific immunotherapy (SLIT) is considered as a valid treatment of respiratory allergies. However, there are few data on large sample size regarding its clinical role in 'real life' in term of reduction of symptoms, rescue medications and prevention of asthma in patients suffering from allergic rhinitis (AR) especially in children. We performed a multicenter, case-control study to evaluate the effect of SLIT in children (age 6-18 yr) with intermittent or persistent AR. 171 children (27% girls and 73% boys) with AR due to seasonal or perennial allergens were enrolled in a multicenter case-control study. Cases (n = 90) were defined as patients with intermittent (64%) or persistent (36%) AR who were treated for at least two consecutive years with specific SLIT with the related allergen extracts (SLITone ALK-Abellò). Controls (n = 81) were defined as sex-age- and type of allergen matched AR children who were never treated with specific immunotherapy and had no asthmatic symptoms at the beginning of observation period. Main outcomes of the study were the rhinoconjunctivitis symptom score (SS) (sneezing, rhinorrea, nasal itch, congestion, ocular itch and watery eyes) with a ranging scale from 0 (=no symptoms) to 3 (=severe symptoms) and the medication score (MS) evaluating symptomatic drug intake (antihystamine and inhaled corticosteroids). SS and MS were evaluated at the end of the observational period in relation with the period, considering the last 12 months, in which patients suffered the highest symptoms levels (i.e., peak of relevant pollen season (seasonal AR) or during the period of maximum allergen exposure in case of perennial AR). Secondary outcome of the study was the development of asthma symptoms during the observation period. SS (mean +/- SD) was 4.5 +/- 2.5 in cases and 9.0 +/- 3.0 in controls (-50%) (p = 0.0001). MS (mean +/- SD) was 2.5 +/- 1.9 and 3.6 +/- 2.1 in the case and control groups, respectively (-31%) (p = 0.0001). At the end of

  19. Structure-based protein engineering efforts with a monomeric TIM variant: the importance of a single point mutation for generating an active site with suitable binding properties.

    Science.gov (United States)

    Alahuhta, Markus; Salin, Mikko; Casteleijn, Marco G; Kemmer, Christian; El-Sayed, Ibrahim; Augustyns, Koen; Neubauer, Peter; Wierenga, Rik K

    2008-04-01

    A monomeric variant of triosephosphate isomerase (TIM) with a new engineered binding groove has been characterized further. In this variant (ml8bTIM), the phosphate binding loop had been shortened, causing the binding site to be much more extended. Here, it is reported that in the V233A variant of ml8bTIM (A-TIM), three important properties of the wild-type TIM active site have been restored: (i) the structural properties of loop-7, (ii) the binding site of a conserved water molecule between loop-7 and loop-8 and (iii) the binding site of the phosphate moiety. It is shown that the active site of A-TIM can bind TIM transition state analogs and suicide inhibitors competently. It is found that the active site geometry of the A-TIM complexes is less compact and more solvent exposed, as in wild-type TIM. This correlates with the observation that the catalytic efficiency of A-TIM for interconverting the TIM substrates is too low to be detected. It is also shown that the A-TIM active site can bind compounds which do not bind to wild-type TIM and which are completely different from the normal TIM substrate, like a citrate molecule. The binding of this citrate molecule is stabilized by hydrogen bonding interactions with the new binding groove.

  20. Danio rerio αE-catenin is a monomeric F-actin binding protein with distinct properties from Mus musculus αE-catenin.

    Science.gov (United States)

    Miller, Phillip W; Pokutta, Sabine; Ghosh, Agnidipta; Almo, Steven C; Weis, William I; Nelson, W James; Kwiatkowski, Adam V

    2013-08-02

    It is unknown whether homologs of the cadherin·catenin complex have conserved structures and functions across the Metazoa. Mammalian αE-catenin is an allosterically regulated actin-binding protein that binds the cadherin·β-catenin complex as a monomer and whose dimerization potentiates F-actin association. We tested whether these functional properties are conserved in another vertebrate, the zebrafish Danio rerio. Here we show, despite 90% sequence identity, that Danio rerio and Mus musculus αE-catenin have striking functional differences. We demonstrate that D. rerio αE-catenin is monomeric by size exclusion chromatography, native PAGE, and small angle x-ray scattering. D. rerio αE-catenin binds F-actin in cosedimentation assays as a monomer and as an α/β-catenin heterodimer complex. D. rerio αE-catenin also bundles F-actin, as shown by negative stained transmission electron microscopy, and does not inhibit Arp2/3 complex-mediated actin nucleation in bulk polymerization assays. Thus, core properties of α-catenin function, F-actin and β-catenin binding, are conserved between mouse and zebrafish. We speculate that unique regulatory properties have evolved to match specific developmental requirements.

  1. Danio rerio αE-catenin Is a Monomeric F-actin Binding Protein with Distinct Properties from Mus musculus αE-catenin*

    Science.gov (United States)

    Miller, Phillip W.; Pokutta, Sabine; Ghosh, Agnidipta; Almo, Steven C.; Weis, William I.; Nelson, W. James; Kwiatkowski, Adam V.

    2013-01-01

    It is unknown whether homologs of the cadherin·catenin complex have conserved structures and functions across the Metazoa. Mammalian αE-catenin is an allosterically regulated actin-binding protein that binds the cadherin·β-catenin complex as a monomer and whose dimerization potentiates F-actin association. We tested whether these functional properties are conserved in another vertebrate, the zebrafish Danio rerio. Here we show, despite 90% sequence identity, that Danio rerio and Mus musculus αE-catenin have striking functional differences. We demonstrate that D. rerio αE-catenin is monomeric by size exclusion chromatography, native PAGE, and small angle x-ray scattering. D. rerio αE-catenin binds F-actin in cosedimentation assays as a monomer and as an α/β-catenin heterodimer complex. D. rerio αE-catenin also bundles F-actin, as shown by negative stained transmission electron microscopy, and does not inhibit Arp2/3 complex-mediated actin nucleation in bulk polymerization assays. Thus, core properties of α-catenin function, F-actin and β-catenin binding, are conserved between mouse and zebrafish. We speculate that unique regulatory properties have evolved to match specific developmental requirements. PMID:23788645

  2. Mutants of monomeric red fluorescent protein mRFP1 at residue 66: structure modeling by molecular dynamics and search for correlations with spectral properties.

    Science.gov (United States)

    Khrameeva, E E; Drutsa, V L; Vrzheshch, E P; Dmitrienko, D V; Vrzheshch, P V

    2008-10-01

    To study the interrelation between the spectral and structural properties of fluorescent proteins, structures of mutants of monomeric red fluorescent protein mRFP1 with all possible point mutations of Glu66 (except replacement by Pro) were simulated by molecular dynamics. A global search for correlations between geometrical structure parameters and some spectral characteristics (absorption maximum wavelength, integral extinction coefficient at the absorption maximum, excitation maximum wavelength, emission maximum wavelength, and quantum yield) was performed for the chromophore and its 6 A environment in mRFP1, Q66A, Q66L, Q66S, Q66C, Q66H, and Q66N. The correlation coefficients (0.81-0.87) were maximal for torsion angles in phenolic and imidazolidine rings as well as for torsion angles in the regions of connection between these rings and chromophore attachment to beta-barrel. The data can be used to predict the spectral properties of fluorescent proteins based on their structures and to reveal promising positions for directed mutagenesis.

  3. The synthesis and crystal structure of 2-(chloroselanylpyridine 1-oxide: the first monomeric organoselenenyl chloride stabilized by an intramolecular secondary Se...O interaction

    Directory of Open Access Journals (Sweden)

    Rizvan K. Askerov

    2016-12-01

    Full Text Available The title compound, C5H4ClNOSe, is the product of the reaction of sulfuryl chloride and 2-selanyl-1-pyridine 1-oxide in dichloromethane. The molecule has an almost planar geometry (r.m.s. deviation = 0.012 Å, and its molecular structure is stabilized by an intramolecular secondary Se...O interaction of 2.353 (3 Å, closing a four-membered N—C—Se...O ring. The title compound represents the first monomeric organoselenenyl chloride stabilized intramolecularly by an interaction of this type. The non-valent attractive Se...O interaction results in a substantial distortion of the geometry of the ipso-carbon atom. The endo-cyclic N—C—Se [102.1 (3°] and exo-cyclic C—C—Se [136.9 (3°] bond angles deviate significantly from the ideal value of 120° for an sp2-hybridized carbon atom, the former bond angle being much smaller than the latter. In the crystal, molecules are linked by C—H...O hydrogen bonds, forming zigzag chains propagating along [010]. The chains, which stack along the a-axis direction, are linked by offset π–π interactions [intercentroid distance = 3.960 (3 Å], forming corrugated sheets parallel to the ab plane.

  4. 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.

  5. Prescripción y vigilancia de la inmunoterapia sublingual con vacunas estandarizadas de ácaros domésticos en un servicio de alergología

    Directory of Open Access Journals (Sweden)

    Mirta Álvarez

    2012-12-01

    Full Text Available Las vacunas terapéuticas para la alergia, también llamadas inmunoterapia alergeno específica, consisten en la administración de dosis progresivamente crecientes del alergeno al cual el individuo está sensibilizado, con el objetivo de alcanzar tolerancia al mismo y disminuir la sintomatología clínica. Se realizó un estudio descriptivo, de corte transversal para determinar la seguridad de las vacunas de ácaros domésticos (VALERGEN, administradas mediante gotas por vía sublingual. Se verificaron sus eventos adversos en pacientes alérgicos, atendidos en el Departamento de Alergología del hospital universitario "Calixto García", que asistieron a cambios de vacunas en el mes de septiembre de 2010, así como la frecuencia de prescripción de vacunas alergénicas en el período enero-septiembre del mismo año. Se incluyeron 130 pacientes con tratamiento de inmunoterapia sublingual con VALERGEN, con una edad media de 19,6 años (rango 1-75; el 40,7% tenía 17 años o menos. El tipo de vacuna más empleada resultó ser la multialergénica (63,8%. El ácaro más empleado fue el Dermatophagoides pteronyssinus, seguido de Blomia tropicalis . El 71,55% de los casos se encontraban en fase de mantenimiento. Se reportaron cuatro eventos adversos (3,1% locales leves, que no requirieron tratamiento ni cambio de pauta de vacunación. Se comprobó que las vacunas sublinguales VALERGEN son seguras y bien toleradas en los pacientes alérgicos.

