HIV-1 dual infection is associated with faster CD4+T cell decline in a cohort of men with primary HIV infection

Background. In vitro, animal, and mathematical models suggest that human immunodeficiency virus (HIV) co- or superinfection would result in increased fitness of the pathogen and, possibly, increased virulence. However, in patients, the impact of dual HIV type 1 (HIV-1) infection on disease progression is unclear, because parameters relevant for disease progression have not been strictly analyzed. The objective of the present study is to analyze the effect of dual HIV-1 infections on disease progression in a well-defined cohort of men who have sex with men. Methods. Between 2000 and 2009, 37 men who had primary infection with HIV-1 subtype B, no indication for immediate need of combination antiretroviral therapy (cART), and sufficient follow-up were characterized with regard to dual infection or single infection and to coreceptor use. Patients were followed to estimate the effect of these parameters on clinical disease progression, as defined by the rate of CD4(+) T-cell decline and the time to initiation of cART. Results. Four patients presented with HIV-1 coinfection; 6 patients acquired HIV-1 superinfection, on average 8.5 months from their primary infection; and 27 patients remained infected with a single strain. Slopes of longitudinal CD4(+) T-cell counts and time-weighted changes from baseline were significantly steeper for patients with dual infection compared with patients with single infection. Multivariate analysis showed that the most important parameter associated with CD4(+) T-cell decline over time was dual infection (P = .001). Additionally, patients with HIV-1 coinfection had a significantly earlier start of cART (P <.0001). Conclusions. Dual HIV-1 infection is the main factor associated with CD4(+) T-cell decline in men who have untreated primary infection with HIV-1 subtype

The Role of the Retinal Nerve Fiber Layer Thickness on OCT in the Evaluation of Papillitis in Childhood Uveitis

PURPOSE: To investigate the diagnostic value of using retinal nerve fiber layer thickness measured on optical coherence tomography (OCT-RNFL) to diagnose papillitis in pediatric uveitis. DESIGN: Retrospective cohort study. METHODS: Demographic and clinical data were collected retrospectively for 257 children with uveitis (with 455 affected eyes). Receiver operating characteristic (ROC) analysis was performed to compare fluorescein angiography (FA, the diagnostic gold standard for papillitis) to OCT-RNFL in a subgroup of 93 patients. An ideal cut-off value for OCT-RNFL was then determined by calculating the highest Youden index. Finally, a multivariate analysis was applied to the clinical ophthalmological data. RESULTS: Based on a subset of 93 patients who underwent both OCT-RNFL and FA, the ideal cut-off OCT-RNFL for diagnosing papillitis was >130 µm, with 79% sensitivity and 85% specificity. Among the entire cohort, the prevalence of OCT-RNFL >130 µm was 19% (27/141), 72% (26/36), and 45% (36/80) in patients with anterior uveitis, intermediate uveitis, and panuveitis, respectively. Our multivariate analysis of the clinical data revealed that OCT-RNFL >130 µm was associated with a higher prevalence of cystoid macular edema, active uveitis, and optic disc swelling on fundoscopy, with odds ratios of 5.3, 4.3, and 13.7, respectively (all P 130 µm in approximately one-third of all children with uveitis and was particularly prevalent in cases of intermediate uveitis and panuveitis

Travel-Related Venous Thrombosis: Results from a Large Population-Based Case Control Study (MEGA Study)

