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2010-01-01
Abstract CpG-containing oligodeoxynucleotides are potent mucosal adjuvants and effective as stand-alone treatment of respiratory infections in mice. Although CpG is also used as a type 1 helper immunomodulator in the treatment of asthma and allergic disease, immune modulation following intranasal application has not been fully characterized yet. Using a B-type CpG, we monitored RNA expression profiles, cytokine production and cellular activation in lung tissue and bronchoalveolar lavages ex vivo and cytokine production of purified cell populations in vitro. CpG triggered the upregulation of many transcripts, including interferon response genes and proinflammatory cytokine genes, between 3 h and 4 days. Overlapping subsets of these cytokine proteins were induced in vitro in purified CD11c+ ...
Intranasal Injection Versus Topical Administration of Epinephrin During Endoscopic Sinus Surgery
Hypertension; Hypotension; Tachycardia; Bradycardia; Arrhythmia
2010-01-01
We have recently shown that intranasal administration of mouse [D-Leu-4]-OB3 reconstituted in Intravail to male Swiss Webster mice resulted in significantly higher bioavailability than commonly used injection methods of delivery. The absorption profile associated with intranasal delivery of mouse [D-Leu-4]-OB3 showed an early peak representing rapid uptake across the nasal mucosa, and a later peak suggesting a gastrointestinal site of absorption. In the present study, we show that gastrointestinal absorption of mouse [D-Leu-4]-OB3 does occur, and that reformulation of mouse [D-Leu-4-OB3 with Intravail significantly enhances its uptake. The pharmacokinetics of orally delivered (by gavage) mouse [D-Leu-4]-OB3 in the absence or presence of Intravail were examined, and compared to previously r...
2010-01-01
ACADEMIC EMERGENCY MEDICINE 2010; 17:1-4 Copyright 2010 by the Society for Academic Emergency Medicine Abstract Objectives: The objective was to determine whether the introduction of intranasal (IN) fentanyl for children with acute pain would reduce the time to analgesic administration in a mixed adult and pediatric emergency department (ED). Methods: A protocol for IN fentanyl (1.5 mg/kg) for children age 1-15 years presenting with acute pain was introduced to the department. All children who received intravenous (IV) morphine in the 7 months prior to the introduction of the protocol and either IV morphine or IN fentanyl in the 7 months after the introduction of the protocol were identified from drug registers. Time to analgesic administration, time to see a doctor, and the ages of patien...
Rhinitis, Allergic, Perennial
2010-01-01
The goal of this research was to evaluate the effectiveness of cationic liposomes for intranasal administration of proteins to the brain. Cationic liposomes were loaded with a model protein, ovalbumin (OVAL), and a 50 g dose was administered intranasally to rats. In qualitative studies, liposomes were loaded with Alexa 488-OVAL and delivery was assessed by fluorescence microscopy. By 6 and 24 h after administration, Alexa 488-OVAL deposits were widely distributed throughout brain, with apparent cellular uptake in midbrain by 6 h after administration. In quantitative studies, liposomes were loaded with 111In-OVAL, and distribution to brain and peripheral tissues was monitored by gamma counting at 1, 4, 6, and 24 h after administration. The highest brain concentrations were achieved at the s...
Pharmacokinetics, efficacy, and tolerability of fentanyl following intranasal versus intravenous administration in adults undergoing third-molar extraction : A randomized, double-blind, double-dummy, two-way, crossover study
2008-01-01
In countries outside of the United States, report SUSPECTED ...
... 2 DOSAGE AND ADMINISTRATION FOR INTRANASAL ADMINISTRATION BY A HEALTH CARE PROVIDER. 2.1 Dosing Information ... vaccine for administration by intranasal spray. ...
June 2009 FluMist US PI Page of 0.2 mL pre-filled, single-use ...
... FOR INTRANASAL ADMINISTRATION BY A HEALTH CARE PROVIDER. ... There are no data regarding co-administration of FluMist with other intranasal preparations. ...
Influenza Virus Vaccine Live, Intranasal (FluMist)
... and Biologics Quality (OCBQ) in the Food and Drug Administration's Center for ... by your firm for FluMist Influenza Virus Vaccine Live, Intranasal, under cover of ...
... FluMist (Intranasal Influenza Virus Vaccine) Questions and Answers. -. Contact Us. Consumer Affairs Branch (CBER). ... Food and Drug Administration. 1401 Rockville Pike ...
Attachment 8: Proprietary Name
... Flonase is an intranasal spray. ... However, the potential for confusion due to dosage form and route of administration dosing interval could occur. ...
Pharmacokinetics of Intranasal Scopolamine Gel Formulation (Inscop)
... Intranasal (IN) administration of medications achieves higher and more reliable bioavailability than from an equivalent PO dose. Methods: To test the safety and reliability of ...
Recall: Influenza A (H1N1) 2009 Monovalent Vaccine Live ...
... Stop distribution/administration of these lots immediately and return any inventory ... of Influenza A (H1N1) 2009 Monovalent Vaccine Live, Intranasal Lot 500751P ...
Influenza A (H1N1) 2009 Monovalent Vaccine Live, Intranasal ...
... The most common adverse events seen with administration of H1N1 LAIV include runny nose/nasal congestion in recipients of all ages and fever in children 2 to ...
September 19, 2007 Approval Letter - Influenza Virus Vaccine Live ...
... Biologics License Application for Influenza Virus Vaccine Live, Intranasal (FluMist®), to ... dosage forms, new indications, new routes of administration, and new ...
FluMist (Intranasal Influenza Virus Vaccine) Questions and Answers
... In children, side effects can include nasal congestion, runny nose, headache ... However, as with medicines, problems may occur after administration of vaccines ...
Guidance for Industry: Guidance for Human Somatic Cell Therapy and ...
... For example, intrapulmonary instillation of adenoviral vectors by intranasal administration in cotton rats or mice is an acceptable alternative to direct ...
Kliniske konsekvenser af intranasal insulinbehandling ved insulinkraevende diabetes mellitus.
1996-01-01
Metabolic control, hypoglycaemia frequency and nasal mucosal physiology were evaluated in 31 insulin-dependent diabetics treated with intranasal insulin at mealtimes for one month and with subcutaneous fast-acting insulin for another month in a randomized crossover trial. During both periods the patients were treated with intermediate-acting insulin at bedtime. Six of the patients were withdrawn from the study during intranasal insulin therapy due to metabolic dysregulation. Insulin concentrations increased more rapidly and decreased more quickly during intranasal as compared with subcutaneous insulin administration. Metabolic control, assessed by haemoglobin A1c concentrations, deteriorated after intranasal as compared with subcutaneous insulin therapy. The bioavailability of intranasally applied insulin was low, since intranasal insulin doses were approximately 20 times higher than subcutaneous doses. The frequency of hypoglycemia was similar during intranasal and subcutaneous insulin therapy, and nasal mucosal physiology was unaffected after intranasal insulin. We conclude that due to low bioavailability and to a high rate of therapeutic failure, intranasal insulin treatment is not a realistic alternative to subcutaneous insulin injections at the present time.
Intranasal insulin therapy: the clinical realities.
1995-01-01
To evaluate metabolic control and safety parameters (hypoglycaemia frequency and nasal mucosa physiology), 31 insulin-dependent diabetic patients were treated with intranasal insulin at mealtimes for 1 month and with subcutaneous fast-acting insulin at meals for another month in an open, crossover randomized trial. During both treatment periods the patients were treated with intermediate-acting insulin at bedtime. Six of the patients were withdrawn from the study during intranasal insulin therapy due to metabolic dysregulation. Serum insulin concentrations increased more rapidly and decreased more quickly during intranasal as compared with subcutaneous insulin administration. Metabolic control deteriorated, as assessed by haemoglobin A1c concentrations, slightly but significantly after intranasal as compared with subcutaneous insulin therapy. The bioavailability of intranasally applied insulin was low, since intranasal insulin doses were approximately 20 times higher than subcutaneous doses. The frequency of hypoglycaemia was similar during intranasal and subcutaneous insulin therapy, and nasal mucosa physiology was unaffected after intranasal insulin. We conclude that due to low bioavailability and to a high rate of therapeutic failure, intranasal insulin treatment is not a realistic alternative to subcutaneous insulin injections at the present time.
... are completed, a New Drug Administration application will be filed with FDA for Phase III clinical assessment and approval for marketing of the formulation. A commercial vendor will be ...
Glucose recovery after intranasal glucagon during hypoglycaemia in man.
1994-01-01
We compared the hyperglycaemic effect of intranasal and intramuscular (i.m.) administration of glucagon after insulin-induced hypoglycaemia. Twelve healthy subjects were examined twice, receiving on both occasions an intravenous insulin bolus. Somatostatin and propranolol were administered to block endogenous glucose counterregulation, and glucose turnover was estimated by a 3-[3H]-glucose infusion. When hypoglycaemia was reached, the subjects received either i.m. glucagon of pancreatic extraction (1 mg) or intranasal genetically engineered glucagon (2 mg). The incremental values for plasma glucose concentrations 15 min after intranasal and i.m. administration of glucagon differed marginally. However, after 5 min the glucose appearance rate, as well as the incremental values for plasma glucose, were significantly higher for the i.m. glucagon treatment. The mean time taken for incremental plasma glucose to exceed 3 mmol.l-1 was significantly shorter for i.m. glucagon. The mean plasma glucagon level increased faster after i.m. glucagon than after intranasal glucagon, and the levels remained higher throughout the study period. We conclude that glucose recovery was significantly better after i.m. administration of glucagon than after intranasal administration. However, the differences between the incremental plasma glucose and the time for incremental plasma glucose to exceed 3 mmol.l-1 were not considered of major clinical importance.
1980-07-01
Tritiated progesterone (/sup 3/H-P) was administered to adult ovariectomized rhesus monkeys by different routes and methods. About 200 Ci of /sup 3/H-P was administered to each monkey by intravenous injection, as eye drops, intranasal spray of a solution containing /sup 3/H-P or intranasal spray of powdered dextrose containing adsorbed /sup 3/H-P. Radioactivity was estimated in cerebrospinal fluid (csf) and serum at 5, 10, 15, 30, 60 and 120 min after administering the steroid, and the data expressed as ratios radioactivity (dpm/ml) in csf and serum. There was no difference in csf: serum ratios following intravenous or ocular routes of administration. The intranasal routes of administration differed from the intravenous and the ocular routes in that the ratios showed a slow but gradual increase and also higher values.