  6. 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.

  7. A c-fos-monomeric red fluorescent protein 1 fusion transgene is differentially expressed in rat forebrain and brainstem after chronic dehydration and rehydration.

    Science.gov (United States)

    Yoshimura, M; Ohkubo, J; Katoh, A; Ohno, M; Ishikura, T; Kakuma, T; Yoshimatsu, H; Murphy, D; Ueta, Y

    2013-05-01

    We have previously shown that an acute osmotic stimulation induces the expression of a c-fos and monomeric red fluorescent protein 1 (mRFP1) fusion transgene in osmosensitive rat brain areas, including the supraoptic (SON) and paraventricular nuclei (PVN). However, the effects of chronic stimuli, such as dehydration, have not been investigated. In the present study, the expression patterns of the c-fos-mRFP1 fusion gene in the forebrain and the brainstem of male and female transgenic rats were studied in seven experimental groups: ad lib. water (euhydration), water deprivation for 12, 24 or 48 h (dehydration) and water deprivation for 46 h + ad lib. water for 2, 6 or 12 h (rehydration). The number of cells that express nuclear mRFP1 fluorescence was quantified in the hypothalamus, the circumventricular organs and the brainstem. Compared to the euhydrated state, the number of transgene expressing cells significantly increased in all forebrain areas and in the rostral ventrolateral medulla after dehydration and 2 h of rehydration. In the nucleus of the solitary tract and area postrema, the number of mRFP1 fluorescent cells was markedly increased after 2 h of rehydration. Although the number of mRFP1 fluorescent cells in the organum vasculosum laminae terminalis, median preoptic nucleus and subfornical organ remained significantly increased after 6 h of rehydration, reaching control levels after 12 h of rehydration, the number of mRFP1 fluorescent cells in the SON and the PVN reached control levels after 6 h of rehydration. There were no significant differences between male and female rats. These results show that the expression of the c-fos-mRFP1 fusion gene changes in the forebrain and the brainstem not only after acute osmotic stimulation, but also after chronic osmotic stimulation. Interestingly, these studies reveal the differential activation of different neuronal groups over the time course of dehydration and rehydration. © 2013 British Society for

  8. X-ray Crystal Structures of Monomeric and Dimeric Peptide Inhibitors in Complex with the Human Neonatal Fc Receptor, FcRn

    Energy Technology Data Exchange (ETDEWEB)

    Mezo, Adam R.; Sridhar, Vandana; Badger, John; Sakorafas, Paul; Nienaber, Vicki (Zenobia); (Biogen)

    2010-10-28

    The neonatal Fc receptor, FcRn, is responsible for the long half-life of IgG molecules in vivo and is a potential therapeutic target for the treatment of autoimmune diseases. A family of peptides comprising the consensus motif GHFGGXY, where X is preferably a hydrophobic amino acid, was shown previously to inhibit the human IgG:human FcRn protein-protein interaction (Mezo, A. R., McDonnell, K. A., Tan Hehir, C. A., Low, S. C., Palombella, V. J., Stattel, J. M., Kamphaus, G. D., Fraley, C., Zhang, Y., Dumont, J. A., and Bitonti, A. J. (2008) Proc. Natl. Acad. Sci. U.S.A., 105, 2337-2342). Herein, the x-ray crystal structure of a representative monomeric peptide in complex with human FcRn was solved to 2.6 {angstrom} resolution. The structure shows that the peptide binds to human FcRn at the same general binding site as does the Fc domain of IgG. The data correlate well with structure-activity relationship data relating to how the peptide family binds to human FcRn. In addition, the x-ray crystal structure of a representative dimeric peptide in complex with human FcRn shows how the bivalent ligand can bridge two FcRn molecules, which may be relevant to the mechanism by which the dimeric peptides inhibit FcRn and increase IgG catabolism in vivo. Modeling of the peptide:FcRn structure as compared with available structural data on Fc and FcRn suggest that the His-6 and Phe-7 (peptide) partially mimic the interaction of His-310 and Ile-253 (Fc) in binding to FcRn, but using a different backbone topology.

  9. 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.

  10. Cryogenic fluorescence and absorption spectroscopy studies on monomeric and dimeric species of 2-butylamino-6-methyl-4-nitropyridine N-oxide

    Science.gov (United States)

    de Klerk, Joost S.; Szemik-Hojniak, Anna; Ariese, Freek; Gooijer, Cees

    2009-02-01

    2-Butylamino-6-methyl-4-nitropyridine- N-oxide (2B6M) belongs to a group of compounds that can undergo not only excited-state intra-, but also intermolecular proton transfer. The latter of course requires the presence of dimeric species. Previously, we have shown that for 2B6M in aprotic non-polar solvents in the liquid state such dimers play no role. Under these conditions, only one single monomeric species exists, exhibiting anomalous fluorescence behavior, i.e. proton transfer not only starting from the lowest excited electronic singlet state, but also from higher excited states. However, we also noted that under frozen, crystalline matrix conditions more species show up in the spectra. In order to study this multi-species system in more detail, we present absorption and fluorescence experiments on 2B6M, recorded in n-octane at various temperatures between 293 and 5 K. High-resolution spectra are included, not only in fluorescence but also in absorption. We demonstrate that under cryogenic conditions three species can be discerned, two of these providing high-resolution spectra with their main 0-0 lines around 452 and 465 nm, respectively. A detailed vibrational analysis of their emission spectra is included. The third species gives broad-banded spectra, in absorption extending to about 520 nm with its long-wavelength maximum around 460 nm, in emission with a maximum around 535 nm. We tentatively assign the three species to a monomer, a H-bonded dimer and a strongly interacting (π-π-stacked) dimer, respectively. We conclude from the excitation spectra that (anomalous) intramolecular proton transfer at higher excited states is still operative under cryogenic conditions. Indications for excited-state intermolecular proton transfer in the stacked dimeric species were not found.

  11. The Q-cycle reviewed: How well does a monomeric mechanism of the bc(1) complex account for the function of a dimeric complex?

    Science.gov (United States)

    Crofts, Antony R; Holland, J Todd; Victoria, Doreen; Kolling, Derrick R J; Dikanov, Sergei A; Gilbreth, Ryan; Lhee, Sangmoon; Kuras, Richard; Kuras, Mariana Guergova

    2008-01-01

    Recent progress in understanding the Q-cycle mechanism of the bc(1) complex is reviewed. The data strongly support a mechanism in which the Q(o)-site operates through a reaction in which the first electron transfer from ubiquinol to the oxidized iron-sulfur protein is the rate-determining step for the overall process. The reaction involves a proton-coupled electron transfer down a hydrogen bond between the ubiquinol and a histidine ligand of the [2Fe-2S] cluster, in which the unfavorable protonic configuration contributes a substantial part of the activation barrier. The reaction is endergonic, and the products are an unstable ubisemiquinone at the Q(o)-site, and the reduced iron-sulfur protein, the extrinsic mobile domain of which is now free to dissociate and move away from the site to deliver an electron to cyt c(1) and liberate the H(+). When oxidation of the semiquinone is prevented, it participates in bypass reactions, including superoxide generation if O(2) is available. When the b-heme chain is available as an acceptor, the semiquinone is oxidized in a process in which the proton is passed to the glutamate of the conserved -PEWY- sequence, and the semiquinone anion passes its electron to heme b(L) to form the product ubiquinone. The rate is rapid compared to the limiting reaction, and would require movement of the semiquinone closer to heme b(L) to enhance the rate constant. The acceptor reactions at the Q(i)-site are still controversial, but likely involve a "two-electron gate" in which a stable semiquinone stores an electron. Possible mechanisms to explain the cyt b(150) phenomenon are discussed, and the information from pulsed-EPR studies about the structure of the intermediate state is reviewed. The mechanism discussed is applicable to a monomeric bc(1) complex. We discuss evidence in the literature that has been interpreted as shown that the dimeric structure participates in a more complicated mechanism involving electron transfer across the dimer

  12. The Q-cycle reviewed: how well does a monomeric mechanism of the bc1 complex account for the function of a dimeric complex?

    Science.gov (United States)

    Crofts, Antony R.; Holland, J. Todd; Victoria, Doreen; Kolling, Derrick R.J.; Dikanov, Sergei A.; Gilbreth, Ryan; Lhee, Sangmoon; Kuras, Richard; Kuras, Mariana Guergova

    2008-01-01

    Recent progress in understanding the Q-cycle mechanism of the bc1 complex is reviewed. The data strongly support a mechanism in which the Qo-site operates through a reaction in which the first electron transfer from ubiquinol to the oxidized iron-sulfur protein is the rate determining step for the overall process. The reaction involves a proton-coupled electron transfer down a hydrogen bond between the ubiquinol and a histidine ligand of the [2Fe-2S] cluster, in which the unfavorable protonic configuration contributes a substantial part of the activation barrier. The reaction is endergonic, and the products are an unstable ubisemiquinone at the Qo-site, and the reduced iron-sulfur protein, the extrinsic mobile domain of which is now free to dissociate and move away from the site to deliver an electron to cyt c1 and liberate the H+. When oxidation of the semiquinone is prevented, it participates in bypass reactions, including superoxide generation if O2 is available. When the b-heme chain is available as acceptor, the semiquinone is oxidized in a process in which the proton is passed to the glutamate of the conserved –PEWY- sequence, and the semiquinone anion passes its electron to heme bL to form the product ubiquinone. The rate is rapid compared to the limiting reaction, and would require movement of the semiquinone closer to heme bL to enhance the rate constant. The acceptor reactions at the Qi-site are still controversial, but likely involve a “two-electron gate” in which a stable semiquinone stores an electron. Possible mechanisms to explain the cytb150 phenomenon are discussed, and the information from pulsed EPR studies about the structure of the intermediate state is reviewed. The mechanism discussed is applicable to a monomeric bc1 complex. We discuss evidence in the literature that has been interpreted as shown that the dimeric structure participates in a more complicated mechanism involving electron transfer across the dimer interface. We show from

  13. 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

  14. Monomeric IgE stimulates NFAT translocation into the nucleus, a rise in cytosol Ca2+, degranulation, and membrane ruffling in the cultured rat basophilic leukemia-2H3 mast cell line.