BACKGROUND: Recent studies have indicated an increased risk of venous thrombosis after air travel. Nevertheless, questions on the magnitude of risk, the underlying mechanism, and modifying factors remain unanswered. METHODS AND FINDINGS: We studied the effect of various modes and duration of travel on the risk of venous thrombosis in a large ongoing case-control study on risk factors for venous thrombosis in an unselected population (MEGA study). We also assessed the combined effect of travel and prothrombotic mutations, body mass index, height, and oral contraceptive use. Since March 1999, consecutive patients younger than 70 y with a first venous thrombosis have been invited to participate in the study, with their partners serving as matched control individuals. Information has been collected on acquired and genetic risk factors for venous thrombosis. Of 1,906 patients, 233 had traveled for more than 4 h in the 8 wk preceding the event. Traveling in general was found to increase the risk of venous thrombosis 2-fold (odds ratio [OR] 2.1; 95% confidence interval [CI] 1.5–3.0). The risk of flying was similar to the risks of traveling by car, bus, or train. The risk was highest in the first week after traveling. Travel by car, bus, or train led to a high relative risk of thrombosis in individuals with factor V Leiden (OR 8.1; 95% CI 2.7–24.7), in those who had a body mass index of more than 30 kg/m(2) (OR 9.9; 95% CI 3.6–27.6), in those who were more than 1.90 m tall (OR 4.7; 95% CI 1.4–15.4), and in those who used oral contraceptives (estimated OR > 20). For air travel these synergistic findings were more apparent, while people shorter than 1.60 m had an increased risk of thrombosis after air travel (OR 4.9; 95% CI 0.9–25.6) as well. CONCLUSIONS: The risk of venous thrombosis after travel is moderately increased for all modes of travel. Subgroups exist in which the risk is highly increased

Long-Term Survival in a Large Cohort of Patients with Venous Thrombosis: Incidence and Predictors

Linda Flinterman and colleagues report on the long-term mortality rate for individuals who have experienced a first venous thrombosis or pulmonary embolism. They describe an ongoing elevated risk of death for individuals who had experienced a venous thrombosis or pulmonary embolism as compared to controls, for up to eight years after the event

Lack of Detection of XMRV in Seminal Plasma from HIV-1 Infected Men in The Netherlands

Background: Xenotropic murine leukaemia virus-related virus (XMRV) is a recently discovered human gammaretrovirus with yet unknown prevalence and transmission route(s). Its presence in prostate stromal fibroblasts and prostatic secretions suggests that XMRV might be sexually transmitted. We chose to study a compartment closely connected to the prostate, a location where XMRV was detected in independent studies. Seminal plasma samples from HIV-1 infected men were examined as they have an increased probability of acquiring sexually transmitted pathogens. Methodology/Principal Findings: We studied the prevalence of XMRV in 93 seminal plasma samples of 54 HIV-1 infected men living in The Netherlands with a nested PCR amplification specifically targeting the XMRV gag gene. As a control for the presence and integrity of retrovirus particles, HIV-1 was amplified from the same samples with a PCR amplification targeting the env gene of the virus, or HIV-1 was quantified with a real-time PCR amplifying part of the pol gene. Conclusions/Significance: Although HIV-1 was amplified from 25 % of the seminal plasma samples, no XMRV was detected, suggesting that either the prevalence of XMRV is very low in The Netherlands, or that XMRV is not naturally present in th

Development of a hypoallergenic recombinant parvalbumin for first-in-man subcutaneous immunotherapy of fish allergy.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access.The FAST (food allergy-specific immunotherapy) project aims at developing safe and effective subcutaneous immunotherapy for fish allergy, using recombinant hypoallergenic carp parvalbumin, Cyp c 1.Preclinical characterization and good manufacturing practice (GMP) production of mutant Cyp (mCyp) c 1.Escherichia coli-produced mCyp c 1 was purified using standard chromatographic techniques. Physicochemical properties were investigated by gel electrophoresis, size exclusion chromatography, circular dichroism spectroscopy, reverse-phase high-performance liquid chromatography and mass spectrometry. Allergenicity was assessed by ImmunoCAP inhibition and basophil histamine release assay, immunogenicity by immunization of laboratory animals and stimulation of patients' peripheral blood mononuclear cells (PBMCs). Reference molecules were purified wild-type Cyp c 1 (natural and/or recombinant). GMP-compliant alum-adsorbed mCyp c 1 was tested for acute toxicity in mice and rabbits and for repeated-dose toxicity in mice. Accelerated and real-time protocols were used to evaluate stability of mCyp c 1 as drug substance and drug product.Purified mCyp c 1 behaves as a folded and stable molecule. Using sera of 26 double-blind placebo-controlled food-challenge-proven fish-allergic patients, reduction in allergenic activity ranged from 10- to 5,000-fold (1,000-fold on average), but with retained immunogenicity (immunization in mice/rabbits) and potency to stimulate human PBMCs. Toxicity studies revealed no toxic effects and real-time stability studies on the Al(OH)3-adsorbed drug product demonstrated at least 20 months of stability.The GMP drug product developed for treatment of fish allergy has the characteristics targeted for in FAST: i.e. hypoallergenicity with retained immunogenicity. These results have warranted first-in-man immunotherapy studies to evaluate the safety of this innovative vaccine.info:eu-repo/grantAgreement/EC/FP7/20187