http://arrow.monash.edu.au/hdl/1959.1/157941
BACKGROUND Heroin overdose is a major cause of death in some countries. Overdose deaths are preventable; with modifiable risk factors including injecting alone, concomitant drug and alcohol use and reduced tolerance after periods of abstinence. In addition, fatalities may be prevented by timely treatment with naloxone, an opiate antagonist. In the community setting, paramedics routinely administer naloxone for suspected opioid overdose. Traditionally, naloxone has been administered via the intramuscular (IM) and intravenous (IV) routes. Drug administration by these routes is problematic to the person administering the drug in a population at higher risk of infection with blood-borne viruses (BBV) because of the risks associated with needlestick injury. Peers witness most overdoses. If fatal, death typically occurs several hours after heroin injection. Naloxone distribution programs have been introduced successfully in some regions to facilitate peer-administered treatment for heroin overdose. Concerns have been raised regarding such programs including incompetent drug administration and unsafe disposal of needles. Administration of naloxone by the intranasal (IN) route to victims of suspected heroin overdose is a novel approach, with recognised advantages including ease of administration and elimination of cross-transmission of infectious disease. In addition, an aerosol spray has advantages for ‘take-home’ distribution. However, evidence to date has been limited to one randomised controlled trial (RCT), co-ordinated by the candidate, and several observational studies. These studies have been limited by small samples and inadequate preparation of naloxone for IN administration. Further well designed research is needed to confirm safety and effectiveness. OBJECTIVES The research reported in this thesis examined: 1. The effectiveness and safety of concentrated IN naloxone compared to IM naloxone for treatment by paramedics of suspected opiate overdose in the prehospital setting; 2. Reported overdose response by current injecting drug users (IDU) during overdose events and compared this to previous research; explored attitudes and willingness of IDUs regarding naloxone distribution for peer administration after heroin overdose; and assessed preferred mode of administration (IV, IM, IN) for peer administration of naloxone. RANDOMISED CONTROLLED TRIAL – INTRANASAL NALOXONE A RCT was performed in the prehospital setting to measure the effectiveness of concentrated IN naloxone in comparison to IM naloxone. One hundred and seventy-two patients treated for suspected opiate overdose were randomised to receive IM (2mg in 5 mL, Min-I-Jet prefilled syringe) or IN (2mg in 1mL) naloxone. The primary outcome measured was the proportion of patients who responded within 10 minutes of naloxone treatment. Secondary outcomes included time to adequate response and requirement for supplementary naloxone. Rates of response within 10 minutes were similar: IN naloxone (60/83, 72%) compared with IM naloxone (69/89, 78%) (Odds Ratio (OR) = 0.8, 95% CI 0.3 to 1.5). No clinically important difference was observed in mean response time (Difference = 0.1 minutes, 95% CI –1.3 to 1.5). However, supplementary naloxone was administered to fewer patients who received IM naloxone (IN: 15/83, 18.1%; IM: 4/89, 4.5%) (OR = 4.8, 95% CI 1.4 to 16.3). PEER RESPONSE TO HEROIN OVERDOSE Data regarding first-aid response to heroin overdose, attitudes of IDUs about peer naloxone treatment after heroin overdose and preferences for mode of administration were collected by survey. Ninety-nine current injecting heroin users who presented to needle syringe exchange programs (NSP) during 2007 were recruited. The findings confirm that heroin overdose is a common occurrence for IDU with 61% reporting a prior overdose event, and 84% reporting having witnessed an overdose in the past. An improvement in response to witnessed heroin overdose was observed in our study, with increased rates of ambulance notification (76% vs 10-56%) and expired air resuscitation (EAR) (44% vs 9-31%) in comparison to previous Australian studies. The large majority of the sample reported positive attitudes towards naloxone distribution (good to very good idea: 89%) and 92% said they were willing to participate in a related training program. Some participants raised concerns about peer administration including the competence of IDUs to administer naloxone in an emergency, victim response on wakening and legal implications. Most (74%) indicated a preference for IN administration in comparison to other administration methods (21%), which was unrelated to any key variable (e.g. age, sex, treatment status). CONCLUSION Concentrated IN naloxone successfully reversed heroin overdose for a high proportion of patients. These results support the administration of IN naloxone by paramedics as first-line treatment for heroin overdose. Heroin users often witness peer overdose and can respond with appropriate life-saving measures including ambulance notification, EAR and correct positioning. In addition, there appears to be strong support amongst Australian IDU for naloxone distribution. IN spray is the preferred route of administration for peer reversal. Publisher: Monash University. Faculty of Medicine, Nursing and Health Sciences. Monash Institute of Health Services Research Contributor: Principal Supervisor: Damien Jolley Other identifier: ethesis-20091120-105034; monash:27017 Language: eng Rights: Open access and full embargo: full embargo to thesis full text for 3 years after 2009.; This thesis is protected by copyright. Copyright in the thesis remains with the author. The Monash University ARROW Repository has a non-exclusive licence to publish and communicate this thesis online.
Axonal transport of rubidium and thallium in the olfactory nerve of mice
2005-07-01
Following intranasal administration of radioactive {sup 86}Rb{sup +} and {sup 201}Tl{sup +} in mice, we observed this direct transport via the olfactory nerve pathway. The {sup 86}RbCl and {sup 201}TlCl solutions were administered to two groups of mice, the unilateral intranasal and intravenous administration groups. After sacrifice, their heads were divided into the right and left side, which were then subdivided into seven parts; the nasal mucosa and brain regions were separated. Following the unilateral intranasal administration, uptake after 6 h by the olfactory bulb was significantly higher on the ipsilateral side ({sup 86}Rb, 0.7 %dose; {sup 201}Tl, 0.5 %dose) than on the contralateral side ({sup 86}Rb, 0.08 %dose; {sup 201}Tl, 0.15 %dose). Moreover, the {sup 86}Rb and {sup 201}Tl that accumulated in the olfactory bulb were gradually transported to other brain regions of the olfactory tract, the telencephalon and the diencephalon on the side corresponding to the nostril used for administration. Significant differences were observed between the right and left side of the brain regions 6 and 12 h after administration. Further, {sup 201}Tl autoradiography clearly showed striped patterns of dense accumulation, localized in the region around the glomerular layer and granule cell layer of the olfactory bulb and around the olfactory cortex. These results provide clear evidence of axonal transport via the olfactory nerve pathway, from nasal cavity to the olfactory bulb, as well as to the olfactory cortex through the synaptic junctions. The olfactory transport of the {sup 86}Rb{sup +} and {sup 201}Tl{sup +} is thought to represent the behavior of K{sup +} in the olfactory system.
Naked siLNA-mediated gene silencing of lung bronchoepithelium EGFP expression after intravenous administration
2009-01-01
The use of systemic siRNA therapeutics for RNA interference-mediated silencing of disease genes is limited by serum instability and inadequate biodistribution. We have previously reported on the EGFP gene silencing effect of chitosan/siRNA nanoparticles in the bronchoepithelium of mice lungs following intranasal delivery and improved serum stability and reduced off-targeting effects in vitro by incorporation of locked nucleic acid (LNA). In this study, we examine the pulmonary gene silencing effect of siLNAs targeting enhanced-green-fluorescent-protein (EGFP) in lung bronchoepithelium upon intravenous delivery of naked siLNAs and upon intranasal delivery of either naked siLNA or chitosan/siLNA nanoparticles. We show that naked siLNA administered intravenously efficiently reduces the EGFP protein expression. A similar effect is obtained with intranasal delivery of chitosan nanoparticles containing siLNA whereas intranasally instilled naked siLNA did not cause a knockdown.
2010-01-01
The establishment and maintenance of stable, long-term male-female relationships, or pair-bonds, are marked by high levels of mutual attraction, selective preference for the partner, and high rates of sociosexual behavior. Central oxytocin (OT) affects social preference and partner-directed social behavior in rodents, but the role of this neuropeptide has yet to be studied in heterosexual primate relationships. The present study evaluated whether the OT system plays a role in the dynamics of social behavior and partner preference during the first 3 weeks of cohabitation in male and female marmosets, Callithrix penicillata. OT activity was stimulated by intranasal administration of OT, and inhibited by oral administration of a non-peptide OT-receptor antagonist (L-368,899; Merck). Social be...
A neural cell adhesion molecule-derived fibroblast growth factor receptor agonist, the FGL-peptide, promotes early postnatal sensorimotor development and enhances social memory retention
2006-01-01
The neural cell adhesion molecule (NCAM) belongs to the immunoglobulin (Ig) superfamily and is composed extracellularly of five Ig-like and two fibronectin type III (F3) modules. It plays a pivotal role in neuronal development and synaptic plasticity. NCAM signals via a direct interaction with the fibroblast growth factor receptor (FGFR). A 15-amino-acid long peptide, the FG loop (FGL) peptide, that is derived from the second F3 module of NCAM has been found to activate FGFR1. We here report that the FGL peptide, when administered intranasally to newborn rats, accelerated early postnatal development of coordination skills. In adult animals s.c. administration of FGL resulted in a prolonged retention of social memory. We found that FGL rapidly penetrated into the blood and cerebrospinal fluid after both intranasal and s.c. administration and remained detectable in the fluids for up to 5 hours.
2010-01-01
Needle-free nonparenteral vaccines offer a number of practical advantages, especially in developing countries. To address the effects of vaccine administration route, we tested mucosal and systemic immune responses against human papillomavirus 16 L1(HPV16L1) protein using intranasal, intravaginal, transdermal, sublingual (SL) and intramuscular routes. The SL route provided the most effective mucosal secretory IgA (sIgA) and serum IgG responses. After a 150mg antigen dose via the SL route, saliva sIgA levels were 7.2- and 5.8-fold higher than those achieved via intravaginal and transdermal routes, respectively. Notably, SL administration even produced 4.6-fold higher levels of vaginal sIgA levels than did intravaginal delivery of 150mg antigen. To enhance the immunogenicity of SL vaccines, ...
Full Text Available.BackgroundWe have previously explored a therapeutic strategy for specifically targeting the profibrotic activity of IL-13 during experimental pulmonary fibrosis using a fusion protein comprised of human IL-13 and a mutated form of Pseudomonas aeruginosa exotoxin A (IL13-PE) and observed that the intranasal delivery of IL13-PE reduced bleomycin-induced pulmonary fibrosis through its elimination of IL-13-responsive cells in the lung. The aim of the present study was to determine whether the presence of an immune response to P. aeruginosa and/or its exotoxin A (PE) would diminish the anti-fibrotic properties of IL13-PE.Methodology/Principal FindingsFourteen days after P. aeruginosa infection, C57BL/6 mice were injected with bleomycin via the intratracheal route. Other groups of mice received 4 doses of saline or IL13-PE by either intranasal or intraperitoneal application, and were challenged i.t. with bleomycin 28 days later. At day 21 after bleomycin, all mice received either saline vehicle or IL13-PE by the intranasal route and histopatological analyses of whole lung samples were performed at day 28 after bleomycin. Intrapulmonary P. aeruginosa infection promoted a neutralizing IgG2A and IgA antibody response in BALF and serum. Surprisingly, histological analysis showed that a prior P. aeruginosa infection attenuated the development of bleomycin-induced pulmonary fibrosis, which was modestly further attenuated by the intranasal administration of IL13-PE. Although prior intranasal administration of IL13-PE failed to elicit an antibody response, the systemic administration of IL13-PE induced a strong neutralizing antibody response. However, the prior systemic sensitization of mice with IL13-PE did not inhibit the anti-fibrotic effect of IL13-PE in fibrotic mice.ConclusionsThus, IL13-PE therapy in pulmonary fibrosis works regardless of the presence of a humoral immune response to Pseudomonas exotoxin A. Interestingly, a prior infection with P. aeruginosa markedly attenuated the pulmonary fibrotic response suggesting that the immune elicitation by this pathogen exerts anti-fibrotic effects.