    Science.gov (United States)

    Pandey, Vinita; Mihara, Shoji; Fensome-Green, Amanda; Bolsover, Stephen; Cockcroft, Shamshad

    2004-04-01

    Mast cells are key regulators in allergy and inflammation, and release histamine, cytokines, and other proinflammatory mediators. In the classical view, IgE acts merely to prime mast cells, attaching to FcepsilonRs but not evoking any cell signaling response until cross-linked by the presence of a multivalent allergen. However, several recent studies have reported that IgE alone can promote cell survival and cytokine production in the absence of cross-linking by allergen. In this study we demonstrate that acute addition of monomeric IgE elicits a wide spectrum of responses in the rat basophilic leukemia-2H3 mast cell line, including activation of phospholipases Cgamma and D, a rise in cytosol Ca(2+), NFAT translocation, degranulation, and membrane ruffling within minutes. Calcium transients persist for hours as long as IgE is present resulting in the maintained translocation of the transcription factor NFAT to the nucleus. Removal of IgE reverses the signaling processes. Our results indicate that, far from simply preparing the cells for a response to allergen, monomeric IgE can stimulate signaling pathways that lead to degranulation, membrane ruffling, and NFAT translocation. The mechanism of activation is likely to be via aggregation of the FcepsilonR1 because activation by IgE can be inhibited with monovalent hapten.

  15. Possible relationship between systemic side effects and sensitization to rPar j 2 in allergic patients submitted to an ultra-rush (20 min) sublingual immunotherapy and selected by component resolved diagnosis.

    Science.gov (United States)

    Rossi, R E; Monasterolo, G; Coco, G; Operti, D

    2005-10-01

    The pollen of Parietaria spp., a weed of the Urticaceae family, is a major cause of respiratory allergy in the Mediterranean area, where the most common species are Parietaria judaica and Parietaria officinalis. In this study, we evaluated the specific serum IgE-binding profiles to individual P. judaica pollen recombinant major allergen, and Phleum pratense cytoskeletal profilin and a 2-EF-hand calcium-binding allergen homologous to cross-reactive Parietaria pollen allergens, in patients allergic to pollen with positive skin test towards Parietaria spp. extract. The present observation included 220 patients from the province of Cuneo, north-west Italy, all suffering from rhino-conjunctivitis and/or asthma selected on the basis of skin test positive to P. judaica extract. The sera were evaluated for specific IgE reactivity to P. judaica pollen major recombinant(r) allergen Par j 2, Phleum pratense pollen allergens rPhl p 7 (2-EF-hand calcium binding protein) and rPhl p 12 (profilin), both identified as cross-reactive Parietaria spp. allergens, using Pharmacia CAP System. Out of 220 patients, 37 patients with IgE reactivity to rPar j 2 and 105 patients sensitized to at least one timothy pollen major allergen (i. e. rPhl p 1, rPhl p 2, natural Phl p 4 and rPhl p 6) were submitted to an ultra-rush protocol of sublingual immunotherapy (SLIT). The occurrence of adverse reactions were evaluated in both groups. All 220 patients with pollinosis and positive in vivo skin prick tests had in vitro positive CAP results to P. judaica natural extract. On the contrary, in these patients the prevalence of Par j 2-specific IgE was only 33.2% (73/220). In fact, 116/220 (52.7%) patients with serum specific IgE to crude Parietaria pollen extract had specific IgE to Phl p 12, 18/220 (8.1%) subjects with specific IgE to rPhl p 12 also exhibited specific IgE to Phl p 7 and 26/220 (11.8%) subjects had specific IgE against rPhl p 7. Particularly, geometric mean (25th-75th percentile) of

  16. A double blind, randomized, placebo controlled trial of the efficacy, quality of life and safety of food allergen-specific sublingual immunotherapy in client owned dogs with adverse food reactions: a small pilot study.

    Science.gov (United States)

    Maina, Elisa; Cox, Eric

    2016-10-01

    Food allergen-specific sublingual immunotherapy (FA-SLIT) has emerged as a novel and successful approach for desensitizing human patients to specific food allergens. It has not been tested in dogs. To investigate the efficacy, quality of life (QoL), tolerability and safety of FA-SLIT in dogs with adverse food reactions (AFR). Dogs with proven AFR were randomized to treatment (T group; n = 7) or placebo (P group; n = 6) to receive either FA-SLIT (based on the results of a food elimination trial) or glycerinated saline, respectively. The treatment was continued daily for 6 months with fortnightly dosage escalations. To evaluate the treatment, pruritus Visual Analog Scale (pVAS), Canine Atopic Dermatitis Extent and Severity Index (CADESI-04), QoL, faecal consistency scores, owner assessment, overall tolerability scores and blood analyses were assessed. Eleven dogs completed the study, two dogs in the T group were withdrawn by the owner after FA-SLIT exacerbated clinical signs of AFR. Statistical tests showed significant protection against food challenge induced clinical signs following FA-SLIT therapy, as indicated by reduced pVAS and CADESI scores (P < 0.05). The QoL did not differ between groups. The treatment was rated as effective or quite effective by 80% of the owners, whereas placebo was rated as ineffective by all owners. FA-SLIT was effective, well tolerated and safe. No severe adverse events were recorded; erythema and pruritus were reported in association with only 0.7% of the dispensed doses. Larger clinical trials with more extended maintenance immunotherapy periods will be needed to provide more precise estimates of efficacy and frequency of adverse events. © 2016 ESVD and ACVD.

  17. Monomeric, trimeric, and tetrameric transition metal complexes (Mn, Fe, Co) containing N,N-bis(2-pyridylmethyl)-2-aminoethanol/-ate: preparation, crystal structure, molecular magnetism and oxidation catalysis.

    Science.gov (United States)

    Shin, Jong Won; Rowthu, Sankara Rao; Hyun, Min Young; Song, Young Joo; Kim, Cheal; Kim, Bong Gon; Min, Kil Sik

    2011-06-07

    The reaction of N,N-bis(2-pyridylmethyl)-2-aminoethanol (bpaeOH), NaSCN/NaN(3), and metal (M) ions [M = Mn(II), Fe(II/III), Co(II)] in MeOH, leads to the isolation of a series of monomeric, trimeric, and tetrameric metal complexes, namely [Mn(bpaeOH)(NCS)(2)] (1), [Mn(bpaeO)(N(3))(2)] (2), [Fe(bpaeOH)(NCS)(2)] (3), [Fe(4)(bpaeO)(2)(CH(3)O)(2)(N(3))(8)] (4), [Co(bpaeOH)(NCS)(2)] (5), and [Co(3)(bpaeO)(2)(NO(3))(N(3))(4)](NO(3)) (6). These compounds have been investigated by single crystal X-ray diffractometry and magnetochemistry. In complex 1 the Mn(II) is bonded to one bpaeOH and two thiocyanate ions, while in complex 2 it is coordinated to a deprotonated bpaeO(-) and two azide ions. The oxidation states of manganese ions are 2+ for 1 and 3+ for 2, respectively, indicating that the different oxidation states depend on the type of binding anions. The structures of monomeric iron(II) and cobalt(II) complexes 3 and 5 with two thiocyanate ions are isomorphous to that of 1. Compounds 1, 2, 3, and 5 exhibit high-spin states in the temperature range 5 to 300 K. 4 contains two different iron(III) ions in an asymmetric unit, one is coordinated to a deprotonated bpaeO(-), an azide ion, and a methoxy group, and the other is bonded to three azide ions and two oxygens from bpaeO(-) and a methoxy group. Two independent iron(III) ions in 4 form a tetranuclear complex by symmetry. 4 displays both ferromagnetic and antiferromagnetic couplings (J = 9.8 and -14.3 cm(-1)) between the iron(III) ions. 6 is a mixed-valence trinuclear cobalt complex, which is formulated as Co(III)(S = 0)-Co(II)(S = 3/2)-Co(III)(S = 0). The effective magnetic moment at room temperature corresponds to the high-spin cobalt(II) ion (∼4.27 μ(B)). Interestingly, 6 showed efficient catalytic activities toward various olefins and alcohols with modest to excellent yields, and it has been proposed that a high-valent Co(V)-oxo species might be responsible for oxygen atom transfer in the olefin epoxidation and

  18. Intercluster compound between a tetrakis{triphenylphosphinegold(I)}oxonium cation and a keggin polyoxometalate (POM): formation during the course of carboxylate elimination of a monomeric triphenylphosphinegold(I) carboxylate in the presence of POMs.

