Pharmacokinetic Modeling of Non-Linear Brain Distribution of Fluvoxamine in the Rat

Introduction. A pharmacokinetic (PK) model is proposed for estimation of total and free brain concentrations of fluvoxamine. Materials and methods. Rats with arterial and venous cannulas and a microdialysis probe in the frontal cortex received intravenous infusions of 1, 3.7 or 7.3 mg.kg j1 of fluvoxamine. Analysis. With increasing dose a disproportional increase in brain concentrations was observed. Th

Fighting Misconceptions to Improve Compliance with Influenza Vaccination among Health Care Workers: An Educational Project

The compliance with influenza vaccination is poor among health care workers (HCWs) due to misconceptions about safety and effectiveness of influenza vaccine. We proposed an educational prospective study to demonstrate to HCWs that influenza vaccine is safe and that other respiratory viruses (RV) are the cause of respiratory symptoms in the months following influenza vaccination. 398 HCWs were surveyed for adverse events (AE) occurring within 48 h of vaccination. AE were reported by 30% of the HCWs. No severe AE was observed. A subset of 337 HCWs was followed up during four months, twice a week, for the detection of respiratory symptoms. RV was diagnosed by direct immunofluorescent assay (DFA) and real time PCR in symptomatic HCWs. Influenza A was detected in five episodes of respiratory symptoms (5.3%) and other RV in 26 (27.9%) episodes. The incidence density of influenza and other RV was 4.3 and 10.8 episodes per 100 HCW-month, respectively. The educational nature of the present study may persuade HCWs to develop a more positive attitude to influenza vaccination

Within-Subject Variability of Interferon-g Assay Results for Tuberculosis and Boosting Effect of Tuberculin Skin Testing: A Systematic Review

Background: Variability in interferon-gamma release assays (IGRAs) results for tuberculosis has implications for interpretation of results close to the cut-point, and for defining thresholds for test conversion and reversion. However, little is known about the within-subject variability (reproducibility) of IGRAs. Several national guidelines recommend a twostep testing procedure (tuberculin skin test [TST] followed by IGRA) for the diagnosis of LTBI. However, the effect of a preceding TST on subsequent IGRA results has been reported in studies with apparently conflicting results. Methodology/Findings: We conducted a systematic review to synthesize evidence on within-subject variability of IGRA results and the potential boosting effect of TST. We searched several databases and reviewed citations of previous reviews on IGRAs. We included studies using commercial IGRAs, in addition to non-commercial versions of the ELISPOT assay. Four studies, fulfilling our predefined criteria, examined within-subject variability and 13 studies evaluated TST effects on subsequent IGRA responses. Meta-analysis was not considered appropriate because of heterogeneity in study methods, assays, and populations. Although based on limited data, within-subject variability was present in all studies but the magnitude varied (16-80%) across studies. A TST induced ‘‘boosting’ ’ of IGRA responses was demonstrated in several studies and although more pronounced in IGRA-positive (i.e. sensitized) individuals, also occurred in a smaller but not insignificant proportion of IGRA-negative subjects. The TST appeared to affect IGRA responses only after 3 days and may apparentl

Comparison of two interferon gamma release assays in the diagnosis of Mycobacterium tuberculosis infection and disease in The Gambia

<p>Abstract</p> <p>Background</p> <p>IFN-γ Release Assays (IGRAs) have been licensed for the diagnosis of latent <it>Mycobacterium tuberculosis </it>infection (LTBI). Their performance may depend on assay format and may vary across populations and settings. We compared the diagnostic performance of an in-house T -cell and commercial whole blood-based IGRAs for the diagnosis of LTBI and TB disease in The Gambia.</p> <p>Methods</p> <p>Newly diagnosed sputum smear positive cases and their household contacts were recruited. Cases and contacts were bled for IGRA and contacts had a Mantoux skin test. We assessed agreement and discordance between the tests and categorized a contact's level of <it>M. tuberculosis </it>exposure according to where s/he slept relative to a case: the same room, same house or a different house. We assessed the relationship between exposure and test results by multiple logistic regression.</p> <p>Results</p> <p>In 80 newly diagnosed TB cases, the sensitivity of ELISPOT was 78.7% and for QFT-GIT was 64.0% (p = 0.047). Of 194 household contacts 57.1% and 58.8% were positive for ELISPOT and QFT-GIT respectively. The overall agreement between both IGRAs for LTBI in contacts was 71.4% and there was no significant discordance (p = 0.29). There was significant discordance between the IGRAs and TST. Neither IGRA nor TST had evidence of false positive results because of Bacille Calmette Guérin (BCG) vaccination. However, agreement between QFT-GIT and TST as well as discordance between both IGRAs and TST were associated with BCG vaccination. Both IGRAs responded to the <it>M. tuberculosis </it>exposure gradient and were positively associated with increasing TST induration (p = 0.003 for ELISPOT and p = 0.001 for QFT-GIT).</p> <p>Conclusion</p> <p>The ELISPOT test is more sensitive than the QFT-GIT for diagnosing TB disease. The two tests perform similarly in the diagnosis of LTBI in TB contacts. Significant discordance between the two IGRAs and between each and the TST remain largely unexplained.</p

Computational Prediction and Molecular Characterization of an Oomycete Effector and the Cognate Arabidopsis Resistance Gene