2009-01-01
Background: Ciclesonide, an intranasal corticosteroid, is administered as a prodrug and is converted to the active metabolite, desisobutyryl ciclesonide, in the upper and lower airways. Previous studies have assessed systemic exposure with the ciclesonide hydrofluoroalkane metered dose inhaler (CIC HFA-MDI) and the ciclesonide aqueous nasal spray (CIC-AQ) formulations. However, systemic exposure with ciclesonide HFA nasal aerosol (CIC-HFA) developed for the treatment of allergic rhinitis has not been investigated. Objective: This study compared the systemic exposure of ciclesonide and desisobutyryl ciclesonide after administration of ciclesonide formulated as an aqueous nasal spray, an HFA nasal aerosol, or as an orally inhaled HFA-MDI. Methods: Healthy adults (aged 18-60 years) were rando...
http://espace.library.uq.edu.au/view/UQ:35269
It has been shown previously that recombinant virus-like particles (VLPs) of papillomavirus can induce VLP-specific humoral and cellular immune responses following parenteral administration. To test whether mucosal administration of bovine papillomavirus type 1 (BPV1) VLPs could produce mucosal as well as systemic immune responses to VLPs, 50 mu g chimeric BPV1 VLPs containing an HPV16 E7 CTL epitope (BPVL1/E7 VLP) was administered intranasally to mice. After two immunisations, L1-specific serum IgG and IgA were observed. L1-specific IgG and IgA were also found in respiratory and vaginal secretions. Both serum and mucosal antibody inhibited papillomavirus VLP-induced agglutination of RBC, indicating that the antibody induced by mucosal immunisation may recognize conformational determinants associated with virus neutralisation. For comparison, VLPs were given intramuscularly, and systemic and mucosal immune responses were generally comparable following systemic or mucosal delivery. However, intranasal administration of VLP induced significantly higher local IgA response in lung, suggesting that mucosally delivered HPV VLP may be more effective for mediating local mucosal immune responses. Intranasal immunisation with HPV6b L1 VLP produced VLP-specific T proliferative responses in splenocytes, and immunisation with BPVL1 VLP containing an HPV16 E7 CTL epitope induced E7-specific CTL responses. We conclude that immunisation with papillomavirus VLPs via mucosal and intramuscular routes, without adjuvant, can elicit specific antibody at mucosal surfaces and also systemic VLP epitope specific T cell responses. These findings suggest that mucosally delivered VLPs may offer an alternative HPV VLP vaccine strategy for inducing protective humoral immunity to anogenital HPV infection, together with cell-mediated immune responses to eliminate any cells which become infected. (C) 1998 Academic Press. Publisher: Academic Press Relation: isMemberOf UQ Diamantina Institute Publications
2010-01-01
The mucosal vaccination is a non-invasive alternative approach for not only mucosal pathogens but also parenteral pathogens, since it induces both mucosal and systemic immunoreactions. The purpose of this study was to evaluate the application of intranasal (i.n.) immunization with a recombinant leishmanial protein against Leishmania infection. BALB/c mice were i.n. administered 1-3 times with Leish-111f plus cholera toxin (CT) adjuvant (Leish-111f/CT). Splenocytes from i.n. immunized mice produced high level of IFN-g but not IL-4 in response to Leish-111f. When infected with 1x10^6 of Leishmania major promastigotes 2 weeks after the final administration, lesion development was completely controlled in all mice i.n. administered with Leish-111f/CT. Mice i.n. administered with Leish-111f alo...
Serum amyloid P component inhibits influenza A virus infections: in vitro and in vivo studies.
2001-01-01
Serum amyloid P component (SAP) binds in vitro Ca(2+)-dependently to several ligands including oligosaccharides with terminal mannose and galactose. We have earlier reported that SAP binds to human influenza A virus strains, inhibiting hemagglutinin (HA) activity and virus infectivity in vitro. These studies were extended to comprise five mouse-adapted influenza A strains, two swine influenza A strains, a mink influenza A virus, a ferret influenza A reassortant virus, a influenza B virus and a parainfluenza 3 virus. The HA activity of all these viruses was inhibited by SAP. Western blotting showed that SAP bound to HA trimers, monomers and HA1 and HA2 subunits of influenza A virus. Binding studies indicated that galactose, mannose and fucose moieties contributed to the SAP reacting site(s). Intranasal administration of human SAP to mice induced no demonstrable toxic reactions, and circulating antibodies against SAP were not detected. Preincubation of virus (A/Japan/57) with SAP prevented primary infection of mice and development of antiviral antibodies. After a single intranasal administration of SAP (40 microg) 1 h before primary infection with virus (2LD(50)), nine out of 10 mice survived on day 10 and these mice approached normal body weight, whereas control mice (one out of five surviving on day 10) died. The data provide evidence of the potential of intranasally administered SAP for prophylactic treatment of influenza A virus infections in humans.
1996-06-01
The novel influenza virus neuraminidase inhibitor GG167 (5-acetylamino-4-guanidino-2,6-anhydro-3, 4,5-trideoxy-D-glycero-D-galacto-non-2-enoic acid) was labelled with {sup 11}C for use in positron emission tomographic studies of drug deposition following intranasal or inhaled administration. [{sup 11}C]GG167 was obtained within a synthesis time of 50min via a two-step procedure, starting from [{sup 11}C]cyanogen bromide. (author).
Expression of the Foxp3 Gene in Spleen Mononuclear Cells of a Mouse Model with Allergic Rhinitis
2009-01-01
Abstract Objective: There is growing speculation that the impairment inregulatory-T-cell (Treg)-mediated dominant tolerance may play an important role in the pathogenesis of allergic rhinitis (AR). The aim of this study was to investigate whether the changes in the forkhead transcription factor 3 (Foxp3) gene expression may aggravate nasal mucosal inflammation in allergic mice, and whether or not these features result from the loss of Tregs. Methods: AR was induced by both intraperitoneal injection and intranasal administration of ovalbumin in BALB/c mice, while the control mice were treated with saline. A comparison of the frequency of CD4+CD25+Foxp3+ Tregs in peripheral blood mononuclear cells of the AR and control mice was made by flow cytometry. Spleen mononuclear cells were used for R...
http://espace.library.uq.edu.au/view/UQ:162472
Virus-like particles (VLPs) have been developed as a vaccine against cervical cancer by Merck (West Point, PA, USA), and have recently been shown in animal studies to provide protection against both seasonal and avian influenza following intranasal administration (Novavax, Rockville, MD, USA). This new class of vaccines offers unprecedented immunoprotection, inherent safety, and a simple route of administration. However, current VLP manufacturing methods are unable to deliver products quickly and at minimal cost. This is in part due to the use of a cell-based processing route for VLP assembly followed by complex purification of the product from similarly sized nanoparticles or intraparticle contaminants. Manufacturing can potentially be simplified by chemical self-assembly of VLPs in a cell-free reactor. Current process optimization methods are empirical, with success gauged by low-resolution analytical techniques such as electron microscopy and ultracentrifugation, resulting in heterogeneous products of variable consistency. We have optimized the assembly of VLPs using fundamental colloidal science principles. By measuring the osmotic second virial coefficient (B22) of VLP precursors in various buffer conditions, we have gained insight into the interactions between the precursors that are responsible for VLP self-assembly. State-of-the-art characterization techniques such as field-flow fractionation have been used to quantitatively assess the quality of assembled VLPs. Understanding the precise nature of the interactions governing self-assembly, and how they are controlled by process parameters, has allowed us to establish a “self-assembly window” – a design and operation tool that gives robust control over this important process stage. Coverage: 2007-01-01T00:00:00Z
2010-01-01
Abstract Background: Intranasal (IN) fentanyl provides rapid and powerful non-parenteral analgesia in the ED. A concentrated solution of fentanyl (300 g/mL) has been used in prior trials, yet many ED use the standard solution at a concentration of 50 g/mL, which is widely available and of low cost. We set out to determine if this lower concentration of fentanyl is also efficacious. Methods: Prospective audit in children aged 5-18 years presenting with upper limb injuries. Patients received IN fentanyl (50 g/mL) at 1.5 g/kg. Patient assessed pain scores were collected 5, 10, 20, 30 and 60 min following IN fentanyl administration using a visual analogue scale or Bieri Faces - Revised scale. Parental scores were used if patients were unable to provide a score. Results: Of the 59 eligible pati...
2009-01-01
Summary Severe dyspnoea is the most threatening symptom of the dying and one of the main reasons for undesirable hospitalisation in end of life. Especially in home care there is a need for a noninvasive, safe and highly effective method for symptom control. Fentanyl is an appropriate drug because of its fast onset and short duration of action. Since 2003 medicated the Palliative Net Easthessia (PNO) more than 600 home care patients with nasal Fentanyl (naF). The method is simple and the user should bear in mind that the substance is highly effective. Both physician and pharmacist should inform themselves adequately before the first use about the basics of the manufacturing and use. Two typical case reports will be shown. Clinical experience let us assume that intranasal administration agai...
2010-01-01
Recent case reports and case series suggest that the atypical antipsychotic quetiapine has the potential for misuse. This includes drug-seeking behaviors motivated by quetiapine as well as inappropriate (intranasal or intravenous) administration. We present an additional case of quetiapine misuse and review other published cases. In general, quetiapine misuse is associated with prior CNS depressant use and is more common in forensic settings. The mechanism of reinforcement for this misuse is unknown, but we hypothesize that it is related to quetiapine's pharmacological profile as an antihistamine with a relative low affinity for dopamine receptors. The risks to individuals and society of exaggerating/simulating symptoms to obtain high-dose quetiapine in the absence of a clinical indication...
Mast Cells Induce Migration of Dendritic Cells in a Murine Model of Acute Allergic Airway Disease
2010-01-01
Abstract Background: The migration of dendritic cells (DCs) from the lungs to the regional lymph nodes is necessary for the development of allergic airway disease. Following activation, mast cells release a variety of stored or de novo-produced inflammatory mediators, several of them being capable of activating DCs. In this study, the role of mast cells on DC migration from the lungs to the thoracic lymph nodes was investigated in sensitized mice. Methods: Mast cell-deficient mice (KitW-sh/W-sh) and their wild-type counterparts were sensitized intraperitoneally with ovalbumine (OVA) in saline and challenged by a single intranasal administration of OVA labeled with a fluorescent dye (OVA-Alexa). Results: Following challenge, the relative and absolute amount of OVA- Alexa-positive DCs was cl...
http://espace.library.uq.edu.au/view/UQ:184165
Virus-like particles (VLPs) are elegant functional architectures formed by the self-assembly of viral structural proteins. VLPs have been developed as vaccines against hepatitis B and cervical cancer, and have recently been shown in animal studies to provide protection against both seasonal and avian influenza following intranasal administration. This new class of vaccines offers unprecedented immunoprotection, inherent safety, and a simple route of administration. To realize the full potential of VLP technology as an efficient and responsive vaccine platform, this project exploits the parallel advancements in recombinant technology, analytical techniques and colloidal science to facilitate the swift and economical delivery of candidate VLP vaccines from laboratory to clinical trials, and ultimately into commercial production. Three areas of VLP production are specifically targeted in this work, i.e., VLP subunit production, particle characterisation and assembly. The major research outcomes in this work are: (i) establishment of a simple and economical VLP subunit production method which eliminates inefficient and complicated purification procedures necessitated by the current in vivo production methods; (ii) development of a high-resolution and high-throughput analytical method for rapid and reliable quality control check of VLP products; and (iii) establishment of the foundation to predict optimal VLP self-assembly conditions through molecular thermodynamics. These research outcomes collectively enhance the quantitative knowledge base in VLP assembly and may ultimately enable the development of a mechanistic and descriptive modelling approach to optimize VLP production. From a fundamental perspective, this work introduces the first experimental technique to measure protein interactions of viral subunits undergoing rapid, irreversible assembly reaction. Such information, when correlated with molecular details and assembly conditions may provide unique insights into the molecular switches responsible for viral assembly, unveiling the fundamental mechanism underpinning viral self-assembly. Coverage: 2009-02-01T00:00:00Z
Rabies vaccines based on live attenuated rabies viruses or recombinant pox viruses expressing the rabies virus (RV) glycoprotein (G) hold the greatest promise of safety and efficacy, particularly for oral immunization of wildlife. However, while these vaccines induce protective immunity in foxes, they are less effective in other animals, and safety concerns have been raised for some of these vaccines. Because canine adenovirus 2 (CAV2) is licensed for use as a live vaccine for dogs and has an excellent efficacy and safety record, we used this virus as an expression vector for the RVG. The recombinant CAV2-RV G produces virus titers similar to those produced by wild-type CAV2, indicating that the RVG gene does not affect virus replication. Comparison of RVG expressed by CAV2-RV G with that of vaccinia-RV G recombinant virus (V-RG) revealed similar amounts of RV G on the cell surface. A single intramuscular or intranasal immunization of mice with CAV2-RVG induced protective immunity in a dose-dependent manner, with no clinical signs or discomfort from the virus infection regardless of the route of administration or the amount of virus.