Clues to Neuro-Degeneration in Niemann-Pick Type C Disease from Global Gene Expression Profiling

BACKGROUND: Niemann-Pick Type C (NPC) disease is a neurodegenerative disease that is characterized by the accumulation of cholesterol and glycosphingolipids in the late endocytic pathway. The majority of NPC cases are due to mutations in the NPC1 gene. The precise function of this gene is not yet known. METHODOLOGY/PRINCIPAL FINDINGS: Using cDNA microarrays, we analyzed the genome-wide expression patterns of human fibroblasts homozygous for the I1061T NPC1 mutation that is characterized by a severe defect in the intracellular processing of low density lipoprotein-derived cholesterol. A distinct gene expression profile was identified in NPC fibroblasts from different individuals when compared with fibroblasts isolated from normal subjects. As expected, NPC1 mutant cells displayed an inappropriate homeostatic response to accumulated intracellular cholesterol. In addition, a number of striking parallels were observed between NPC disease and Alzheimer's disease. CONCLUSIONS/SIGNIFICANCE: Many genes involved in the trafficking and processing of amyloid precursor protein and the microtubule binding protein, tau, were more highly expressed. Numerous genes important for membrane traffic and the cellular regulation of calcium, metals and other ions were upregulated. Finally, NPC fibroblasts exhibited a gene expression profile indicative of oxidative stress. These changes are likely contributors to the pathophysiology of Niemann-Pick Type C disease

Risk factors for Coronavirus disease 2019 (Covid-19) death in a population cohort study from the Western Cape province, South Africa

Risk factors for coronavirus disease 2019 (COVID-19) death in sub-Saharan Africa and the effects of human immunodeficiency virus (HIV) and tuberculosis on COVID-19 outcomes are unknown. We conducted a population cohort study using linked data from adults attending public-sector health facilities in the Western Cape, South Africa. We used Cox proportional hazards models, adjusted for age, sex, location, and comorbidities, to examine the associations between HIV, tuberculosis, and COVID-19 death from 1 March to 9 June 2020 among (1) public-sector “active patients” (≥1 visit in the 3 years before March 2020); (2) laboratory-diagnosed COVID-19 cases; and (3) hospitalized COVID-19 cases. We calculated the standardized mortality ratio (SMR) for COVID-19, comparing adults living with and without HIV using modeled population estimates.Among 3 460 932 patients (16% living with HIV), 22 308 were diagnosed with COVID-19, of whom 625 died. COVID19 death was associated with male sex, increasing age, diabetes, hypertension, and chronic kidney disease. HIV was associated with COVID-19 mortality (adjusted hazard ratio [aHR], 2.14; 95% confidence interval [CI], 1.70–2.70), with similar risks across strata of viral loads and immunosuppression. Current and previous diagnoses of tuberculosis were associated with COVID-19 death (aHR, 2.70 [95% CI, 1.81–4.04] and 1.51 [95% CI, 1.18–1.93], respectively). The SMR for COVID-19 death associated with HIV was 2.39 (95% CI, 1.96–2.86); population attributable fraction 8.5% (95% CI, 6.1–11.1)