    Science.gov (United States)

    Nomiya, Kenji; Yoshida, Takuya; Sakai, Yoshitaka; Nanba, Arisa; Tsuruta, Shinichiro

    2010-09-20

    The preparation and structural characterization of a novel intercluster compound, [{Au(PPh(3))}(4)(μ(4)-O)](3)[α-PW(12)O(40)](2)·4EtOH (1), constructed between a tetrakis{triphenylphosphinegold(I)}oxonium cation and a saturated α-Keggin polyoxometalate (POM) are described. The tetragold(I) cluster oxonium cation was formed during the course of carboxylate elimination of a monomeric phosphinegold(I) carboxylate complex, i.e., [Au((R,S)-pyrrld)(PPh(3))] [(R,S)-Hpyrrld = (R,S)-2-pyrrolidone-5-carboxylic acid], in the presence of the free acid form of a Keggin POM, H(3)[α-PW(12)O(40)]·7H(2)O. The liquid-liquid diffusion between the upper water/EtOH phase containing the Keggin POM and the lower CH(2)Cl(2) phase containing the monomeric gold(I) complex gave a pure crystalline sample of 1 in good yield (42.1%, 0.242 g scale). Complex 1 was formed by ionic interaction between the tetragold(I) cluster cation and the Keggin POM anion. As a matter of fact, the POM anion in 1 can be exchanged with the BF(4)(-) anion using an anion-exchange resin (Amberlyst A-27) in BF(4)(-) form. By using other Keggin POMs, such as H(4)[α-SiW(12)O(40)]·10H(2)O and H(3)[α-PMo(12)O(40)]·14H(2)O, the same tetragold(I) cluster cation was also formed, i.e., in the forms of [{Au(PPh(3))}(4)(μ(4)-O)](2)[α-SiW(12)O(40)]·2H(2)O (2) and [{Au(PPh(3))}(4)(μ(4)-O)](3)[α-PMo(12)O(40)](2)·3EtOH (3). Compounds 1-3, as dimethyl sulfoxide-soluble, EtOH- and Et(2)O-insoluble dark-yellowish white solids, were characterized by complete elemental analysis, thermogravimetric and differential thermal analyses, Fourier transform IR, X-ray crystallography, and solid-state (CPMAS (31)P and (29)Si) and solution ((31)P{(1)H} and (1)H) NMR spectroscopy. The molecular structures of 1 and 2 were successfully determined. The tetragold(I) cluster cation was composed of four PPh(3)Au(I) units bridged by a central μ(4)-oxygen atom in the geometry of a trigonal pyramid or distorted tetrahedron.

  19. Three-dimensional structure of FEZ-1, a monomeric subclass B3 metallo-beta-lactamase from Fluoribacter gormanii, in native form and in complex with D-captopril.

    Science.gov (United States)

    García-Sáez, I; Mercuri, P S; Papamicael, C; Kahn, R; Frère, J M; Galleni, M; Rossolini, G M; Dideberg, O

    2003-01-24

    The beta-lactamases are involved in bacterial resistance to penicillin and related compounds. Members of the metallo-enzyme class are now found in many pathogenic bacteria and are thus becoming of major clinical importance. The structures of the Zn-beta-lactamase from Fluoribacter gormanii (FEZ-1) in the native and in the complex form are reported here. FEZ-1 is a monomeric enzyme, which possesses two zinc-binding sites. These structures are discussed in comparison with those of the tetrameric L1 enzyme produced by Stenotrophomonas maltophilia. From this analysis, amino acids involved in the oligomerization of L1 are clearly identified. Despite the similarity in fold, the active site of FEZ-1 was found to be significantly different. Two residues, which were previously implicated in function, are not present in L1 or in FEZ-1. The broad-spectrum substrate profile of Zn-beta-lactamases arises from the rather wide active-site cleft, where various beta-lactam compounds can be accommodated.

  20. Stereospecific approach to the synthesis of ring-A oxygenated sarpagine indole alkaloids. Total synthesis of the dimeric indole alkaloid P-(+)-dispegatrine and six other monomeric indole alkaloids.

    Science.gov (United States)

    Edwankar, Chitra R; Edwankar, Rahul V; Namjoshi, Ojas A; Liao, Xuebin; Cook, James M

    2013-07-05

    The first regio- and stereocontrolled total synthesis of the bisphenolic, bisquaternary alkaloid (+)-dispegatrine (1) has been accomplished in an overall yield of 8.3% (12 reaction vessels) from 5-methoxy-d-tryptophan ethyl ester (17). A crucial late-stage thallium(III) mediated intermolecular oxidative dehydrodimerization was employed in the formation of the C9-C9' biaryl axis in 1. The complete stereocontrol observed in this key biaryl coupling step is due to the asymmetric induction by the natural sarpagine configuration of the monomer lochnerine (6) and was confirmed by both the Suzuki and the oxidative dehydrodimerization model studies on the tetrahydro β-carboline (35). The axial chirality of the lochnerine dimer (40) and in turn dispegatrine (1) was established by X-ray crystallography and was determined to be P(S). Additionally, the first total synthesis of the monomeric indole alkaloids (+)-spegatrine (2), (+)-10-methoxyvellosimine (5), (+)-lochnerine (6), lochvinerine (7), (+)-sarpagine (8), and (+)-lochneram (11) were also achieved via the common pentacyclic intermediate 16.

  1. 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.

  2. Spectroscopic (FT-IR, FT-Raman, UV-Vis) analysis, conformational, HOMO-LUMO, NBO and NLO calculations on monomeric and dimeric structures of 4-pyridazinecarboxylic acid by HF and DFT methods

    Science.gov (United States)

    Eşme, A.; Sağdınç, S. G.

    2017-11-01

    In this study, the Fourier transform infrared (FT-IR) and Fourier transform Raman (FT-Raman) spectra of 4-pyridazinecarboxylic acid (4PCA) in solid phase were recorded and analyzed. Quantum chemical calculations of the optimized molecular structure, energies, conformational, UV-Vis, nonlinear optical (NLO) and natural bond orbital (NBO) analysis, molecular surfaces, Mulliken charges, and vibrational studies for 4PCA were performed using the ab initio Hartree-Fock (HF) and density functional theory (DFT/B3LYP) methods with 6-311++G(d,p) basis set. Obtained results on the geometric structure and vibrational frequencies are compared with observed data. The dimeric structure of 4PCA with DFT/B3LYP/6-311++G(d,p) level caused by the shifts of Osbnd H and Cdbnd O bands in the vibrational spectra of 4PCA were also studied. Moreover, the spectroscopic and theoretical results were compared with the corresponding properties for monomeric and dimeric structures of 4PCA. The calculated highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) energies also confirm that charge transfer occurs within the molecule. NBO analysis confirms the presence of intramolecular charge transfer and the hydrogen bonding interaction. The detailed vibrational assignments were performed with the HF and DFT calculations, and the potential energy distribution (PED) was obtained by the Vibrational Energy Distribution Analysis (VEDA4) program.

  3. 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.

  4. Adsorption properties of p-methyl red monomeric-to-pentameric dye aggregates on anatase (101) titania surfaces: first-principles calculations of dye/TiO₂ photoanode interfaces for dye-sensitized solar cells.

    Science.gov (United States)

    Zhang, Lei; Cole, Jacqueline M

    2014-09-24

    The optical and electronic properties of dye aggregates of p-methyl red on a TiO2 anatase (101) surface were modeled as a function of aggregation order (monomer to pentameric dye) via first-principles calculations. A progressive red-shifting and intensity increase toward the visible region in UV-vis absorption spectra is observed from monomeric-to-tetrameric dyes, with each molecule in a given aggregate binding to one of the four possible TiO2 (101) adsorption sites. The pentamer exhibits a blue-shifted peak wavelength in the UV-vis absorption spectra and less absorption intensity in the visible region in comparison; a corresponding manifestation of H-aggregation occurs since one of these five molecules cannot occupy an adsorption site. This finding is consistent with experiment. Calculated density of states (DOS) and partial DOS spectra reveal similar dye···TiO2 nanocomposite conduction band characteristics but different valence band features. Associated molecular orbital distributions reveal dye-to-TiO2 interfacial charge transfer in all five differing aggregate orders; meanwhile, the level of intramolecular charge transfer in the dye becomes progressively localized around its azo- and electron-donating groups, up to the tetrameric dye/TiO2 species. Dye adsorption energies and dye coverage levels are calculated and compared with experiment. Overall, the findings of this case study serve to aid the molecular design of azo dyes toward better performing DSSC devices wherein they are incorporated. In addition, they provide a helpful example reference for understanding the effects of dye aggregation on the adsorbate···TiO2 interfacial optical and electronic properties.

  5. Adsorption Properties of p -Methyl Red Monomeric-to-Pentameric Dye Aggregates on Anatase (101) Titania Surfaces: First-Principles Calculations of Dye/TiO 2 Photoanode Interfaces for Dye-Sensitized Solar Cells

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Lei [Cavendish; Cole, Jacqueline M. [Cavendish; Argonne National Laboratory, 9700 South Cass Avenue, Argonne, Illinois 60439, United States

    2014-08-29

    The optical and electronic properties of dye aggregates of p-methyl red on a TiO2 anatase (101) surface were modeled as a function of aggregation order (monomer to pentameric dye) via first principles calculations. A progressive red-shifting and intensity increase toward the visible region in UV/vis absorption spectra is observed from monomeric-to-tetrameric dyes, with each molecule in a given aggregate binding to one of the four possible TiO2 (101) adsorption sites. The pentamer exhibits a blue-shifted peak wave- length in the UV/vis absorption spectra and less absorption intensity in the visible region in comparison; a corresponding manifestation of H-aggregation occurs since one of these five molecules cannot occupy an adsorption site. This finding is consistent with experiment. Calculated density of states (DOS) and partial DOS spectra reveal similar dye…TiO2 nanocomposite conduction band characteristics but different valence band features. Associated molecular orbital distributions reveal dye-to-TiO2 interfacial charge transfer in all five differing aggregate orders; meanwhile, the level of intramolecular charge transfer in the dye becomes progressively localized around its azo- and electron-donating groups, up to the tetrameric dye/TiO2 species. Dye adsorption energies and dye coverage levels are calculated and compared with experiment. Overall, the findings of this case study serve to aid the molecular design of azo dyes towards better performing DSSC devices wherein they are incorporated. In addition, they provide a helpful example reference for understanding the effects of dye aggregation on the adsorbate…TiO2 interfacial optical and electronic properties.

  6. Fluorescent visualisation of the hypothalamic oxytocin neurones activated by cholecystokinin-8 in rats expressing c-fos-enhanced green fluorescent protein and oxytocin-monomeric red fluorescent protein 1 fusion transgenes.