Interferon-lambda contributes to innate immunity of mice against influenza A virus but not against hepatotropic viruses
2008-01-01
Virus-infected cells secrete a broad range of interferon (IFN) subtypes which in turn trigger the synthesis of antiviral factors that confer host resistance. IFN-alpha, IFN-beta and other type I IFNs signal through a common universally expressed cell surface receptor, whereas IFN-lambda uses a distinct receptor complex for signaling that is not present on all cell types. Since type I IFN receptor-deficient mice (IFNAR1(0/0)) exhibit greatly increased susceptibility to various viral diseases, it remained unclear to which degree IFN-lambda might contribute to innate immunity. To address this issue we performed influenza A virus infections of mice which carry functional alleles of the influenza virus resistance gene Mx1 and which, therefore, develop a more complete innate immune response to influenza viruses than standard laboratory mice. We demonstrate that intranasal administration of IFN-lambda readily induced the antiviral factor Mx1 in mouse lungs and efficiently protected IFNAR1(0/0) mice from lethal influenza virus infection. By contrast, intraperitoneal application of IFN-lambda failed to induce Mx1 in the liver of IFNAR1(0/0) mice and did not protect against hepatotropic virus infections. Mice lacking functional IFN-lambda receptors were only slightly more susceptible to influenza virus than wild-type mice. However, mice lacking functional receptors for both IFN-alpha/beta and IFN-lambda were hypersensitive and even failed to restrict usually non-pathogenic influenza virus mutants lacking the IFN-antagonistic factor NS1. Interestingly, the double-knockout mice were not more susceptible against hepatotropic viruses than IFNAR1(0/0) mice. From these results we conclude that IFN-lambda contributes to inborn resistance against viral pathogens infecting the lung but not the liver.
Epidemiology of pollution-induced airway disease in Japan
1997-12-31
Air pollution has been implicated as one of the factors responsible for the increased incidence of allergic diseases seen over recent years. Epidemiological studies in Japan demonstrate that atopic subjects living in urban areas are more likely to suffer from the effects of air pollution, with increased coughing, sputum production, wheezing and throat irritation. Furthermore, animal studies show that high concentrations of pollutant gases can promote airway sensitization. The incidence of allergic Rhinitis and asthma have been shown to be greater in areas where there is heavy traffic and hence high levels of automobile exhaust emissions. Intranasal administration of diesel exhaust particles in mice produces a stimulatory effect on immunoglobulin E production, and a similar finding has also been shown with suspended particulate matter in air. Air pollutants, such as ozone and nitrogen dioxide (NO{sub 2}), have been shown to stimulate the production of granulocyte-macrophage colony stimulating factor, which may play a vital role in airway hyperreactivity and asthma. In comparative studies of asthma in urban and rural areas, history of airway infection and a younger age of onset were found to be significantly greater in urban areas. When the asthmatic patients were divided into two groups according to environmental NO{sub 2} levels (group I: NO{sub 2}>30 ppb, group II: NO{sub 2}<30 ppb), no significant difference regarding the various parameters was noted between the two groups, except for a greater severity of asthma in adults in group I, and a greater severity in chrildren in group II. These studies imply that air pollution may be one reason for the increase in allergic diseases in Japan, but a definitive conclusion cannot be drawn, and further, investigation is warranted. (au)
Efficacy of the New Neuraminidase Inhibitor CS-8958 against H5N1 Influenza Viruses
2010-02-01
Full Text Available.Currently, two neuraminidase (NA) inhibitors, oseltamivir and zanamivir, which must be administrated twice daily for 5 days for maximum therapeutic effect, are licensed for the treatment of influenza. However, oseltamivir-resistant mutants of seasonal H1N1 and highly pathogenic H5N1 avian influenza A viruses have emerged. Therefore, alternative antiviral agents are needed. Recently, a new neuraminidase inhibitor, R-125489, and its prodrug, CS-8958, have been developed. CS-8958 functions as a long-acting NA inhibitor in vivo (mice) and is efficacious against seasonal influenza strains following a single intranasal dose. Here, we tested the efficacy of this compound against H5N1 influenza viruses, which have spread across several continents and caused epidemics with high morbidity and mortality. We demonstrated that R-125489 interferes with the NA activity of H5N1 viruses, including oseltamivir-resistant and different clade strains. A single dose of CS-8958 (1,500 µg/kg) given to mice 2 h post-infection with H5N1 influenza viruses produced a higher survival rate than did continuous five-day administration of oseltamivir (50 mg/kg twice daily). Virus titers in lungs and brain were substantially lower in infected mice treated with a single dose of CS-8958 than in those treated with the five-day course of oseltamivir. CS-8958 was also highly efficacious against highly pathogenic H5N1 influenza virus and oseltamivir-resistant variants. A single dose of CS-8958 given seven days prior to virus infection also protected mice against H5N1 virus lethal infection. To evaluate the improved efficacy of CS-8958 over oseltamivir, the binding stability of R-125489 to various subtypes of influenza virus was assessed and compared with that of other NA inhibitors. We found that R-125489 bound to NA more tightly than did any other NA inhibitor tested. Our results indicate that CS-8958 is highly effective for the treatment and prophylaxis of infection with H5N1 influenza viruses, including oseltamivir-resistant mutants.
http://hdl.handle.net/2440/3018
Copyright © 2003, American Society for Microbiology.The LuxS protein is required for the biosynthesis of the type 2 autoinducer (AI-2), which is involved in quorum sensing in a wide range of bacterial species. We have determined the effects of a defined luxS mutation on the virulence of Streptococcus pneumoniae. Although the luxS mutant displayed reduced virulence relative to its wild-type parent, the type 2 strain D39, it was by no means avirulent in a mouse model. After intranasal administration, the luxS mutant was able to colonize the nasopharynx of the mouse as efficiently as the wild type. However, it was less able to spread from the nasopharynx to the lungs or the blood. Intraperitoneal coadministration studies indicated that the luxS mutant was less fit and was readily outcompeted by wild-type D39. However, when administered on its own by this route, the mutant was able to proliferate and cause fatal systemic disease, albeit at a lower rate than the wild type. Western blot analysis of whole-cell lysates of the mutant and its parent did not reveal any differences in the levels of several well-characterized virulence proteins. However, analysis of Coomassie blue-stained protein profiles after separation by sodium dodecyl sulfate-polyacrylamide gel electrophoresis showed that mutation of luxS had pleiotropic effects on protein expression in all cellular compartments. This is consistent with the product of luxS having a regulatory role in S. pneumoniae. This is the first report of a direct role for luxS (and by inference, AI-2) in the virulence of a gram-positive pathogen. However, the fact that mutagenesis of luxS does not completely attenuate S. pneumoniae has implications for the possible use of AI-2 antagonists for treatment of pneumococcal infections.Uwe H. Stroeher, Adrienne W. Paton, A. David Ogunniyi, and James C. Paton Publisher: American Society for Microbiology Contributor: School of Molecular and Biomedical Science Other identifier: Infection and Immunity, 2003; 71 (6):3206-3212; 0019-9567; 0020030187; 10.1128/IAI.71.6.3206-3212.2003 Language: en_US Source: http://iai.asm.org/cgi/content/abstract/71/6/3206
Recently, there have been increasing reports that nano-sized component of particulate matter can reach the brain and may be associated with neurodegenerative diseases. Previously, our laboratory has studied the effect of intranasal instillation of nano-sized carbon black (CB) (14 nm and 95 nm) on brain cytokine and chemokine mRNA expressions and found that 14-nm CB increased IL-1{beta}, TNF-{alpha}, CCL2 and CCL3 mRNA expressions in the olfactory bulb, not in the hippocampus of mice. To investigate the effect of a single administration of nanoparticles on neurotransmitters and proinflammatory cytokines in a mouse olfactory bulb, we performed in vivo microdialysis and real-time PCR methods. Ten-week-old male BALB/c mice were implanted with guide cannula in the right olfactory bulb and, 1 week later, were instilled vehicle or CB (14 nm, 250 {mu}g) intranasally. Six hours after the nanoparticle instillation, the mice were intraperitoneally injected with normal saline or 50 {mu}g of bacteria cell wall component lipoteichoic acid (LTA), which may potentiate CB-induced neurologic effect. Extracellular glutamate and glycine levels were significantly increased in the olfactory bulb of CB-instilled mice when compared with vehicle-instilled control mice. Moreover, we found that LTA further increased glutamate and glycine levels. However, no alteration of taurine and GABA levels was observed in the olfactory bulb of the same mice. We also detected immunological changes in the olfactory bulb 11 h after vehicle or CB instillation and found that IL-1{beta} mRNA expression was significantly increased in CB- and LTA-treated mice when compared with control group. However, TNF-{alpha} mRNA expression was increased significantly in CB- and saline-treated mice when compared with control group. These findings suggest that nanoparticle CB may modulate the extracellular amino acid neurotransmitter levels and proinflammatory cytokine IL-1 {beta} mRNA expressions synergistically with LTA in the mice olfactory bulb.
Full Text Available.The current pandemic (H1N1) 2009 virus remains transmissible among humans worldwide with cases of reverse zoonosis, providing opportunities to produce more pathogenic variants which could pose greater human health concerns. To investigate whether recent seasonal human or swine H1N1 vaccines could induce cross-reactive immune responses against infection with the pandemic (H1N1) 2009 virus, mice, ferrets or mini-pigs were administered with various regimens (once or twice) and antigen content (1.77, 3.5 or 7.5 µg HA) of a-Brsibane/59/07, a-CAN01/04 or RgCA/04/09xPR8 vaccine. Receipt of a-CAN01/04 (2-doses) but not a-Brisbane/59/07 induced detectable but modest (20–40 units) cross-reactive serum antibody against CA/04/09 by hemagglutinin inhibition (HI) assays in mice. Only double administration (7.5 µg HA) of both vaccine in ferrets could elicit cross-reactivity (30–60 HI titers). Similar antigen content of a-CAN01/04 in mini-pigs also caused a modest ∼30 HI titers (twice vaccinated). However, vaccine-induced antibody titers could not suppress active virus replication in the lungs (mice) or virus shedding (ferrets and pigs) of immunized hosts intranasally challenged with CA/04/09. Furthermore, neither ferrets nor swine could abrogate aerosol transmission of the virus into naïve contact animals. Altogether, these results suggest that neither recent human nor animal H1N1 vaccine could provide complete protectivity in all animal models. Thus, this study warrants the need for strain-specific vaccines that could yield the optimal protection desired for humans and/or animals.
