Cellular immune responses to diluted and undiluted aventis pasteur smallpox vaccine

BACKGROUND: Recent primary vaccine trials of diluted Aventis Pasteur smallpox vaccine (APSV) demonstrated that immunization "take" rates, defined by the presence of a vesicle or pustule ("take") at the inoculation site 6-11 days after immunization, did not differ between the dilution groups. To our knowledge, there have been no studies that examine the cellular immune response or that distinguish CD4(+) T cell responses from CD8(+) T cell responses after primary immunization with varying dilutions of APSV. METHODS: In the present study, we examined the cellular immune response in vaccinia-naive healthy adults (n=91) receiving inoculations with an undiluted or diluted (1:5 and 1:10) suspension of the APSV, using an intracellular cytokine staining assay. RESULTS: The diluted vaccine induced vaccinia virus (VV)-specific CD4(+) and CD8(+) T cell responses 1 month after primary immunization that were comparable to those induced by undiluted vaccine. The cellular immune responses were correlated with the reactogenicity profile of subjects and did not differ between dilution groups. Furthermore, expression of the interleukin-7 receptor alpha chain, which has been proposed to distinguish antigen-specific T cells that differentiate into long-lived memory T cells, did not differ among groups, suggesting that dilution of the vaccine does not affect the quantity of VV-specific memory T cells. CONCLUSIONS: APSV is an effective smallpox vaccine inducing strong humoral and cellular immune responses after a primary immunization even at diluted doses.     

Cognitive function in normal-weight, overweight, and obese older adults: an analysis of the Advanced Cognitive Training for Independent and Vital Elderly cohort

OBJECTIVES: To assess how elevated body mass index (BMI) affects cognitive function in elderly people. DESIGN: Cross-sectional study. SETTING: Data for this cross-sectional study were taken from a multicenter randomized controlled trial, the Advanced Cognitive Training for Independent and Vital Elderly trial. PARTICIPANTS: The analytic sample included 2,684 normal-weight, overweight, or obese subjects aged 65 to 94. MEASUREMENTS: Evaluation of cognitive abilities was performed in several domains: global cognition, memory, reasoning, and speed of processing. Cross-sectional association between body weight status and cognitive functions was analyzed using multiple linear regression. RESULTS: Overweight subjects had better performance on a reasoning task (beta=0.23, standard error (SE)=0.11, P=.04) and the Useful Field of View (UFOV) measure (beta=-39.46, SE=12.95, P=.002), a test of visuospatial speed of processing, after controlling for age, sex, race, years of education, intervention group, study site, and cardiovascular risk factors. Subjects with class I (BMI 30.0-34.9 kg/m2) and class II (BMI>35.0 kg/m2) obesity had better UFOV measure scores (beta=-38.98, SE=14.77, P=.008; beta=-35.75, SE=17.65, and P=.04, respectively) in the multivariate model than normal-weight subjects. The relationships between BMI and individual cognitive domains were nonlinear. CONCLUSION: Overweight participants had better cognitive performance in terms of reasoning and visuospatial speed of processing than normal-weight participants. Obesity was associated with better performance in visuospatial speed of processing than normal weight. The relationship between BMI and cognitive function should be studied prospectively.     

Impaired corticomuscular and interhemispheric cortical beta oscillation coupling in amyotrophic lateral sclerosis

Objectives

The neural activity of the primary motor cortex is variably synchronised with contralateral peripheral electromyographic signals, which is thought to facilitate long-range communication through the motor system. Such corticomuscular coherence (CMC) is typically observed in the beta-band (15–30?Hz) range during steady force production. We aimed to measure pathological alteration to CMC resulting from ALS.