    Science.gov (United States)

    Katoh, A; Shoguchi, K; Matsuoka, H; Yoshimura, M; Ohkubo, J-I; Matsuura, T; Maruyama, T; Ishikura, T; Aritomi, T; Fujihara, H; Hashimoto, H; Suzuki, H; Murphy, D; Ueta, Y

    2014-05-01

    The up-regulation of c-fos gene expression is widely used as a marker of neuronal activation elicited by various stimuli. Anatomically precise observation of c-fos gene products can be achieved at the RNA level by in situ hybridisation or at the protein level by immunocytochemistry. Both of these methods are time and labour intensive. We have developed a novel transgenic rat system that enables the trivial visualisation of c-fos expression using an enhanced green fluorescent protein (eGFP) tag. These rats express a transgene consisting of c-fos gene regulatory sequences that drive the expression of a c-fos-eGFP fusion protein. In c-fos-eGFP transgenic rats, robust nuclear eGFP fluorescence was observed in osmosensitive brain regions 90 min after i.p. administration of hypertonic saline. Nuclear eGFP fluorescence was also observed in the supraoptic nucleus (SON) and paraventricular nucleus (PVN) 90 min after i.p. administration of cholecystokinin (CCK)-8, which selectively activates oxytocin (OXT)-secreting neurones in the hypothalamus. In double transgenic rats that express c-fos-eGFP and an OXT-monomeric red fluorescent protein 1 (mRFP1) fusion gene, almost all mRFP1-positive neurones in the SON and PVN expressed nuclear eGFP fluorescence 90 min after i.p. administration of CCK-8. It is possible that not only a plane image, but also three-dimensional reconstruction image may identify cytoplasmic vesicles in an activated neurone at the same time. © 2014 British Society for Neuroendocrinology.

  7. 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

    Energy Technology Data Exchange (ETDEWEB)

    Kishimoto, Miori, E-mail: miori@mx6.et.tiki.ne.j [Department of Clinical Veterinary Science, Obihiro University of Agriculture and Veterinary Medicine, Nishi 2-11 Inada-cho, Obihiro 080-8555 (Japan); Doi, Shoko, E-mail: s16024@st.obihiro.ac.j [Department of Clinical Veterinary Science, Obihiro University of Agriculture and Veterinary Medicine, Nishi 2-11 Inada-cho, Obihiro 080-8555 (Japan); Shimizu, Junichiro, E-mail: s01163@st.obihiro.ac.j [Department of Clinical Veterinary Science, Obihiro University of Agriculture and Veterinary Medicine, Nishi 2-11 Inada-cho, Obihiro 080-8555 (Japan); Lee, Ki-Ja, E-mail: s01173@st.obihiro.ac.j [Department of Clinical Veterinary Science, Obihiro University of Agriculture and Veterinary Medicine, Nishi 2-11 Inada-cho, Obihiro 080-8555 (Japan); Iwasaki, Toshiroh, E-mail: bpag2180@cc.tuat.ac.j [Department of Veterinary Internal Medicine, Tokyo University of Agriculture and Technology, Saiwai-cho, 3-5-8, Fuchu 183-8509 (Japan); Miyake, Yoh-Ichi, E-mail: miyake@obihiro.ac.j [Department of Clinical Veterinary Science, Obihiro University of Agriculture and Veterinary Medicine, Nishi 2-11 Inada-cho, Obihiro 080-8555 (Japan); Yamada, Kazutaka, E-mail: kyamada@obihiro.ac.j [Department of Clinical Veterinary Science, Obihiro University of Agriculture and Veterinary Medicine, Nishi 2-11 Inada-cho, Obihiro 080-8555 (Japan)

    2010-10-15

    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.

  8. Reversal of Zolpidem Intoxication By Sublingual Flumazenil

    Science.gov (United States)

    2008-11-01

    pregnancy test immediately prior to each experimental session. One subject was dropped from the analyses due to presenting with Lasik surgery two days prior...benzodiazepine antagonism by flumazenil and aminophylline. Pharmacotherapy , 16(6), 1166-1172. Caldwell JL, Prazinko BF, Rowe T, et al. (2003). Improving

  9. Sublingual immunotherapy for the treatment of allergies

    African Journals Online (AJOL)

    2016-05-22

    May 22, 2016 ... Allergies refer to a hypersensitivity disorder of the immune system, and are the fifth leading chronic disease group globally. The broader name, allergic rhinoconjunctivitis (the involvement of the eyes and nose), is not that well known, and is commonly referred to as allergic rhinitis. Allergic rhinitis presents ...

  10. Buprenorphine Sublingual and Buccal (opioid dependence)

    Science.gov (United States)

    ... and naloxone are used to treat opioid dependence (addiction to opioid drugs, including heroin and narcotic painkillers). ... are pregnant, plan to become pregnant, or are breastfeeding. If you become pregnant while taking or using ...

  11. 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

  12. Synthesis and characterization of monomeric and dimeric ...

    African Journals Online (AJOL)

    2000-01-19

    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 ... The small value of E/D is consistent with the observed symmetry of the complex. (Received January 19, 2000; revised July 6, 2000) Bull. Chem. Soc.

  13. Water-Soluble Fe(II)−H2O Complex with a Weak O−H Bond Transfers a Hydrogen Atom via an Observable Monomeric Fe(III)−OH

    Science.gov (United States)

    Brines, Lisa M.; Coggins, Michael K.; Poon, Penny Chaau Yan; Toledo, Santiago; Kaminsky, Werner; Kirk, Martin L.

    2015-01-01

    Understanding the metal ion properties that favor O−H bond formation versus cleavage should facilitate the development of catalysts tailored to promote a specific reaction, e.g., C−H activation or H2O oxidation. The first step in H2O oxidation involves the endothermic cleavage of a strong O−H bond (BDFE = 122.7 kcal/mol), promoted by binding the H2O to a metal ion, and by coupling electron transfer to proton transfer (PCET). This study focuses on details regarding how a metal ion’s electronic structure and ligand environment can tune the energetics of M(HO−H) bond cleavage. The synthesis and characterization of an Fe(II)−H2O complex, 1, that undergoes PCET in H2O to afford a rare example of a monomeric Fe(III)−OH, 7, is described. High-spin 7 is also reproducibly generated via the addition of H2O to {[FeIII(OMe2N4(tren))]2-(µ-O)}2+ (8). The O−H bond BDFE of Fe(II)−H2O (1) (68.6 kcal/mol) is calculated using linear fits to its Pourbaix diagram and shown to be 54.1 kcal/mol less than that of H2O and 10.9 kcal/mol less than that of [Fe(II)(H2O)6]2+. The O−H bond of 1 is noticeably weaker than the majority of reported Mn+(HxO−H) (M = Mn, Fe; n+ = 2+, 3+; x = 0, 1) complexes. Consistent with their relative BDFEs, Fe(II)−H2O (1) is found to donate a H atom to TEMPO•, whereas the majority of previously reported Mn+−O(H) complexes, including [MnIII(SMe2N4(tren))(OH)]+ (2), have been shown to abstract H atoms from TEMPOH. Factors responsible for the weaker O−H bond of 1, such as differences in the electron-donating properties of the ligand, metal ion Lewis acidity, and electronic structure, are discussed. PMID:25611075

  14. Water-soluble Fe(II)-H2O complex with a weak O-H bond transfers a hydrogen atom via an observable monomeric Fe(III)-OH.

    Science.gov (United States)

    Brines, Lisa M; Coggins, Michael K; Poon, Penny Chaau Yan; Toledo, Santiago; Kaminsky, Werner; Kirk, Martin L; Kovacs, Julie A

    2015-02-18

    Understanding the metal ion properties that favor O-H bond formation versus cleavage should facilitate the development of catalysts tailored to promote a specific reaction, e.g., C-H activation or H2O oxidation. The first step in H2O oxidation involves the endothermic cleavage of a strong O-H bond (BDFE = 122.7 kcal/mol), promoted by binding the H2O to a metal ion, and by coupling electron transfer to proton transfer (PCET). This study focuses on details regarding how a metal ion's electronic structure and ligand environment can tune the energetics of M(HO-H) bond cleavage. The synthesis and characterization of an Fe(II)-H2O complex, 1, that undergoes PCET in H2O to afford a rare example of a monomeric Fe(III)-OH, 7, is described. High-spin 7 is also reproducibly generated via the addition of H2O to {[Fe(III)(O(Me2)N4(tren))]2-(μ-O)}(2+) (8). The O-H bond BDFE of Fe(II)-H2O (1) (68.6 kcal/mol) is calculated using linear fits to its Pourbaix diagram and shown to be 54.1 kcal/mol less than that of H2O and 10.9 kcal/mol less than that of [Fe(II)(H2O)6](2+). The O-H bond of 1 is noticeably weaker than the majority of reported M(n+)(HxO-H) (M = Mn, Fe; n+ = 2+, 3+; x = 0, 1) complexes. Consistent with their relative BDFEs, Fe(II)-H2O (1) is found to donate a H atom to TEMPO(•), whereas the majority of previously reported M(n+)-O(H) complexes, including [Mn(III)(S(Me2)N4(tren))(OH)](+) (2), have been shown to abstract H atoms from TEMPOH. Factors responsible for the weaker O-H bond of 1, such as differences in the electron-donating properties of the ligand, metal ion Lewis acidity, and electronic structure, are discussed.

  15. Synthesis and characterization of monomeric manganese(II and cobalt(III complexes of the hexadentate amine ligand N,N,N',N'-tetrakis(2-pyridylmethylethane-1,2-diamine, C26H28N6(tpen

    Directory of Open Access Journals (Sweden)

    Kirsten Michelsen

    2004-06-01

    Full Text Available The syntheses and characterization of complexes of manganese(II and cobalt(III with the potentially hexadentate ligand N,N,N',N'-tetrakis(2-pyridylmethylethane-1,2-diamine, C26H28N6 (tpen, are described. The monomeric manganese(II complex [Mn(C26H28N6(H2O](ClO42 (1 crystallizes in the monoclinic space group C2/c with 4 formula units in a cell of dimensions a = 15.080(1 Å, b = 10.101(1 Å, c = 19.426(2 Å and β = 94.6l(l°. The structure has been refined to a final value of the conventional R-factor of 0.0401 based on 2586 observed independent reflections. 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. The related cobalt(III complex, [Co(C26H28N6] (C1O43 (4 crystallizes in the monoclinic space group P21/n with 4 formula units in a cell of dimensions a = 9.829(2 Å, b = 18.364(4 Å, c = 18.128(4 Å and β = 93.64(3°. The structure has been refined to a final value of the conventional R-factor of 0.0526 based on 3574 observed independent reflections. The complex is approximately octahedral, the coordination being provided by the six nitrogen atoms of the tpen ligand. The EPR spectrum of 1 diluted into the corresponding Cd(II host has been simulated with the parameters g = 2.00, A = 0.0080 cm-1, D = 0.116 cm-1, and E = 0.0013 cm-1. The small value of E/D is consistent with the observed symmetry of the complex.