http://hdl.handle.net/2440/7184
Copyright © 2004 by the American Diabetes Association.Leonard C. Harrison, Margo C. Honeyman, Cheryl E. Steele, Natalie L. Stone, Elena Sarugeri, Ezio Bonifacio, Jennifer J. Couper, and Peter G. Colman Publisher: American Diabetes Association Contributor: School of Paediatrics and Reproductive Health : Paediatrics Other identifier: Diabetes Care, 2004; 27 (10):2348-2355; 0149-5992; 0020041818 Language: en_US Source: http://care.diabetesjournals.org/cgi/content/abstract/27/10/2348
http://hdl.handle.net/2440/53166
Copyright © 2008 Published by Elsevier Inc.Lona L. Christrup, David Foster, Lars D. Popper, Tine Troen and Richard Uptonhttp://www.elsevier.com/wps/find/journaldescription.cws_home/525050/description#description Publisher: Elsevier Contributor: School of Medicine : Anaesthesia and Intensive Care Other identifier: Clinical Therapeutics, 2008; 30 (3):469-481; 0149-2918; 0020080549; 10.1016/j.clinthera.2008.03.001; 000254962400004 Language: en
http://arrow.unisa.edu.au:8081/1959.8/62529
None Available Publisher: Harvey Whitney Books Company Relation: ; Format: 8 Other identifier: ISSN:10600280 Coverage: ARROW@UNISA Language: en-aus Rights: Copyright 2008 Harvey Whitney Books Company
http://arrow.unisa.edu.au/vital/access/manager/Repository/unisa:39828
None Available Publisher: Elsevier Relation: ; Format: 13 Other identifier: ISBN:01492918; RM:0000034532; unisa:39828 Coverage: ; ARROW@UNISA Language: en-aus Source: Clinical therapeutics vol. 30, no. 3, pp. 469-481 0 Rights: Copyright status unknown
2008-07-01
We are developing a vaccine for toxoplasmosis, using ionizing radiation as a tool. Here we analyzed the production of systemic and intestinal immunity, with protection studies, in several strains of inbred mice, by oral or parenteral route, using 255 Gy irradiated tachyzoites of T. gondii RH strain, with challenge with cysts of ME- 49 strain. C57Bl/6j, BALB/c and C57Bl/6j IFN-{gamma}{sup -/-} mice were immunized with 10{sup 7} irradiated tachyzoites, be parenteral or oral route. Those preparations, both by parenteral or oral routes, induced the production of specific IgG, mainly of the lgG2b subclass, and IgA immunoglobulins in serum, , as determined by ELISA. IgM production was negligible. Parenteral immunized mice showed higher IgG avidity maturation, as compared to oral immunized mice. Fecal excretion of IgG, IgA and IgM was detected in stools of immunized animals, more intense in oral immunized mice. In cellular immunity studies, induced by antigen, with detection of cytokine production by quantitative real-time PCR, there are a great production of IFN-y by spleen cells, with lower levels in Peyer patches cells, where there are a greater IL-2 production. Challenge studies in immunized mice demonstrated protection to infection in all used schedules, greater in BALB/c mice. C57Bl/6j IFN-{gamma} -{sup /-} mice, when immunized, showed no signs of disease and produced similar or greater levels of antibodies than wild type mice. They also excreted S-lgA and S-IgM in stools, but with low numbers of brain cysts in parenteral immunized mice, despite similar mortality. Our data points to a fair possibility of use of those irradiated parasites as an oral vaccine, devised to use for veterinary or wild felines vaccination, reducing the production of oocysts by those hosts and interrupting the chain transmission of human toxoplasmosis. (author)
BackgroundWe have previously explored a therapeutic strategy for specifically targeting the profibrotic activity of IL-13 during experimental pulmonary fibrosis using a fusion protein...Full Text Available
TRIGEMINAL UPTAKE AND CLEARANCE OF INHALED MANGANESECHLORIDE IN RATS AND MICE
2003-12-09
Inhaled manganese (Mn) can enter the olfactory bulbs via the olfactory epithelium, and can then be further transported trans-synaptically to deeper brain structures. In addition to olfactory neurons, the nasal cavity is innervated by the maxillary division of the trigeminal nerve that projects to the spinal trigeminal nucleus. Direct uptake and transport of inhaled metal particles in the trigeminal system has not been investigated previously. We studied the uptake, deposition, and clearance of soluble Mn in the trigeminal system following nose-only inhalation of environmentally relevant concentrations. Rats and mice were exposed for 10 days (6 hours/day, 5 days/week) to air or MnCl2 aerosols containing 2.3 {+-} 1.3mg Mn/m{sup 3} with mass median aerodynamic diameter (MMAD) of 3.1 {+-} 1.4 {micro}m for rats and 2.0 {+-} 0.09 mg Mn/m{sup 3} MnCl{sup 2} with MMAD of 1.98 {+-} 0.12 {micro}m for mice. Mn concentrations in the trigeminal ganglia and spinal trigeminal nucleus were measured 2 hours (0 day), 7, 14, or 30 days post-exposure using Proton Induced X-ray Emission (PIXE). Manganese-exposed rats and mice showed statistically elevated levels of Mn in trigeminal ganglia 0, 7 and 14 days after the 10 day exposure period when compared to control animals. The Mn concentration gradually decreased over time with a clearance rate (t{sub 1/2}) of 7-8 days. Rats and mice were similar in both average accumulated Mn levels in trigeminal ganglia and in rates of clearance. We also found a small but significant elevation of Mn in the spinal trigeminal nucleus of mice 7 days post-exposure and in rats 0 and 7 days post-exposure. Our data demonstrate that the trigeminal nerve can serve as a pathway for entry of inhaled Mn to the brain in rodents following nose-only exposure and raise the question of whether entry of toxicants via this pathway may contribute to development of neurodegenerative diseases.
2010-02-01
Sickle cell disease (SCD) is characterized by intravascular hemolysis and inflammation coupled to a 400-fold greater incidence of invasive pneumococcal infection resulting in fulminant, lethal pneumococcal...Full Text Available
2010-02-01
Full Text Available.Sickle cell disease (SCD) is characterized by intravascular hemolysis and inflammation coupled to a 400-fold greater incidence of invasive pneumococcal infection resulting in fulminant, lethal pneumococcal sepsis. Mechanistically, invasive infection is facilitated by a proinflammatory state that enhances receptor-mediated endocytosis of pneumococci into epithelial and endothelial cells. As statins reduce chronic inflammation, in addition to their serum cholesterol-lowering effects, we hypothesized that statin therapy might improve the outcome of pneumococcal infection in SCD. In this study, we tested this hypothesis in an experimental SCD mouse model and found that statin therapy prolonged survival following pneumococcal challenge. The protective effect resulted in part from decreased platelet-activating factor receptor expression on endothelia and epithelia, which led to reduced bacterial invasion. An additional protective effect resulted from inhibition of host cell lysis by pneumococcal cholesterol-dependent cytotoxins (CDCs), including pneumolysin. We conclude therefore that statins may be of prophylactic benefit against invasive pneumococcal disease in patients with SCD and, more broadly, in settings of bacterial pathogenesis driven by receptor-mediated endocytosis and the CDC class of toxins produced by Gram-positive invasive bacteria.
Full Text Available.BackgroundChronic inflammations, atherosclerosis and obesity, are major risk factors for cardiovascular diseases. Immune modulation of the inflammatory response has shown promise in animal models of atherogenesis and metabolic disease. Tableted dietary supplement, V-6, containing pooled antigens derived from pig adipose tissue has been administered daily to 12 volunteers for 2 months.ResultsNo significant changes were observed in liver ALT and AST enzymes, i.e., 28 vs 23.8 IU and 22.6 vs 24.8 IU, with p = 0.07 and p = 0.49, respectively. Creatinine decreased; 0.88 vs 0.84 mg/dL (p = 0.05) while BUN moved upward; 14.5 vs 17.5 mg/dL (p = 0.01), but both values remained within normal range. Blood glucose remained within normal range; 96.1 vs 101.1 mg/dL (p = 0.04). Complete blood cell analysis has not revealed any change except slight increase in hemoglobin; 13.13 to 13.96 g/dL (p = 0.0002); hematocrit and red blood cells count 40.3 to 42.3% (p = 0.02) and 5.15 to 5.35 × 106 cells/mm3 (p = 0.03) respectively. Blood pressure systolic and diastolic values were not affected, i.e., 116.1 vs 116.3 (p = 0.12) and 76.8 vs 76.6 (p = 0.99). Body weight and body mass index (BMI) remained same; 66.4 vs 66.3 kg (p = 0.47) and 25.7 vs 25.6 kg/m2 (p = 0.2). Body fat deposit indices, such as abdomen; mid-arm; and thigh circumferences declined by 3.5 cm (p = 0.008); 1.2 cm (p = 0.004); and 3.0 cm (p = 0.0007) respectively. The total cholesterol and LDL levels did not change; 195.5 vs 195.1 (-0.2%; p = 0.8) and 113.4 vs 120.3 (6.1%; p = 0.08) respectively. Triglycerides have been reduced but not statistically significant; 168.1 vs 118 mg/dL (-29.8%; p = 0.2). In contrast, HDL content had risen by 29.7% from 39.4 to 51.1 mg/dL in all 12 patients (p = 0.000003). TG/HDL ratio - a marker of insulin resistance - was reduced from 4.78 to 2.56 (-46.5%; p = 0.04).ConclusionsThese results demonstrate that V-6 is safe and has a potential as an anti-atherogenic and overweight/obesity immune intervention.
BackgroundChronic inflammations, atherosclerosis and obesity, are major risk factors for cardiovascular diseases. Immune modulation of the inflammatory response has shown promise...Full Text Available
Pulsed estrogen therapy in prevention of postmenopausal osteoporosis. A 2-year randomized, double blind, placebo-controlled study.
2003-01-01
The aim of this study was to evaluate the efficacy of pulsed estrogen therapy (intranasal 17beta-estradiol) in the prevention of postmenopausal bone loss. A total of 386 women (40-65 years old), less than 5 years past menopause, were randomized to intranasal placebo, 17beta-estradiol 150 micro g, or 300 micro g daily for 2 years. Women with an intact uterus received micronised progesterone 200 mg per day, 14 days of each 28-day cycle. Women randomised to placebo-treatment received placebo progesterone. The primary endpoints were changes in BMD at the spine (L2-L4) and femoral neck. Secondary endpoints were changes in bone turnover markers: serum osteocalcin (sOC) as a marker of bone formation and urinary C-terminal telopeptides (uCTX) as a marker of bone resorption. BMD increased at all measured sites in women receiving active treatment in a dose-related manner, the difference compared to placebo being 5.2% and 6.7% at the spine, and 3.2% and 4.7 % at the hip, respectively, with 150 microg and 300 microg ( P
Pulmonary macrophage and epithelial cells
1977-01-01
Separate abstracts were prepared for the 41 papers presented at the conference. Abstracts of two papers have appeared in previous issues of Energy Research Abstracts. (HLW)
Pseudomonas aeruginosa can establish life-long airways chronic infection in patients with cystic fibrosis (CF) with pathogenic variants distinguished from initially acquired strain....Full Text Available
Full Text Available.Pseudomonas aeruginosa can establish life-long airways chronic infection in patients with cystic fibrosis (CF) with pathogenic variants distinguished from initially acquired strain. Here, we analysed chemical and biological activity of P. aeruginosa Pathogen-Associated Molecular Patterns (PAMPs) in clonal strains, including mucoid and non-mucoid phenotypes, isolated during a period of up to 7.5 years from a CF patient. Chemical structure by MS spectrometry defined lipopolysaccharide (LPS) lipid A and peptidoglycan (PGN) muropeptides with specific structural modifications temporally associated with CF lung infection. Gene sequence analysis revealed novel mutation in pagL, which supported lipid A changes. Both LPS and PGN had different potencies when activating host innate immunity via binding TLR4 and Nod1. Significantly higher NF-kB activation, IL-8 expression and production were detected in HEK293hTLR4/MD2-CD14 and HEK293hNod1 after stimulation with LPS and PGN respectively, purified from early P. aeruginosa strain as compared to late strains. Similar results were obtained in macrophages-like cells THP-1, epithelial cells of CF origin IB3-1 and their isogenic cells C38, corrected by insertion of cystic fibrosis transmembrane conductance regulator (CFTR). In murine model, altered LPS structure of P. aeruginosa late strains induces lower leukocyte recruitment in bronchoalveolar lavage and MIP-2, KC and IL-1β cytokine levels in lung homogenates when compared with early strain. Histopathological analysis of lung tissue sections confirmed differences between LPS from early and late P. aeruginosa. Finally, in this study for the first time we unveil how P. aeruginosa has evolved the capacity to evade immune system detection, thus promoting survival and establishing favourable conditions for chronic persistence. Our findings provide relevant information with respect to chronic infections in CF.