Outbreaks of human coronavirus in a paediatric and neonatal intensive care unit

Human coronavirus 229E (HCoV) has been recently recognized as a potential agent of nosocomial viral respiratory infections (NRVI) in high-risk infants. We have confirmed this as fact through the study of a 1-year period of HCoV outbreaks occurring during a prospective survey of NRVI in a paediatric and neonatal intensive care unit (PNICU) using new molecular techniques for HCoV detection. Nasal samples obtained at admission and weekly thereafter for all hospitalised children, as well as monthly nasal samples from staff, were analysed using immunofluorescence for respiratory syncitial virus (RSV), influenza viruses A and B, paramyxoviruses 1, 2, 3 and adenoviruses. RT-PCR was used for HCoV detection. During the year 1998, 43 HCoV-related NRVI were detected in 152 neonates (incidence 28.3%), and 7 HCoV-related NRVI were found in 92 children (incidence 7.6%). Three HCoV-related outbreaks were observed (February, August and December), associated with a high prevalence of HCoV infection in the staff. During the August outbreak, 50% to 78% of hospitalised neonates and children were infected. Seventy-five percent of hospitalised preterm neonates with a gestational age less than 32 weeks and 52.4% of staff members were infected. Risk factors for NRVI in neonates were birth weight, gestational age, ventilation, oxygenation and hospitalisation length. Ninety-two percent of infected preterm neonates were symptomatic, mainly with bradycardia and respiratory worsening. These data provide additional evidence for a possibly significant role of HCoV in NRVI in a PNICU. The role of staff or hospitalised children in spreading HCoV is hypothesised.     

Recurrent multistate outbreak of Salmonella Newport associated with tomatoes from contaminated fields, 2005

Salmonella Newport causes more than an estimated 100,000 infections annually in the United States. In 2002, tomatoes grown and packed on the eastern shore of Virginia contaminated with a pan-susceptible S. Newport strain caused illness in 510 patients in 26 states. In July-November 2005, the same strain caused illness in at least 72 patients in 16 states. We conducted a case-control study during the 2005 outbreak, enrolling 29 cases and 140 matched neighbourhood controls. Infection was associated with eating tomatoes (matched odds ratio 9.7, 95% confidence interval 3.3-34.9). Tomatoes were traced back to the eastern shore of Virginia, where the outbreak strain was isolated from pond water used to irrigate tomato fields. Two multistate outbreaks caused by one rare strain, and identification of that strain in irrigation ponds 2 years apart, suggest persistent contamination of tomato fields. Further efforts are needed to prevent produce contamination on farms and throughout the food supply chain.     

A meal enriched with soy isoflavones increases nitric oxide-mediated vasodilation in healthy postmenopausal women

Evidence from infusion studies suggests that soy isoflavones influence nitric oxide-dependent vasorelaxation. It is uncertain whether orally consumed isoflavones have similar effects. Healthy postmenopausal women (n = 22) consumed 2 low-fat test meals in random order 1 wk apart, with 80 mg isoflavones (ISO) or without isoflavones (CON). Endothelium-dependent vasodilation, assessed by brachial artery flow-mediated dilatation (FMD), was measured in fasting subjects, and 4 and 6 h following the test meal, in addition to blood pressure and pulse wave analysis to derive the peripheral augmentation index (pAIx). Blood samples were taken after fasting, and 5 and 7 h following the test meal for serum isoflavone, plasma 8-isoprostane F(2alpha), nitric oxide metabolites (NOx), glucose, and triacylglycerol analysis. Serum genistein and daidzein concentrations (geometric mean, 95% CI) reached 1.49 (1.20-1.84) micromol/L and 0.95 (0.70-1.30) micromol/L, respectively, following ISO (7 h). FMD and plasma NOx concentrations were greater following ISO compared with CON, indicating better postprandial endothelial function. FMD values (%, mean +/- SD) were: CON, 5.49 +/- 2.32, 4.35 +/- 2.32, 4.40 +/- 2.26; ISO, 5.38 +/- 1.91, 5.08 +/- 1.74, 6.11 +/- 2.60, at baseline, 4 h, and 6 h, respectively (P < 0.01). Plasma NOx concentrations (micromol/L, mean +/- SD) were: CON, 20.0 +/- 5.1, 16.8 +/- 5.1, 23.1 +/- 6.0; ISO, 18.6 +/- 6.3, 19.5 +/- 5.1, 21.3 +/- 10.1, at baseline, 5 h, and 7 h, respectively (P < 0.005). Treatment did not affect pAIx, blood pressure, or plasma 8-isoprostane F(2alpha) concentrations. In conclusion, consuming an isoflavone-enriched low-fat meal acutely increases endothelium-dependent vasodilation in postmenopausal women. Regular consumption of soy isoflavones may protect against endothelial dysfunction.     