  16. Electrophysiological effects of kainic acid on vasopressin-enhanced green fluorescent protein and oxytocin-monomeric red fluorescent protein 1 neurones isolated from the supraoptic nucleus in transgenic rats.

    Science.gov (United States)

    Ohkubo, J; Ohbuchi, T; Yoshimura, M; Maruyama, T; Ishikura, T; Matsuura, T; Suzuki, H; Ueta, Y

    2014-01-01

    The supraoptic nucleus (SON) contains two types of magnocellular neurosecretory cells: arginine vasopressin (AVP)-producing and oxytocin (OXT)-producing cells. We recently generated and characterised two transgenic rat lines: one expressing an AVP-enhanced green fluorescent protein (eGFP) and the other expressing an OXT-monomeric red fluorescent protein 1 (mRFP1). These transgenic rats enable the visualisation of AVP or OXT neurones in the SON. In the present study, we compared the electrophysiological responses of AVP-eGFP and OXT-mRFP1 neurones to glutamic acid in SON primary cultures. Glutamate mediates fast synaptic transmission through three classes of ionotrophic receptors: the NMDA, AMPA and kainate receptors. We investigated the contributions of the three classes of ionotrophic receptors in glutamate-induced currents. Three different antagonists were used, each predominantly selective for one of the classes of ionotrophic receptor. Next, we focused on the kainate receptors (KARs). We examined the electrophysiological effects of kainic acid (KA) on AVP-eGFP and OXT-mRFP1 neurones. In current clamp mode, KA induced depolarisation and increased firing rates. These KA-induced responses were inhibited by the non-NMDA ionotrophic receptor antagonist 6-cyano-7-nitroquinoxaline-2,3(1H4H)-dione in both AVP-eGFP and OXT-mRFP1 neurones. In voltage clamp mode, the application of KA evoked inward currents in a dose-dependent manner. The KA-induced currents were significantly larger in OXT-mRFP1 neurones than in AVP-eGFP neurones. This significant difference in KA-induced currents was abolished by the GluK1-containing KAR antagonist UBP302. At high concentrations (250-500 μm), the specific GluK1-containing KAR agonist (RS)-2-amino-3-(3-hydroxy-5-tert-butylisoxazol-4-yl) propanoic acid (ATPA) induced significantly larger currents in OXT-mRFP1 neurones than in AVP-eGFP neurones. Furthermore, the difference between the AVP-eGFP and OXT-mRFP1 neurones in the ATPA currents

  17. 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

  18. Gum pigmentation: an unusual adverse effect of sublingual immunotherapy

    National Research Council Canada - National Science Library

    Goh, Anne; Chiang, Wen Chin; Kang, Liew Woei; Rao, Rajeshwar; Lim, Hwee Hoon; Chng, Chai Kiat

    2014-01-01

    .... This is pigmentation of the gums which can occur anytime during the course of the immunotherapy. It resolves on stopping the immunotherapy and is likely due to a local inflammatory process occurring in the gums of these children. There is no associated pain or itching with the pigmentation. It can persist as long as the child is on the immunotherapy.

  19. 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...

  20. Sublingual atropine for the treatment of severe and hyoscine ...

    African Journals Online (AJOL)

    antagonism and impaired deglutition have been hypothesised as probable underlying mechanisms.3 A few ... Oral hyoscine hydrobromide was administered for 4 weeks (titrated gradually up to 900 mcg/day) without notable improvement in the patient's hypersalivation. This restricted any further increase in the dose of ...

  1. 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, ...

  2. Optical Control over Monomeric and Multimeric Protein Hybrids

    NARCIS (Netherlands)

    Putri, Rindia Maharani

    2017-01-01

    Living materials are based on proteins that adapt and change in structure and function continuously when in use; cellular microtubules, ATP synthases and ribosomes are but a few examples. Breathing life into semi-synthetic materials would allow improved understanding over protein regulation and

  3. 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.

  4. Predicting Homogeneous Pilus Structure from Monomeric Data and Sparse Constraints

    Directory of Open Access Journals (Sweden)

    Ke Xiao

    2015-01-01

    Full Text Available Type IV pili (T4P and T2SS (Type II Secretion System pseudopili are filaments extending beyond microbial surfaces, comprising homologous subunits called “pilins.” In this paper, we presented a new approach to predict pseudo atomic models of pili combining ambiguous symmetric constraints with sparse distance information obtained from experiments and based neither on electronic microscope (EM maps nor on accurate a priori symmetric details. The approach was validated by the reconstruction of the gonococcal (GC pilus from Neisseria gonorrhoeae, the type IVb toxin-coregulated pilus (TCP from Vibrio cholerae, and pseudopilus of the pullulanase T2SS (the PulG pilus from Klebsiella oxytoca. In addition, analyses of computational errors showed that subunits should be treated cautiously, as they are slightly flexible and not strictly rigid bodies. A global sampling in a wider range was also implemented and implied that a pilus might have more than one but fewer than many possible intact conformations.

  5. Ischemic Monomeric Neuropathy in a Woman with Sickle Cell Anaemia

    Directory of Open Access Journals (Sweden)

    Alexandra Agapidou

    2016-01-01

    Full Text Available Sickle cell disease is an inherited haemoglobinopathy that can affect multiple organs and systems. The most common neurological complication in sickle cell disease is stroke and silent cerebral infarcts. Peripheral nervous system involvement has been described but is exceedingly rare. Herein, we describe the case of a young woman who presented with acute flaccid paralysis and sensory loss of the left lower extremity in the context of a painful vasoocclusive crisis which resolved rapidly after receiving an emergency automated red cell exchange transfusion.

  6. 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.

  7. Total Monomeric Anthocyanin and Total Flavonoid Content of Processed Purple

    OpenAIRE

    Potato Florentina Damşa; Alexandru Woinaroschy

    2016-01-01

    It is well known that processing change physical and chemical composition of foods, thus affecting the content in bioactive substances. Potatoes are almost always consumed after processing (baked, fried or boiled) making it critical to understand the effect of such processing techniques on the containing in bioactive compounds. In order to determine the influence of processing on the content of anthocyanin pigments and flavonoids was achieved the extraction of these compounds from...

  8. 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.

  9. 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.

  10. Synthesis of monomeric and polymeric alkali and alkaline earth ...

    Indian Academy of Sciences (India)

    trimethylsilyl)amide with phosphinoselenoic amide ligand (1) at ambient temperature. The calcium complex 4 was prepared by two synthetic routes: in the first method, commonly known as salt metathesis reaction, the potassium complex 2 was ...

  11. Light-induced structural changes in a monomeric bacteriophytochrome

    NARCIS (Netherlands)

    Takala, Heikki; Niebling, Stephan; Berntsson, Oskar; Björling, Alexander; Lehtivuori, Heli; Häkkänen, Heikki; Panman, Matthijs; Gustavsson, Emil; Hoernke, Maria; Newby, Gemma; Zontone, Federico; Wulff, Michael; Menzel, Andreas; Ihalainen, Janne A.; Westenhoff, Sebastian

    2016-01-01

    Phytochromes sense red light in plants and various microorganism. Light absorption causes structural changes within the protein, which alter its biochemical activity. Bacterial phytochromes are dimeric proteins, but the functional relevance of this arrangement remains unclear. Here, we use

  12. Genetic diversity of the monomeric prolamins and hordein in hulless ...

    African Journals Online (AJOL)

    STORAGESEVER

    2009-05-04

    May 4, 2009 ... Alvarez GB, Broccoli A, Martin LM (2006a). Genetic diversity and structure in a natural Hordeum chilense populations based on gliadins analysis.PL. Syst. Evol. 261: 11-18. Alvarez GB, Broccoli A, Martin LM (2006b). Variability and genetic diversity for gliadins in natural populations of Hordeum chilense.

  13. 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

  14. Monomeric oxovanadium(IV) compounds of the general formula cis-[V(IV)(=O)(X)(L(NN))(2)](+/0) [X = OH(-), Cl(-), SO(4)(2)(-) and L(NN) = 2,2'-bipyridine (bipy) or 4,4'-disubstituted bipy].