Full Text Available.BackgroundSubstantial empirical evidence has demonstrated that individuals who are socially isolated or have few positive social connections seem to age at a faster rate and have more chronic diseases. Oxytocin is a neurohypophyseal hormone hypothesized to coordinate both the causes and effects of positive social interactions, and may be involved in positive physiological adaptations such as buffering the deleterious effects of stress and promoting resilience. The proposed research will examine whether and how oxytocin influences responses to stress in humans and will consider effects in relation to those of social support.Methods/DesignExperimental research will be used to determine whether exogenously administered oxytocin (intranasal) influences psychological and physiological outcomes under conditions of stress across gender and age in adulthood. Hypotheses to be tested are: 1) Oxytocin ameliorates the deleterious neuroendocrine, cardiovascular, and subjective effects of stress; 2) Oxytocin and social support have similar and additive stress-buffering effects; 3) Oxytocin effects are stronger in women versus men; and 4) Oxytocin effects are similar across a range of adult ages. Hypotheses will be tested with a placebo-controlled, double-blind study using a sample of healthy men and women recruited from the community. Participants are randomly assigned to receive either oxytocin or placebo. They undergo a social stress manipulation with and without social support (randomly assigned), and outcome measures are obtained at multiple times during the procedure.DiscussionUnderstanding the determinants of healthy aging is a major public health priority and identifying effective measures to prevent or delay the onset of chronic diseases is an important goal. Experimental research on oxytocin, social relationships, and health in adulthood will contribute to the scientific knowledge base for maximizing active life and health expectancy. At conclusion of the study we will have solid evidence concerning the effects of oxytocin on stress response and whether it has similar effects across age and gender groups. A neurobiological understanding of resilience can inform efforts for both prevention and intervention of diseases or problems common in later life.Trial registrationClinical trial identification number is NCT01011465.
BackgroundSubstantial empirical evidence has demonstrated that individuals who are socially isolated or have few positive social connections seem to age at a faster rate and have...Full Text Available
1977-05-01
Separate abstracts were prepared for individual sections of this publication. In addition to research reports the publication also contains organization charts, author index, and appendixes showing data on selected parameters relative to life-span dose-effect studies with inhaled /sup 239/PuO/sub 2/, /sup 238/PuO/sub 2/, and /sup 239/Pu in beagles. (HLW)
2008-01-01
Full Text Available
Non-allergic rhinitis: a case report and review
Rhinitis is characterized by rhinorrhea, sneezing, nasal congestion, nasal itch and/or postnasal drip. Often the first step in arriving at a diagnosis is to exclude or diagnose sensitivity to inhalant...Full Text Available
Non-allergic rhinitis: a case report and review
Full Text Available.Rhinitis is characterized by rhinorrhea, sneezing, nasal congestion, nasal itch and/or postnasal drip. Often the first step in arriving at a diagnosis is to exclude or diagnose sensitivity to inhalant allergens. Non-allergic rhinitis (NAR) comprises multiple distinct conditions that may even co-exist with allergic rhinitis (AR). They may differ in their presentation and treatment. As well, the pathogenesis of NAR is not clearly elucidated and likely varied. There are many conditions that can have similar presentations to NAR or AR, including nasal polyps, anatomical/mechanical factors, autoimmune diseases, metabolic conditions, genetic conditions and immunodeficiency. Here we present a case of a rare condition initially diagnosed and treated as typical allergic rhinitis vs. vasomotor rhinitis, but found to be something much more serious. This case illustrates the importance of maintaining an appropriate differential diagnosis for a complaint routinely seen as mundane. The case presentation is followed by a review of the potential causes and pathogenesis of NAR.
Full Text Available.BackgroundThe current epidemics of type 2 diabetes mellitus (T2DM), non-alcoholic steatohepatitis (NASH), and Alzheimer's disease (AD) all represent insulin-resistance diseases. Previous studies linked insulin resistance diseases to high fat diets or exposure to streptozotocin, a nitrosamine-related compound that causes T2DM, NASH, and AD-type neurodegeneration. We hypothesize that low-level exposure to nitrosamines that are widely present in processed foods, amplifies the deleterious effects of high fat intake in promoting T2DM, NASH, and neurodegeneration.MethodsLong Evans rat pups were treated with N-nitrosodiethylamine (NDEA) by i.p. Injection, and upon weaning, they were fed with high fat (60%; HFD) or low fat (5%; LFD) chow for 6 weeks. Rats were evaluated for cognitive impairment, insulin resistance, and neurodegeneration using behavioral, biochemical, molecular, and histological methods.ResultsNDEA and HFD ± NDEA caused T2DM, NASH, deficits in spatial learning, and neurodegeneration with hepatic and brain insulin and/or IGF resistance, and reductions in tau and choline acetyltransferase levels in the temporal lobe. In addition, pro-ceramide genes, which promote insulin resistance, were increased in livers and brains of rats exposed to NDEA, HFD, or both. In nearly all assays, the adverse effects of HFD+NDEA were worse than either treatment alone.ConclusionsEnvironmental and food contaminant exposures to low, sub-mutagenic levels of nitrosamines, together with chronic HFD feeding, function synergistically to promote major insulin resistance diseases including T2DM, NASH, and AD-type neurodegeneration. Steps to minimize human exposure to nitrosamines and consumption of high-fat content foods are needed to quell these costly and devastating epidemics.
BackgroundThe current epidemics of type 2 diabetes mellitus (T2DM), non-alcoholic steatohepatitis (NASH), and Alzheimer's disease (AD) all represent insulin-resistance diseases....Full Text Available
New means to monitor the effect of glucocorticoid therapy in children
2010-03-07
Full Text Available.AIM: To study the individual effects of glucocorticoid (GC) therapy on the state of immune activation in patient serum.METHODS: We developed a novel assay in which the effect of corticosteroid-treated patient serum on healthy donor peripheral blood mononuclear cells (target cells) was studied, with a panel of markers for effector [interferon (IFN)γ and interleukin (IL)-5] and regulatory T cells (FOXP3 and glucocorticoid-induced tumor necrosis factor receptor, GITR). The study group comprised 19 children with inflammatory bowel disease. The individual effect of patient serum on target cells was analyzed prior to GC therapy and 2 wk later.RESULTS: The effect of GC therapy mediated by patient serum was seen as a decrease in the target cells expression of regulatory T-cell-related markers GITR (median suppression 24%, range of suppression 1%-63%, in 2 cases increase of 6% and 77%, P < 0.01 for mitogen-activated target cells) and FOXP3 (median suppression 33%, range of suppression 0%-79%, in one case an increase of 173%, P < 0.05 for resting cells), and secretion of IFNγ [from a mean of 87 700 pg/mL (SD 33 900 pg/mL) to 60 900 pg/mL (SD 44 200 pg/mL) in mitogen-activated target cells, 13 of the cases showed a decrease, P < 0.01]. The total or weight-related prednisolone dose did not correlate with the patient-serum-induced changes in the target cell markers.CONCLUSION: GC response could be monitored at an individual level by studying the effect of patient serum on signaling pathways of target immune cells.
New means to monitor the effect of glucocorticoid therapy in children
2010-03-07
AIM: To study the individual effects of glucocorticoid (GC) therapy on the state of immune activation in patient serum.METHODS: We developed a novel assay in which the effect of corticosteroid-treated...Full Text Available
2010-01-01
Saponin fractions of Quillaja saponaria Molina (QS) have cytotoxic activity against cancer cells in vitro, but are too toxic to be useful in the clinic. The toxic effect...Full Text Available
2010-01-01
Full Text Available.Saponin fractions of Quillaja saponaria Molina (QS) have cytotoxic activity against cancer cells in vitro, but are too toxic to be useful in the clinic. The toxic effect was abolished by converting QS fractions into stable nanoparticles through the binding of QS to cholesterol. Two fractions of QS were selected for particle formation, one with an acyl-chain (ASAP) was used to form killing and growth-inhibiting (KGI) particles, and the other without the acyl-chain (DSAP) was used to formulate blocking and balancing effect (BBE) particles. KGI showed significant growth inhibiting and cancer cell-killing activities in nine of 10 cell lines while BBE showed that on one cell line. The monoblastoid lymphoma cell line U937 was selected for analyzing the mode of action. Low concentrations of KGI (0.5 and 2 μg/mL) induced irreversible exit from the cell cycle, differentiation measured by cytokine production, and eventually programmed cell death (apoptosis). Compared to normal human monocytes, the U937 cells were 30-fold more sensitive to KGI. The nontoxic BBE blocked the cell killing effect of KGI in a concentration-dependent manner. In conclusion, the formulation of QS into nanoparticles has the potential of becoming a new class of anticancer agents.
2010-01-01
Full Text Available.Air pollutant exposure has been linked to a rise in wheezing illnesses. Clinical data highlight that exposure to mainstream tobacco smoke (MS) and environmental tobacco smoke (ETS) as well as exposure to diesel exhaust particles (DEP) could promote allergic sensitization or aggravate symptoms of asthma, suggesting a role for these inhaled pollutants in the pathogenesis of asthma. Mouse models are a valuable tool to study the potential effects of these pollutants in the pathogenesis of asthma, with the opportunity to investigate their impact during processes leading to sensitization, acute inflammation and chronic disease. Mice allow us to perform mechanistic studies and to evaluate the importance of specific cell types in asthma pathogenesis. In this review, the major clinical effects of tobacco smoke and diesel exhaust exposure regarding to asthma development and progression are described. Clinical data are compared with findings from murine models of asthma and inhalable pollutant exposure. Moreover, the potential mechanisms by which both pollutants could aggravate asthma are discussed.
2010-01-01
Air pollutant exposure has been linked to a rise in wheezing illnesses. Clinical data highlight that exposure to mainstream tobacco smoke (MS) and environmental tobacco smoke (ETS) as well as exposure...Full Text Available
Microrna let-7: an emerging next-generation cancer therapeutic
2010-02-01
In recent years, various rna-based technologies have been under evaluation as potential next-generation cancer therapeutics. Micrornas (mirnas), known to regulate the cell...Full Text Available
Microrna let-7: an emerging next-generation cancer therapeutic
2010-02-01
Full Text Available.In recent years, various rna-based technologies have been under evaluation as potential next-generation cancer therapeutics. Micrornas (mirnas), known to regulate the cell cycle and development, are deregulated in various cancers. Thus, they might serve as good targets or candidates in an exploration of anticancer therapeutics. One attractive candidate for this purpose is let-7 (“lethal-7”).Let-7 is underexpressed in various cancers, and restoration of its normal expression is found to inhibit cancer growth by targeting various oncogenes and inhibiting key regulators of several mitogenic pathways. In vivo, let-7 administration was found effective against mouse-model lung and breast cancers, and our computational prediction supports the possible effectiveness of let-7 in estrogen receptor (er)–positive metastatic breast cancer. Data also suggest that let-7 regulates apoptosis and cancer stem cell (csc) differentiation and can therefore be tested as a potential therapeutic in cancer treatment. However, the exact role of let-7 in cancer is not yet fully understood. There is a need to understand the causative molecular basis of let-7 alterations in cancer and to develop proper delivery systems before proceeding to therapeutic applications. This article attempts to highlight certain critical aspects of let-7’s therapeutic potential in cancer.