Hyaloperonospora arabidopsidis (Hpa) is an obligate biotroph oomycete pathogen of the model plant Arabidopsis thaliana and contains a large set of effector proteins that are translocated to the host to exert virulence functions or trigger immune responses. These effectors are characterized by conserved amino-terminal translocation sequences and highly divergent carboxyl-terminal functional domains. The availability of the Hpa genome sequence allowed the computational prediction of effectors and the development of effector delivery systems enabled validation of the predicted effectors in Arabidopsis. In this study, we identified a novel effector ATR39-1 by computational methods, which was found to trigger a resistance response in the Arabidopsis ecotype Weiningen (Wei-0). The allelic variant of this effector, ATR39-2, is not recognized, and two amino acid residues were identified and shown to be critical for this loss of recognition. The resistance protein responsible for recognition of the ATR39-1 effector in Arabidopsis is RPP39 and was identified by map-based cloning. RPP39 is a member of the CC-NBS-LRR family of resistance proteins and requires the signaling gene NDR1 for full activity. Recognition of ATR39-1 in Wei-0 does not inhibit growth of Hpa strains expressing the effector, suggesting complex mechanisms of pathogen evasion of recognition, and is similar to what has been shown in several other cases of plant-oomycete interactions. Identification of this resistance gene/effector pair adds to our knowledge of plant resistance mechanisms and provides the basis for further functional analyses

Uloga testova otpuštanja interferona gama u nadzoru nad tuberkulozom

Tuberculosis is still one of the major global public health threats. Countries with low incidence must focus on exhausting the reservoir of future cases by preventing reactivation. Therefore, it is important to identify and effectively treat those individuals who have latent tuberculosis infection and who may develop active disease. The tuberculin skin test has been the standard for detection of immune response against M. tuberculosis since the beginning of the 20th century. The new millennium has brought advancement in the diagnosis of latent tuberculosis infection. The name of the new blood test is interferon-gamma release assay (IGRA). Croatia is a middle-incidence country with a long decreasing trend and developed tuberculosis control. To reach low incidence and finally eliminate tuberculosis, its tuberculosis programme needs a more aggressive approach that would include intensive contact investigation and treatment of persons with latent tuberculosis infection. This article discusses the current uses of IGRA and its role in tuberculosis control.Tuberkuloza je i danas jedan od vodećih javnozdravstvenih problema. Zemlje s niskom incidencijom fokusiraju se na iscrpljivanje rezervoara budućih slučajeva sprječavanjem reaktivacije bolesti. To se odnosi na traženje i učinkovito liječenje infi ciranih osoba, primarno onih koje su u riziku od obolijevanja nakon infekcije. Tuberkulinski test je od početka 20. stoljeća bio standard u otkrivanju imunosnog odgovora na kontakt s Mycobacterium tuberculosis. Novo tisućljeće donijelo je određeni napredak u obliku novih testova za dijagnozu latentne tuberkulozne infekcije, krvne testove otpuštanja interferona gama. Hrvatska je zemlja srednje incidencije tuberkuloze s dugogodišnjim silaznim trendom i razvijenim protutuberkuloznim aktivnostima. U težnji prema niskoj incidenciji i u konačnici eliminaciji tuberkuloze potrebne su opsežnije aktivnosti unutar državnog programa nadzora nad tuberkulozom, uključujući intenzivnu obradu kontakata i probir na postojanje latentne tuberkulozne infekcije. Ovaj rad razmatra trenutačnu uporabu IGRE (engl. interferon - gamma release assay) i njezinu ulogu u nadzoru nad tuberkulozom

Meta-Analysis of the Immunogenicity and Tolerability of Pandemic Influenza A 2009 (H1N1) Vaccines

Background: Although the 2009 (H1N1) influenza pandemic officially ended in August 2010, the virus will probably circulate in future years. Several types of H1N1 vaccines have been tested including various dosages and adjuvants, and meta-analysis is needed to identify the best formulation. Methods: We searched MEDLINE, EMBASE, and nine clinical trial registries to April 2011, in any language for randomized clinical trials (RCTs) on healthy children, adolescents, adults and the elderly. Primary outcome was the seroconversion rate according to hemagglutinination-inhibition (HI); secondary outcomes were adverse events. For the primary outcome, we used head-to-head meta-analysis and multiple-treatments meta-analysis. Results: Eighteen RCTs could be included in all primary analyses, for a total of 76 arms (16,725 subjects). After 2 doses, all 2009 H1N1 split/subunit inactivated vaccines were highly immunogenic and overcome CPMP seroconversion criteria. After 1 dose only, all split/subunit vaccines induced a satisfactory immunogenicity (> = 70%) in adults and adolescents, while only some formulations showed acceptable results for children and elderly (non-adjuvanted at high-doses and oil-in-water adjuvanted vaccines). Vaccines with oil-in-water adjuvants were more immunogenic than both nonadjuvanted and aluminum-adjuvanted vaccines at equal doses and their immunogenicity at doses < = 6 μg (even with as little as 1.875 μg of hemagglutinin antigen) was not significantly lower than that achieved after higher doses. Finally, the rate of serious vaccine-related adverse events was low for all 2009 H1N1 vaccines (3 cases, resolved in 10 days, out of 22826 vaccinated subjects). However, mild to moderate adverse reactions were more (and very) frequent for oil-in-water adjuvanted vaccines. Conclusions: Several one-dose formulations might be valid for future vaccines, but 2 doses may be needed for children, especially if a low-dose non-adjuvanted vaccine is used. Given that 15 RCTs were sponsored by vaccine manufacturers, future trials sponsored by non-industry agencies and comparing vaccines using different types of adjuvants are needed