    Science.gov (United States)

    Triantafillou, Georgios D; Tolis, Evagelos I; Terzis, Aris; Deligiannakis, Yiannis; Raptopoulou, Catherine P; Sigalas, Michael P; Kabanos, Themistoklis A

    2004-01-12

    Reaction of [V(IV)OCl(2)(THF)(2)] in aqueous solution with 2 equiv of AgBF(4) or AgSbF(6) and then with 2 equiv of 2,2'-bipyridine (bipy), 4,4'-di-tert-butyl-2,2'-bipyridine (4,4'-dtbipy), or 4,4'-di-methyl-2,2'-bipyridine (4,4'-dmbipy) affords compounds of the general formula cis-[V(IV)O(OH)(L(NN))(2)]Y [where L(NN) = bipy, Y = BF(4)(-) (1), L(NN) = 4,4'-dtbipy, Y = BF(4)(-) (2.1.2H(2)O), L(NN) = 4,4'-dmbipy, Y = BF(4)(-) (3.2H(2)O), and L(NN) = 4,4'-dtbipy, Y = SbF(6)(-) (4)]. Sequential addition of 1 equiv of Ba(ClO(4))(2) and then of 2 equiv of bipy to an aqueous solution containing 1 equiv of V(IV)OSO(4).5H(2)O yields cis-[V(IV)O(OH)(bipy)(2)]ClO(4) (5). The monomeric compounds 1-5 contain the cis-[V(IV)O(OH)](+) structural unit. Reaction of 1 equiv of V(IV)OSO(4).5H(2)O in water and of 1 equiv of [V(IV)OCl(2)(THF)(2)] in ethanol with 2 equiv of bipy gives the compounds cis-[V(IV)O(OSO(3))(bipy)(2)].CH(3)OH.1.5H(2)O (6.CH(3)OH.1.5H(2)O) and cis-[V(IV)OCl(bipy)(2)]Cl (7), respectively, while reaction of 1 equiv of [V(IV)OCl(2)(THF)(2)] in CH(2)Cl(2) with 2 equiv of 4,4'-dtbipy gives the compound cis-[V(IV)OCl(4,4'-dtbipy)(2)]Cl.0.5CH(2)Cl(2) (8.0.5CH(2)Cl(2)). Compounds cis-[V(IV)O(BF(4))(4,4'-dtbipy)(2)]BF(4) (9), cis-[V(IV)O(BF(4))(4,4'-dmbipy)(2)]BF(4) (10), and cis-[V(IV)O(SbF(6))(4,4'-dtbipy)(2)]SbF(6) (11) were synthesized by sequential addition of 2 equiv of 4,4'-dtbipy or 4,4'-dmbipy and 2 equiv of AgBF(4) or AgSbF(6) to a dichloromethane solution containing 1 equiv of [V(IV)OCl(2)(THF)(2)]. The crystal structures of 2.1.2H(2)O, 6.CH(3)OH.1.5H(2)O, and 8.0.5CH(2)Cl(2) were demonstrated by X-ray diffraction analysis. Crystal data are as follows: Compound 2.1.2H(2)O crystallizes in the orthorhombic space group Pbca with (at 298 K) a = 21.62(1) A, b = 13.33(1) A, c = 27.25(2) A, V = 7851(2) A(3), Z = 8. Compound 6.CH(3)OH.1.5H(2)O crystallizes in the monoclinic space group P2(1)/a with (at 298 K) a = 12.581(4) A, b = 14.204(5) A, c = 14.613(6) A, beta

  15. 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.

  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 IgG4 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 IgG4 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. Allergen specific immunotherapy has no influence on standard chemistry and hematology laboratory parameters in clinical studies.

    Science.gov (United States)

    Häfner, Dietrich; Gödicke, Viola; Narkus, Annemie

    2014-01-01

    A set of standard clinical chemistry and hematology parameters are usually measured during clinical studies. The major outcome of these standard tests is to control that the drug investigated does not lead to pathophysiological changes in respective organs or blood. In some cases based on scientific rationale such tests may not be needed. In this paper we report on a standard set of clinical chemistry and hematology laboratory parameters measured before and after treatment in three different immunotherapy studies, representing different routes of administration and different formulations. Thirteen hematological laboratory parameters and eight clinical chemistry parameters were evaluated from three double-blind, placebo-controlled, randomized, multi-centre, phase III studies. The three studies include one with sublingual immunotherapy (n = 185), one subcutaneous immunotherapy trial with an aluminium hydroxide-adsorbed recombinant hypoallergenic Bet v1-FV (n = 211) and one with pre-seasonal subcutaneous immunotherapy with a 6-grass pollen allergoid (n = 154). Allergen specific immunotherapy with both administration forms and formulations respectively did not show any influence on any of the 21 laboratory parameters analyzed. Few patients had a change in laboratory parameters from within normal range at baseline to either below or above at end-of-treatment. No differences between active and placebo were seen with respect to number of patients with such a change. This study with different preparations and routes of application indicates that the value of repeated measurements of standard clinical chemistry and hematology parameters during allergen immunotherapy should be discussed further.

  18. 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.

  19. Effect of pre-operative sub-lingual misoprostol versus intravenous ...

    African Journals Online (AJOL)

    Background: Caesarean operation remains the most common abdominal surgery in women and has immense benefits to both mother and baby when employed. Haemorrhage, however, remains the greatest challenge associated with its outcome. Objective: To compare the effectiveness of pre-operative sub-lingual ...

  20. Sublingual gland excision: a dissection carried out following adjacent anatomical structures.

    Science.gov (United States)

    Wood, Graham; Syyed, Nazlie; Wales, Craig

    2016-10-01

    We describe an anatomical and simple technique for the removal of the submandibular gland that has good outcomes and minimal complications. Copyright © 2016 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.

  1. 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

    of this tablet in children and adolescents with grass pollen-related allergic rhinitis. METHODS: In this multinational, randomized, double-blind, placebo-controlled study, 278 children (5-17 years of age) with grass pollen-related rhinoconjunctivitis (confirmed by means of a positive grass pollen skin prick test...

  2. Clinical review: Clinical imaging of the sublingual microcirculation in the critically ill - where do we stand?

    NARCIS (Netherlands)

    R. Bezemer (Rick); S.A. Bartels (Sebastiaan); J. Bakker (Jan); C. Ince (Can)

    2012-01-01

    textabstractA growing body of evidence exists associating depressed microcirculatory function and morbidity and mortality in a wide array of clinical scenarios. It has been suggested that volume replacement therapy using fluids and/or blood in combination with vasoactive agents to modulate macro-

  3. Sublingual grass allergen tablet immunotherapy provides sustained clinical benefit with progressive immunologic changes over 2 years

    NARCIS (Netherlands)

    Dahl, Ronald; Kapp, Alexander; Colombo, Giselda; De Monchy, Jan G. R.; Rak, Sabina; Emminger, Waltraud; Riis, Bente; Gronager, Pernille M.; Durham, Stephen R.

    Background: This is an interim analysis of a randomized, double-blind, placebo-controlled phase III trial with 3 years of daily treatment with grass tablet immunotherapy (GRAZAX; ALK-Abello A/S, Horsholm, Denmark) or placebo, followed by 2 years of follow-up to assess the persistent efficacy.

  4. 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.

  5. Improvement of shrimp allergy after sublingual immunotherapy for house dust mites: a case report.

    Science.gov (United States)

    Cortellini, G; Spadolini, I; Santucci, A; Cova, V; Conti, C; Corvetta, A; Passalacqua, G

    2011-10-01

    The appropriateness of house dust mite specific immunotherapy in patients allergic to shrimps still remains unclear We present a clinical case as an immunological model for the strong sensitization to tropomyosin with symptoms of anaphylaxis due to shrimps and coexisting asthma due to house dust mite. The improvement in respiratory symptoms for house dust mite and in the food challenge for shrimps during mite immunotherapy with a known and high dosage of tropomyosin suggests the hypothesis that efficacy of mite immunotherapy in food allergy to tropomyosin may be dose dependent.

  6. Sublingual immunization with M2-based vaccine induces broad protective immunity against influenza

    National Research Council Canada - National Science Library

    Shim, Byoung-Shik; Choi, Young Ki; Yun, Cheol-Heui; Lee, Eu-Gene; Jeon, Yoon Seong; Park, Sung-Moo; Cheon, In Su; Joo, Dong-Hyun; Cho, Chung Hwan; Song, Min-Suk; Seo, Sang-Uk; Byun, Young-Ho; Park, Hae-Jung; Poo, Haryoung; Seong, Baik Lin; Kim, Jae Ouk; Nguyen, Huan Huu; Stadler, Konrad; Kim, Dong Wook; Hong, Kee-Jong; Czerkinsky, Cecil; Song, Man Ki

    2011-01-01

    The ectodomain of matrix protein 2 (M2e) of influenza A virus is a rationale target antigen candidate for the development of a universal vaccine against influenza as M2e undergoes little sequence variation amongst human influenza A strains...

  7. Clinical Features and Treatment Outcomes of 41 Dogs with Sublingual Ectopic Thyroid Neoplasia

    National Research Council Canada - National Science Library

    Broome, M.R; Peterson, M.E; Walker, J.R

    2014-01-01

    ... cervical location results in ectopic cranial mediastinal, heart base thyroid tissue, or both. Thyroid tumors in dogs are relatively common, representing approximately 1–3% of all neoplasia in the dog. Tumors arising from ectopic thyroid tissue are considered relatively rare, but such ectopic thyroid neoplasia has been documented in ...

  8. 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

    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...

  9. Changes in the volume status of haemodialysis patients are reflected in sublingual microvascular perfusion

    NARCIS (Netherlands)

    Bemelmans, Remy H. H.; Boerma, E. Christiaan; Barendregt, Jos; Ince, Can; Rommes, Johannes H.; Spronk, Peter E.

    2009-01-01

    Background. After the introduction of sidestream darkfield imaging (SDF) of the microcirculation, it has become clear that in sepsis, microcirculatory alterations can exist in the absence of systemic haemodynamic abnormalities. However, it is unclear whether this phenomenon also occurs in the

  10. Mechanism of crosslinking of proteins by glutaraldehyde II. Reaction with monomeric and polymeric collagen.

    Science.gov (United States)

    Cheung, D T; Nimni, M E

    1982-01-01

    Collagen in three different states, i.e. native soluble molecules, denatured molecules and reconstituted fibers, was exposed to various concentrations of glutaraldehyde. The degree of intramolecular and intermolecular crosslink formation was evaluated by measuring collagen solubility, beta and gamma chain formation, resistance towards cleavage by CNBr or collagenase digestion. Modification of lysyl residues was measured by amino acid analysis. When dilute collagen solutions were reacted with low concentrations of glutaraldehyde, intramolecular crosslinks were observed as the predominant crosslinks. When the glutaraldehyde concentration was increased, the collagen became more insoluble, indicating the formation of intermolecular crosslinks. When reconstituted collagen fibers were reacted with low concentrations of glutaraldehyde, intermolecular crosslinks were formed, which prevented the material from being solubilized by CNBr. However, these materials could still be solubilized by collagenase. When the glutaraldehyde concentration was increased, the materials became resistant to collagenase, while there was only a small increase in the number of lysyl residues modified. This reflects an increase in the molecular length of the glutaraldehyde polymers extending from the initial glutaraldehyde and lysyl residue reaction sites rather than an increase in the actual number of crosslinking sites.