Kinetics of major histocompatibility class I antigen presentation in acute infection
2008-01-01
Abstract Not Provided
Inhalation Toxicology Research Institute annual report, October 1, 1987--September 30, 1988
1988-12-01
The mission of the Inhalation Toxicology Research Institute is to investigate the nature and magnitude of human health effects that result from the inhalation of airborne materials at home, in the work place, or in the general environment. Diseases of the respiratory tract are major causes of suffering and death, and many of these diseases are directly related to the materials that people breathe. The Institute's research is directed toward obtaining a better understanding of the basic biology of the respiratory tract and the mechanisms by which inhaled materials produce respiratory disease. Special attention is focused on studying the airborne materials released by various energy technologies, as well as those associated with national defense activities. The research uses a wide-ranging, comprehensive array of investigative approaches that are directed toward characterizing the source of the airborne material, following the material through its potential transformation in the air, identifying the mechanisms that govern its inhalation and deposition in the respiratory tract, and determining the fate of these inhaled materials in the body and the health effects they produce. The ultimate objectives are to determine the roles played by inhaled materials in the development of disease processes and to estimate the risk they pose to humans who may be exposed to them.
Understanding the requirements for protection against pneumococcal carriage and pneumonia will greatly benefit efforts in controlling these diseases. Several proteins and polysaccharide capsule have...Full Text Available
Full Text Available.Understanding the requirements for protection against pneumococcal carriage and pneumonia will greatly benefit efforts in controlling these diseases. Several proteins and polysaccharide capsule have recently been implicated in the virulence of and protective immunity against Streptococcus pneumonia. Pneumococcal surface protein A (PspA) is highly conserved among S. pneumonia strains, inhibits complement activation, binds lactoferrin, elicits protective systemic immunity against pneumococcal infection, and is necessary for full pneumococcal virulence. Identification of PspA peptides that optimally bind human leukocyte antigen (HLA) would greatly contribute to global vaccine efforts, but this is hindered by the multitude of HLA polymorphisms. Here, we have used an experimental data set of 54 PspA peptides and in silico methods to predict peptide binding to HLA and murine major histocompatibility complex (MHC) class II. We also characterized spleen- and cervical lymph node (CLN)-derived helper T lymphocyte (HTL) cytokine responses to these peptides after S. pneumonia strain EF3030-challenge in mice. Individual, yet overlapping peptides, 15 amino acids in length revealed residues 199 to 246 of PspA (PspA199–246) consistently caused the greatest IFN-γ, IL-2, IL-5 and proliferation as well as moderate IL-10 and IL-4 responses by ex vivo stimulated splenic and CLN CD4+ T cells isolated from S. pneumonia strain EF3030-challeged F1 (B6×BALB/c) mice. IEDB, RANKPEP, SVMHC, MHCPred, and SYFPEITHI in silico analysis tools revealed peptides in PspA199–246 also interact with a broad range of HLA-DR, -DQ, and -DP allelles. These data suggest that predicted MHC class II-peptide binding affinities do not always correlate with T helper (Th) cytokine or proliferative responses to PspA peptides, but when used together with in vivo validation can be a useful tool to choose candidate pneumococcal HTL epitopes.
FcγRIIb Inhibits Allergic Lung Inflammation in a Murine Model of Allergic Asthma
Full Text Available.Allergic asthma is characterized by airway eosinophilia, increased mucin production and allergen-specific IgE. Fc gamma receptor IIb (FcγRIIb), an inhibitory IgG receptor, has recently emerged as a negative regulator of allergic diseases like anaphylaxis and allergic rhinitis. However, no studies to date have evaluated its role in allergic asthma. Our main objective was to study the role of FcγRIIb in allergic lung inflammation. We used a murine model of allergic airway inflammation. Inflammation was quantified by BAL inflammatory cells and airway mucin production. FcγRIIb expression was measured by qPCR and flow cytometry and the cytokines were quantified by ELISA. Compared to wild type animals, FcγRIIb deficient mice mount a vigorous allergic lung inflammation characterized by increased bronchoalveolar lavage fluid cellularity, eosinophilia and mucin content upon ragweed extract (RWE) challenge. RWE challenge in sensitized mice upregulated FcγRIIb in the lungs. Disruption of IFN-γ gene abrogated this upregulation. Treatment of naïve mice with the Th1-inducing agent CpG DNA increased FcγRIIb expression in the lungs. Furthermore, treatment of sensitized mice with CpG DNA prior to RWE challenge induced greater upregulation of FcγRIIb than RWE challenge alone. These observations indicated that RWE challenge upregulated FcγRIIb in the lungs by IFN-γ- and Th1-dependent mechanisms. RWE challenge upregulated FcγRIIb on pulmonary CD14+/MHC II+ mononuclear cells and CD11c+ cells. FcγRIIb deficient mice also exhibited an exaggerated RWE-specific IgE response upon sensitization when compared to wild type mice. We propose that FcγRIIb physiologically regulates allergic airway inflammation by two mechanisms: 1) allergen challenge mediates upregulation of FcγRIIb on pulmonary CD14+/MHC II+ mononuclear cells and CD11c+ cells by an IFN-γ dependent mechanism; and 2) by attenuating the allergen specific IgE response during sensitization. Thus, stimulating FcγRIIb may be a therapeutic strategy in allergic airway disorders.
FcγRIIb Inhibits Allergic Lung Inflammation in a Murine Model of Allergic Asthma
Allergic asthma is characterized by airway eosinophilia, increased mucin production and allergen-specific IgE. Fc gamma receptor IIb (FcγRIIb), an inhibitory IgG receptor, has recently emerged...Full Text Available
2010-02-01
Full Text Available.BackgroundHypersensitivity pneumonitis (HP) is an interstitial lung disease that develops following repeated exposure to inhaled particulate antigens. The family of Fcγ receptors (FcγRs) has emerged as central regulators for modulating both pro-and anti-inflammatory responses. However, the role of FcγRs in the development of HP has not been investigated yet.MethodsTo explore the functional roles of FcγRs in HP, FcγR-/- and B6 mice were challenged with Saccharopolyspora rectivirgula (SR) antigen intranasally, and compared these mice in terms of the histological change, infiltrated immune cells in BALF and in vitro immune responses.ResultsFcγR-/- mice exhibited attenuation of HP in terms of histological alterations, and reduced numbers of neutrophils and macrophages in and the increased CD4:CD8 ratio of bronchoalveolar lavage fluid. The lungs of FcγR-/- mice showed high production of Th2 cytokine such as IL-4 and slightly low production of Th1 cytokine, INF-γ compared to those of B6 mice. However, SR-specific adaptive immune responses of FcγR-/- mice were similar to those of B6 mice.ConclusionThese results demonstrate that activating Fcγ receptors play an important role in activating neutrophils and macrophages in pulmonary inflammation and inducing Th1 differentiation by regulating cytokine expression in SR-induced HP.
2010-02-01
BackgroundHypersensitivity pneumonitis (HP) is an interstitial lung disease that develops following repeated exposure to inhaled particulate antigens. The family of Fcγ receptors...Full Text Available
Expression and Function of Macrophage Migration Inhibitory Factor (MIF) in Melioidosis
Full Text Available.BackgroundMacrophage migration inhibitory factor (MIF) has emerged as a pivotal mediator of innate immunity and has been shown to be an important effector molecule in severe sepsis. Melioidosis, caused by Burkholderia pseudomallei, is an important cause of community-acquired sepsis in Southeast-Asia. We aimed to characterize the expression and function of MIF in melioidosis.Methodology and Principal FindingsMIF expression was determined in leukocytes and plasma from 34 melioidosis patients and 32 controls, and in mice infected with B. pseudomallei. MIF function was investigated in experimental murine melioidosis using anti-MIF antibodies and recombinant MIF. Patients demonstrated markedly increased MIF mRNA leukocyte and MIF plasma concentrations. Elevated MIF concentrations were associated with mortality. Mice inoculated intranasally with B. pseudomallei displayed a robust increase in pulmonary and systemic MIF expression. Anti-MIF treated mice showed lower bacterial loads in their lungs upon infection with a low inoculum. Conversely, mice treated with recombinant MIF displayed a modestly impaired clearance of B. pseudomallei. MIF exerted no direct effects on bacterial outgrowth or phagocytosis of B. pseudomallei.ConclusionsMIF concentrations are markedly elevated during clinical melioidosis and correlate with patients' outcomes. In experimental melioidosis MIF impaired antibacterial defense.
Expression and Function of Macrophage Migration Inhibitory Factor (MIF) in Melioidosis
BackgroundMacrophage migration inhibitory factor (MIF) has emerged as a pivotal mediator of innate immunity and has been shown to be an important effector molecule in severe sepsis....Full Text Available
The current pandemic (H1N1) 2009 virus remains transmissible among humans worldwide with cases of reverse zoonosis, providing opportunities to produce more pathogenic variants which could pose greater...Full Text Available
Environmental Sciences Division annual progress report for period ending September 30, 1983
1984-04-01
This annual report summarizes activities in the Aquatic Ecology, Earth Sciences, Environmental Analyses, and Terrestrial Ecology sections, as well as in the Fossil Energy, Biomass, Low-Level Waste Research and Management, and Global Carbon Cycle Programs. Separate abstracts have been prepared for each section. (ACR)
Efficacy of the New Neuraminidase Inhibitor CS-8958 against H5N1 Influenza Viruses
2010-02-01
Currently, two neuraminidase (NA) inhibitors, oseltamivir and zanamivir, which must be administrated twice daily for 5 days for maximum therapeutic effect, are licensed for the treatment of influenza....Full Text Available
Fungi in the genus Pneumocystis cause pneumonia (PCP) in hosts with debilitated immune systems and are emerging as co-morbidity factors associated with chronic diseases such as COPD....Full Text Available
Full Text Available.Fungi in the genus Pneumocystis cause pneumonia (PCP) in hosts with debilitated immune systems and are emerging as co-morbidity factors associated with chronic diseases such as COPD. Limited therapeutic choices and poor understanding of the life cycle are a result of the inability of these fungi to grow outside the mammalian lung. Within the alveolar lumen, Pneumocystis spp., appear to have a bi-phasic life cycle consisting of an asexual phase characterized by binary fission of trophic forms and a sexual cycle resulting in formation of cysts, but the life cycle stage that transmits the infection is not known. The cysts, but not the trophic forms, express β -1,3-D-glucan synthetase and contain abundant β -1,3-D-glucan. Here we show that therapeutic and prophylactic treatment of PCP with echinocandins, compounds which inhibit the synthesis of β -1,3-D-glucan, depleted cysts in rodent models of PCP, while sparing the trophic forms which remained in significant numbers. Survival was enhanced in the echincandin treated mice, likely due to the decreased β -1,3-D-glucan content in the lungs of treated mice and rats which coincided with reductions of cyst numbers, and dramatic remodeling of organism morphology. Strong evidence for the cyst as the agent of transmission was provided by the failure of anidulafungin-treated mice to transmit the infection. We show for the first time that withdrawal of anidulafungin treatment with continued immunosuppression permitted the repopulation of cyst forms. Treatment of PCP with an echinocandin alone will not likely result in eradication of infection and cessation of echinocandin treatment while the patient remains immunosuppressed could result in relapse. Importantly, the echinocandins provide novel and powerful chemical tools to probe the still poorly understood bi-phasic life cycle of this genus of fungal pathogens.