Predicting Tipranavir and Darunavir Resistance Using Genotypic,Phenotypic, and Virtual Phenotypic Resistance Patterns: an Independent Cohort Analysis of Clinical Isolates Highly Resistant to All Other Protease Inhibitors

Genotypic interpretation systems (GISs) for darunavir and tipranavir susceptibility are rarely tested by the use of independent data sets. The virtual phenotype (the phenotype determined by Virco [the “Vircotype”]) was used to interpret all genotypes in Québec, Canada, and phenotypes were determined for isolates predicted to be resistant to all protease inhibitors other than darunavir and tipranavir. We used multivariate analyses to predict relative phenotypic susceptibility to darunavir and tipranavir. We compared the performance characteristics of the Agence Nationale de Recherche sur le Sida scoring algorithm, the Stanford HIV database scoring algorithm (with separate analyses of the discrete and numerical scores), the Vircotype, and the darunavir and tipranavir manufacturers'' scores for prediction of the phenotype. Of the 100 isolates whose phenotypes were determined, 89 and 72 were susceptible to darunavir and tipranavir, respectively. In multivariate analyses, the presence of I84V and V82T and the lack of L10F predicted that the isolates would be more susceptible to darunavir than tipranavir. The presence of I54L, V32I, and I47V predicted that the isolates would be more susceptible to tipranavir. All GISs except the system that provided the Stanford HIV database discrete score performed well in predicting the darunavir resistance phenotype (R² = 0.61 to 0.69); the R² value for the Stanford HIV database discrete scoring system was 0.38. Other than the system that provided the Vircotype (R² = 0.80), all GISs performed poorly in predicting the tipranavir resistance phenotype (R² = 0.00 to 0.31). In this independent cohort harboring highly protease inhibitor-resistant HIV isolates, reduced phenotypic susceptibility to darunavir and tipranavir was rare. Generally, GISs predict susceptibility to darunavir substantially better than they predict susceptibility to tipranavir.HIV-infected patients harboring multidrug-resistant virus face limited protease inhibitor (PI) treatment options. Studies suggest that approximately 10% of HIV-infected patients initiating therapy experience triple-class treatment failure (18), although this rate may be declining as the treatment options improve (4). For those patients given therapy prior to the availability of highly active antiretroviral therapy, the rate of triple-class resistance exceeds 20% (25a).Approved in June 2005, tipranavir is a nonpeptidic PI specifically developed for the management of patients harboring PI-resistant virus. In clinical trials, the use of tipranavir resulted in a virologic response superior to that achieved with the comparator PIs (11). However, tipranavir requires twice-daily dosing and coadministration with 200 mg of ritonavir and food and has many drug-drug interactions and an adverse side effect profile. Patients given tipranavir have increased rates of hepatotoxicity, hyperlipidemia, rash, and therapy discontinuation than patients receiving a comparator PI; and the use of tipranavir has been linked to intracranial hemorrhage (1).In June 2006, the U.S. Food and Drug Administration approved twice-daily darunavir coadministered with 100 mg ritonavir for use by treatment-experienced adults. The use of darunavir resulted in a virologic response superior to that achieved with the comparator PIs in patients harboring PI-resistant virus (2, 16). In those pivotal studies, darunavir had a side effect profile similar to that of the comparator PIs, other than a lower incidence of diarrhea.While darunavir and tipranavir are both active against isolates highly resistant to PIs, they have not been compared directly in clinical studies, although one analysis suggests that darunavir may have more activity (12). Given the lack of clinical data, the interpretation of genotypic resistance test results is often used to choose between darunavir and tipranavir.Over 20 genotypic interpretation systems (GISs) have been developed to interpret the complex patterns of amino acid substitutions seen with PI-associated resistance (14, 15, 20), but their performance characteristics have rarely been compared. Given the complexity of PI-associated resistance, a phenotype can be determined to better characterize resistance, although clinical data in support of such a strategy are limited (17). For drugs for which limited clinical data are available, such as darunavir and tipranavir, the phenotype may provide a more reliable measure of the activity of a drug, as the phenotype measures in vitro susceptibility to specific drugs and the genotype analyzes the sequence information of the virus and infers drug resistance from the mutations present.In the study described here we compared the ability of several of the most commonly used GISs (those of the Agence Nationale de Recherche sur le Sida [ANRS] and the Stanford HIV database, the Virco system for the determination of the virtual phenotype [Vircotype], and the darunavir and tipranavir manufacturers'' scores) to predict the phenotypes for resistance to darunavir and tipranavir for a set of highly resistant clinical isolates and developed a model that may be used to predict the relative susceptibility to darunavir and tipranavir (4a, 21, 23; www.hivfrenchresistance.org/; Virco).(This study was presented at the 5th International AIDS Society [IAS] Conference on HIV Pathogenesis, Treatment, and Prevention, 19 to 22 July 2009, Cape Town, South Africa [abstr. WEPEB202].)