  11. Microinjected photoreactivating enzymes from Anacystis and Saccharomyces monomerize dimers in chromatin of human cells

    NARCIS (Netherlands)

    J.C.M. Zwetsloot; W. Vermeulen (Wim); J.H.J. Hoeijmakers (Jan); A. Yasui (Akira); A.P.M. Eker (André); D. Bootsma (Dirk)

    1985-01-01

    textabstractPhotoreactivating enzymes (PRE) from the yeast Saccharomyces cerevisiae and the cyanobacterium Anacystis nidulans have been injected into the cytoplasm of repair-proficient human fibroblasts in culture. After administration of photoreactivation light, PRE-injected cells displayed a

  12. Improved monomeric red, orange and yellow fluorescent proteins derived from Discosoma sp. red fluorescent protein

    NARCIS (Netherlands)

    Shaner, Nathan C; Campbell, Robert E; Steinbach, Paul A; Giepmans, Ben N G; Palmer, Amy E; Tsien, Roger Y

    2004-01-01

    Fluorescent proteins are genetically encoded, easily imaged reporters crucial in biology and biotechnology. When a protein is tagged by fusion to a fluorescent protein, interactions between fluorescent proteins can undesirably disturb targeting or function. Unfortunately, all wild-type yellow-to-red

  13. Characterization of smallest active monomeric lipase from novel rhizopus strain: application in transesterification.

    Science.gov (United States)

    Kantak, Jayshree B; Prabhune, Asmita A

    2012-04-01

    An extracellular lipase-producing fungus was isolated from oil-rich soil. This fungus belongs to the genus Rhizopus and clades with Rhizopus oryzae. Lipase was purified to homogeneity from this novel fungal source using ammonium sulphate precipitation followed by Q-Sepharose chromatography. The extracellular lipase was purified 8.6-fold, and enzymatic properties were studied. The molecular mass of the purified enzyme was estimated to be 17 kD by sodium dodecyl sulphate-polyacrylamide gel electrophoresis and 16.25 kD by matrix-assisted laser desorption ionization/time-of-flight analysis. The native molecular mass was estimated to be 17.5 kD by gel filtration, indicating the protein to be monomer. The optimum pH and temperature for the enzyme catalysis were 7.0 °C and 40 °C, respectively. Enzyme was stable in pH range 6.0-7.0 and retains 95-100% activity when incubated at 50 °C for 1 h. The pI of the purified lipase was 4.2. Enzyme was stable in the organic solvents such as ethanol, hexane and methanol for 2 h. Purified enzyme was used for transesterification of oleic acid in the presence of ethanol for production of oleic acid ethyl ester with a conversion efficiency of 66% after 24 h at 30 °C.

  14. Volumetric properties underlying ligand binding in a monomeric hemoglobin: a high-pressure NMR study.

    Science.gov (United States)

    Dellarole, Mariano; Roumestand, Christian; Royer, Catherine; Lecomte, Juliette T J

    2013-09-01

    The 2/2 hemoglobin of the cyanobacterium Synechococcus sp. PCC 7002, GlbN, coordinates the heme iron with two histidines and exists either with a b heme or with a covalently attached heme. The binding of exogenous ligands displaces the distal histidine and induces a conformational rearrangement involving the reorganization of internal void volumes. The formation of passageways within the resulting conformation is thought to facilitate ligand exchange and play a functional role. Here we monitored the perturbation induced by pressure on the ferric bis-histidine and cyanide-bound states of GlbN using (1)H-(15)N HSQC NMR spectroscopy. We inspected the outcome with a statistical analysis of 170 homologous 2/2 hemoglobin sequences. We found that the compression landscape of GlbN, as represented by the variation of an average chemical shift parameter, was highly sensitive to ligand swapping and heme covalent attachment. Stabilization of rare conformers was observed at high pressures and consistent with cavity redistribution upon ligand binding. In all states, the EF loop was found to be exceptionally labile to pressure, suggesting a functional role as a semi-flexible hinge between the adjacent helices. Finally, coevolved clusters presented a common pattern of compensating pressure responses. The high-pressure dissection combined with protein sequence analysis established locations with volumetric signatures relevant to residual communication of 2/2 hemoglobins. This article is part of a Special Issue entitled: Oxygen Binding and Sensing Proteins. Copyright © 2013 Elsevier B.V. All rights reserved.

  15. Monomeric and polymeric forms of ependymin: a brain extracellular glycoprotein implicated in memory consolidation processes.

    Science.gov (United States)

    Shashoua, V E

    1988-07-01

    Ependymin, a brain extracellular glycoprotein that appears to be implicated in neural circuit modifications associated with the process of memory consolidation, can rapidly polymerize into fibrous aggregates when the Ca2+ concentration in solution is reduced by the addition of EGTA or by dialysis. Such aggregates, once formed, could not be redissolved in boiling 1% SDS in 6 M urea, acetic acid, saturated aqueous potassium thiocyanate, and trifluoroacetic acid. They were, however, soluble in formic acid. Investigations of the immunological properties of ependymin indicated that various monomers, oligomers and polymers of the molecule with differing carbohydrate contents can be obtained. The polymerization properties of the ependymins may play an important role in their functions in memory consolidation mechanisms.

  16. 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

  17. 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.

  18. 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

  19. The Monomeric GTPase Rab35 Regulates Phagocytic Cup Formation and Phagosomal Maturation in Entamoeba histolytica.

    Science.gov (United States)

    Verma, Kuldeep; Datta, Sunando

    2017-03-24

    One of the hallmarks of amoebic colitis is the detection of Entamoeba histolytica (Eh) trophozoites with ingested erythrocytes. Therefore, erythrophagocytosis is traditionally considered as one of the most important criteria to identify the pathogenic behavior of the amoebic trophozoites. Phagocytosis is an essential process for the proliferation and virulence of this parasite. Phagocytic cargo, upon internalization, follows a defined trafficking route to amoebic lysosomal degradation machinery. Here, we demonstrated the role of EhRab35 in the early and late phases of erythrophagocytosis by the amoeba. EhRab35 showed large vacuolar as well as punctate vesicular localization. The spatiotemporal dynamics of vacuolar EhRab35 and its exchange with soluble cytosolic pool were monitored by fluorescence recovery after photobleaching experiments. Using extensive microscopy and biochemical methods, we demonstrated that upon incubation with RBCs EhRab35 is recruited to the site of phagocytic cups as well as to the nascent phagosomes that harbor Gal/GalNAc lectin and actin. Overexpression of a dominant negative mutant of EhRab35 reduced phagocytic cup formation and thereby reduced RBC internalization, suggesting a potential role of the Rab GTPase in the cup formation. Furthermore, we also performed a phagosomal maturation assay and observed that the activated form of EhRab35 significantly increased the rate of RBC degradation. Interestingly, this mutant also significantly enhanced the number of acidic compartments in the trophozoites. Taken together, our results suggest that EhRab35 is involved in the initial stage of phagocytosis as well as in the phagolysosomal biogenesis in E. histolytica and thus contributes to the pathogenicity of the parasite. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  20. Engineering an enhanced, thermostable, monomeric bacterial luciferase gene as a reporter in plant protoplasts.

    Science.gov (United States)

    Cui, Boyu; Zhang, Lifeng; Song, Yunhong; Wei, Jinsong; Li, Changfu; Wang, Tietao; Wang, Yao; Zhao, Tianyong; Shen, Xihui

    2014-01-01

    The application of the luxCDABE operon of the bioluminescent bacterium Photorhabdus luminescens as a reporter has been published for bacteria, yeast and mammalian cells. We report here the optimization of fused luxAB (the bacterial luciferase heterodimeric enzyme) expression, quantum yield and its application as a reporter gene in plant protoplasts. The fused luxAB gene was mutated by error prone PCR or chemical mutagenesis and screened for enhanced luciferase activity utilizing decanal as substrate. Positive luxAB mutants with superior quantum yield were subsequently shuffled by DNase I digestion and PCR assembly for generation of recombinants with additional increases in luciferase activity in bacteria. The coding sequence of the best recombinant, called eluxAB, was then optimized further to conform to Arabidopsis (Arabidopsis thaliana) codon usage. A plant expression vector of the final, optimized eluxAB gene (opt-eluxAB) was constructed and transformed into protoplasts of Arabidopsis and maize (Zea mays). Luciferase activity was dramatically increased for opt-eluxAB compared to the original luxAB in Arabidopsis and maize cells. The opt-eluxAB driven by two copies of the 35S promoter expresses significantly higher than that driven by a single copy. These results indicate that the eluxAB gene can be used as a reporter in plant protoplasts. To our knowledge, this is the first report to engineer the bacterium Photorhabdus luminescens luciferase luxAB as a reporter by directed evolution which paved the way for further improving the luxAB reporter in the future.

  1. Development and validation of analytical methods for monomeric and oligomeric migrants from nylon 12 packaging materials.

    NARCIS (Netherlands)

    Stoffers, N.H.; Brandl, F.; Linssen, J.P.H.; Franz, R.

    2003-01-01

    Analytical methods for the determination of laurolactam-the monomer of nylon 12-as well as the cyclic dimer and trimer were established. High performance liquid chromatography using ultraviolet (HPLC-UV) and mass spectrometric detection (HPLC-MS) were both found suitable to identify and quantify

  2. 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.

  3. Spectroscopic Characterization of a Monomeric, Cyclopentadienyl-Based Rhenium(V) Dioxo Complex

    DEFF Research Database (Denmark)

    Raju, Suresh; Jastrzebski, Johann T. B. H.; Lutz, Martin

    2015-01-01

    Mononuclear, coordinatively unsaturated rhenium(V) dioxo species of the type XReO2 (X = Me, substituted cyclopentadienyl) have long been postulated as intermediates in rhenium-catalyzed deoxydehydration, but their characterization was precluded because of aggregation into dimeric or oligomeric st...