2004-07-02
Administration of {sup 14}C-Moli1901 (duramycin, 2622U90), a 19 amino acid polycyclic peptide by intratracheal instillation (approximately 100 {micro}g) into the left cranial lobe of the lung of beagle dogs resulted in retention of 64% of the dose in the left cranial lobe for up to 28 days. In this study, we used accelerator mass spectrometry (AMS) to quantify Moli901 following administration of only 0.045 {micro}Ci of {sup 14}C-Moli901 per dog. Limits of quantitation of AMS were 0.03 (urine) to 0.3 (feces) ng equiv. Moli1901/g. Whole blood and plasma concentrations of {sup 14}C were <5ng/ml at all times after the dose. Concentrations of {sup 14}C in whole blood and plasma declined over the first day after the dose and rose thereafter, with the rise in plasma concentrations lagging behind those in whole blood. During the first 3 days after the dose, plasma accounted for the majority of {sup 14}C in whole blood, but after that time, plasma accounted for only 25-30% of the {sup 14}C in whole blood. Tissue (left and right caudal lung lobe, liver, kidney, spleen, brain) and bile concentrations were low, always less than 0.25% the concentrations found in the left cranial lung lobe. Approximately 13% of the dose was eliminated in urine and feces in 28 days, with fecal elimination accounting for about 10% of the dose. The data presented here are consistent with that obtained in other species. Moli1901 is slowly absorbed and excreted from the lung, and it does not accumulate in other tissues. Moli1901 is currently in the clinic and has proven to be safe in single dose studies in human volunteers and cystic fibrosis patients by the inhalation route. No information on the disposition of the compound in humans is available. This study in dogs demonstrates the feasibility of obtaining that information using {sup 14}C-Moli1901 and AMS.
Deletion of a coordinate regulator of type 2 cytokine expression in mice
2001-07-30
Mechanisms underlying the differentiation of stable T helper subsets will be important in understanding how discrete types of immunity develop in response to different pathogens. An evolutionarily conserved {approx}400 base pair non-coding sequence in the IL-4/IL-13 intergenic region, designated CNS-1, was deleted in mice. The capacity to develop Th2 cells was compromised in vitro and in vivo in the absence of CNS-1. Despite the profound effect in T cells, mast cells from CNS-1-deleted mice maintained their capacity to produce IL-4. A T cell-specific element critical for optimal expression of type 2 cytokines may represent evolution of a regulatory sequence exploited by adaptive immunity.
Cellular adaptive immune response against porcine circovirus type 2 in subclinically infected pigs
Full Text Available.BackgroundPorcine circovirus type 2 (PCV2) is a dominant causative agent of postweaning multisystemic wasting syndrome (PMWS), a multifactorial disease complex with putative immunosuppressive characteristics. Little is known about adaptive PCV2-specific immune responses in infected pigs. Therefore, the T and B cell responses following PCV2 infection in 3-week old SPF piglets infected with PCV2 or PCV2 plus porcine parvovirus (PPV) were studied.ResultsAll animals were asymptomatically infected. At 7 days post infection (d p.i.), B lymphocyte and T lymphocyte numbers decreased in the dual infected, but not in the single infected piglets. At this time point a transient PCV2 viraemia was noted in the PCV2 infected groups. Antibodies against the infecting virus were detectable at day 24-28 p.i. for anti-PCV2 antibodies and at day 10 p.i. for anti-PPV antibodies, with no apparent influence of PCV2 on the early PPV antibody development. In the animals infected with PPV alone, IFN-γ secreting cells (SC) that were not specific for PCV2 were detected by ELISPOT assay at day 7 p.i. Interestingly, this response was absent in the PCV2/PPV dual infected animals. PCV2-specific IFN-γ SC were observed in the PCV2/PPV infected group at 7 d p.i. and in the PCV2 single infected group at 21 d p.i. A reduction in the numbers of IFN-γ SC was observed following anti-CD4 and anti-CD8 antibody treatment, suggesting roles for both CD4+ and CD8+ T cells in the response against PCV2 infection. This was supported by an observed increase in the percentage of IFN-γ positive CD8hi cytotoxic T cells as well as IFN-γ positive CD8-/low helper T cells after PCV2 in vitro re-stimulation.ConclusionsInfection of weaned SPF piglets with PCV2 alone or combined with PPV does not induce disease and in both cases a relatively slow anti-PCV2 antibody response and weak T lymphocyte responses were found. Knowledge on such immunological characteristics is important for both PCV2 pathogenesis and vaccination.
Cellular adaptive immune response against porcine circovirus type 2 in subclinically infected pigs
BackgroundPorcine circovirus type 2 (PCV2) is a dominant causative agent of postweaning multisystemic wasting syndrome (PMWS), a multifactorial disease complex with putative immunosuppressive...Full Text Available
Biosecurity reference : CFR-listed agent and toxin summaries.
2003-09-01
This reference document provides summary information on the animal, plant, zoonotic, and human pathogens and toxins regulated and categorized by 9 CFR 331 and 7 CFR 121, 'Agricultural Bioterrorism Protection Act of 2002; Possession, Use and Transfer of Biological Agents and Toxins,' and 42 CFR 73, 'Possession, Use, and Transfer of Select Agents and Toxins.' Summary information includes, at a minimum, a description of the agent and its associated symptoms; often additional information is provided on the diagnosis, treatment, geographic distribution, transmission, control and eradication, and impacts on public health.
Bioremediation of petroleum hydrocarbo-contaminated soils, comprehensive report, December 1999
2000-04-01
The US Department of Energy and the Institute for Ecology of Industrial Areas (IETU), Katowice, Poland have been cooperating in the development and implementation of innovative environmental remediation technologies since 1995. A major focus of this program has been the demonstration of bioremediation techniques to cleanup the soil and sediment associated with a waste lagoon at the Czechowice Oil Refinery (CZOR) in southern Poland. After an expedited site characterization (ESC), treatability study, and risk assessment study, a remediation system was designed that took advantage of local materials to minimize cost and maximize treatment efficiency. U.S. experts worked in tandem with counterparts from the IETU and CZOR throughout this project to characterize, assess and subsequently, design, implement and monitor a bioremediation system. The CZOR, our industrial partner for this project, was chosen because of their foresight and commitment to the use of new approaches for environmental restoration. This program sets a precedent for Poland in which a portion of the funds necessary to complete the project were provided by the company responsible for the problem. The CZOR was named by PIOS (State Environmental Protection Inspectorate of Poland) as one of the top 80 biggest polluters in Poland. The history of the CZOR dates back more than 100 years to its establishment by the Vacuum Oil Company (a U.S. company and forerunner of Standard Oil). More than a century of continuous use of a sulfuric acid-based oil refining method by the CZOR has produced an estimated 120,000 tons of acidic, highly weathered, petroleum sludge. This waste has been deposited into three open, unlined process waste lagoons, 3 meters deep, now covering 3.8 hectares. Initial analysis indicated that the sludge was composed mainly of high molecular weight paraffinic and polynuclear aromatic hydrocarbons (PAHs). The overall objective of this full-scale demonstration project was to characterize, assess and remediate one of these lagoons. The remediation tested and evaluated a combination of U.S. and Polish-developed biological remediation technologies. Specifically, the goal of the demonstration was to reduce the environmental risk from PAH compounds in soil and to provide a green zone (grassy area) adjacent to the site boundary. The site was characterized using the DOE-developed Expedited Site Characterization (ESC) methodology. Based on the results of the ESC, a risk assessment was conducted using established U.S. procedures. Based on the results of the ESC and risk assessment, a 0.3-hectare site, the smallest of the waste lagoons, was selected for a modified aerobic biopile demonstration. This Executive Summary and the supporting report and appendices document the activities and results of this cooperative venture.
Bioremediation of Petroleum Hydrocarbon-Contaminated Soils, Comprehensive Report
2001-01-12
The US Department of Energy and the Institute for Ecology of Industrial Areas, Katowice, Poland have been cooperating in the development and implementation of innovative environmental remediation technologies since 1995. U.S. experts worked in tandem with counterparts from the IETU and CZOR throughout this project to characterize, assess and subsequently, design, implement and monitor a bioremediation system.
2010-05-01
In this study, specific sequences within three genes (3D, VP4 and 2B) of the foot-and-mouth disease virus (FMDV) genome were determined to be effective RNAi targets. These sequences are highly conserved...Full Text Available
2010-05-01
Full Text Available.In this study, specific sequences within three genes (3D, VP4 and 2B) of the foot-and-mouth disease virus (FMDV) genome were determined to be effective RNAi targets. These sequences are highly conserved among different serotype viruses based on sequence analysis. Small interfering RNA (siRNA)-expressing plasmids (p3D-NT19, p3D-NT56, pVP4-NT19, pVP4-NT65 and p2B-NT25) were constructed to express siRNA targeting 3D, VP4 and 2B, respectively. The antiviral potential of these siRNA for various FMDV isolates was investigated in baby hamster kidney (BHK-21) cells and suckling mice. The results show that these siRNA inhibited virus yield 10- to 300-fold for different FMDV isolates of serotype O and serotype Asia I at 48 h post infection in BHK-21 cells compared to control cells. In suckling mice, p3D-NT56 and p2B-NT25 delayed the death of mice. Twenty percent to 40% of the animals that received a single siRNA dose survived 5 days post infection with serotype O or serotype Asia I. We used an attenuated Salmonella choleraesuis (C500) vaccine strain, to carry the plasmid that expresses siRNA directed against the polymerase gene 3D (p3D-NT56) of FMDV. We used guinea pigs to evaluate the inhibitory effects of recombinant S. cho (p3D-NT56/S. cho) on FMDV infection. The results show that 80% of guinea pigs inoculated with 109 CFU of p3D-NT56/S. cho and challenged 36 h later with 50 ID50 of homologous FMDV were protected. We also measured the antiviral activity of p3D-NT56/S. cho in swine. The results indicate that 100% of the animals treated with 5 × 109 CFU of p3D-NT56/S. cho were protected in 9 days.
Annual report of National Institute of Radiological Science, April 1995 - March 1996
1997-03-01
This annual report presents a brief summary of the research activities and the achievements in the Institute for fiscal year 1995 (from April 1995 to March 1996). The clinical trial of cancer therapy using heavy ion beams is making progress with successful results. Various kinds of basic researches using the same heavy ion beams are also growing up gradually in an open use system available to many researchers not only inside but also outside the Institute. Studies of newly assembled research groups are also going to appear. The Institute is covering a very wide area of comprehensive radiological sciences including physics, chemistry, biomedical sciences, clinical research and environmental science. The recent publications, list of keywords, author index, and organization and staff are included in this report. (M.N.)
2003-10-15
Air pollution is a public health problem, in spite of more severe norms in matter of emissions rates, a stricter surveillance of the atmospheric pollution and the decrease of levels of some atmospheric pollutants. this situation has lead to the creation of a programme A.p.h.e.i.s. in 1999, in order to supply to Europeans authorities information on air pollution. In the report are presented the results of E.I.S. (evaluation of sanitary impact) made in towns.
Intranasal delivery to the central nervous system: Mechanisms and experimental considerations
2010-01-01
The blood-brain barrier (BBB) limits the distribution of systemically administered therapeutics to the central nervous system (CNS), posing a significant challenge to drug development efforts to treat neurological and psychiatric diseases and disorders. Intranasal delivery is a noninvasive and convenient method that rapidly targets therapeutics to the CNS, bypassing the BBB and minimizing systemic exposure. This review focuses on the current understanding of the mechanisms underlying intranasal delivery to the CNS, with a discussion of pathways from the nasal cavity to the CNS involving the olfactory and trigeminal nerves, the vasculature, the cerebrospinal fluid, and the lymphatic system. In addition to the properties of the therapeutic, deposition of the drug formulation within the nasal...
2010-01-01
Background Pain sensitizes the central nervous system via N-methyl-D-aspartate receptors (NMDARs) leading to an enhancement of pain perception. However, the enhanced responsiveness of pain-processing areas can be suppressed by subanaesthetic doses of the NMDAR antagonist xenon. To analyse the strength of the analgesic effect of low-dose xenon using new economical application methods, we tested xenon applied nasally in an experimental human pain setting. Methods We tested 10 healthy volunteers using a multimodal experimental pain testing in a randomized double-blind placebo-controlled repeated measures study. Xenon was administered using a novel low-pressure intranasal application device. Additionally, we measured xenon concentrations in blood samples obtained from intracranial veins of exp...
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