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A catalogue of putative HIV-1 protease host cell substrates
No full textProcessing of human immunodeficiency virus (HIV) proteins by the HIV-1 protease is essential for HIV infectivity. In addition, several studies have revealed cleavage of human proteins by this viral protease during infection; however, no large-scale HIV-1 protease degradomics study has yet been performed. To identify putative host substrates in an unbiased manner and on a proteome-wide scale, we used positional proteomics to identify peptides reporting protein processing by the HIV-1 protease, and a catalogue of over 120 cellular HIV-1 protease substrates processed in vitro was generated. This catalogue includes previously reported substrates as well as recently described interaction partners of HIV-1 proteins. Cleavage site alignments revealed a specificity profile in good correlation with previous studies, even though the ELLE consensus motif was not cleaved efficiently when incorporated into peptide substrates due to subsite cooperativity. Our results are further discussed in the context of HIV-1 infection and the complex substrate recognition by the viral protease
Possible implication of NFKB1A and NKG2D genes in susceptibility to HTLV-1-associated myelopathy/tropical spastic paraparesis in Peruvian patients infected with HTLV-1
No full textThe human T-cell lymphotropic virus type 1 (HTLV-1) is the etiological agent of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), a progressive disease causing paraparesis of the lower limbs. Only a minority of persons infected with HTLV-1 develop HAM/TSP. Universal susceptibility factors for HAM/TSP are not known. The viral genotype is similar in asymptomatic carriers and HAM/TSP patients. High proviral load has been associated consistently with HAM/TSP, but this factor does not explain fully the presence of disease in HTLV-1-infected subjects. Most likely, host genetic factors will play an important role in HAM/TSP development. A two-stage case-control study was carried out to evaluate the association between HAM/TSP and candidate single nucleotide polymorphisms (SNPs) from 45 genes in addition to six human leukocyte antigen (HLA) alleles. Ancestry-informative markers were used to correct for population stratification. Several SNPs belonging to NFKB1A and NKG2D showed a trend of association in both stages. The fact that the direction of the association observed in the first stage was the same in the second stage suggests that NFKB1A and NKG2D may be implicated in the development of HAM/TSP. Further replication studies in independent HTLV-1 patient groups should validate further these associations. J. Med. Virol. 84:319-326, 2012. (c) 2011 Wiley Periodicals, Inc
Task-shifting to community health workers: evaluation of the performance of a peer-led model in an antiretroviral program in Uganda
No full textTask shifting to community health workers (CHW) has received recognition. We examined the performance of community antiretroviral therapy and tuberculosis treatment supporters (CATTS) in scaling up antiretroviral therapy (ART) in Reach Out, a community-based ART program in Uganda. Retrospective data on home visits made by CATTS were analyzed to examine the CATTS ability to perform home visits to patients based on the model's standard procedures. Qualitative interviews conducted with 347 randomly selected patients and 47 CATTS explored their satisfaction with the model. The CATTS ability to follow-up with patients worsened from patients requiring daily, weekly, monthly, to three-monthly home visits. Only 26% and 15% of them correctly home visited patients with drug side effects and a missed clinic appointment, respectively. Additionally, 83% visited stable pre-ART and ART patients (96%) more frequently than required. Six hundred eighty of the 3650 (18%) patients were lost to follow-up (LTFU) during the study period. The mean number of patients LTFU per CATTS was 40.5. Male (p=0.005), worked for longer durations (p=0.02), and had lower education (p=0.005). An increased number of patients (p=0.01) were associated with increased LTFU. Ninety-two percent of the CATTS felt the model could be improved by reducing the workload. CATTS who were HIV positive, female, not residing in the same village as their patients, more educated, married, on ART, and spent less time with the patients were rated better by their patients. The Reach-Out CHW model is labor-intensive. Triaged home visits could improve performance and allow CATTS time to focus on patients requiring more intensive follow-up
Fine-needle aspiration for diagnosis of tuberculous lymphadenitis in children in Bangui, Central African Republic
No full textN2 - BACKGROUND: Tuberculosis (TB) is a major cause of childhood morbidity and mortality in developing countries. One of the main difficulties is obtaining adequate specimens for bacteriological confirmation of the disease in children.The aim of this study is to evaluate the adequacy of fine-needle aspiration (FNA) for the diagnosis of TB. METHODS: In a prospective study conducted at the paediatric hospital in Bangui in 2007--2009, we used fine-needle aspiration to obtain samples for diagnosis of TB from 131 children aged 0--17 years with persistent lymphadenitis. RESULTS: Fine-needle aspiration provided samples that could be used for bacteriological confirmation of TB. Ziehl-Neelsen staining for acid-fast bacilli was positive in 42.7% of samples, and culture identified TB in 67.2% of cases. Of 75 samples that were stain-negative, 49 (65.3%) were culture-positive, while 12 stain-positive samples remained culture-negative. Ten of the 12 stain-positive, culture-negative samples were from patients who had received previous antimicrobial therapy. With regard to phenotypic drug susceptibility, 81/88 strains (91.1%) were fully susceptible to isoniazid, rifampicin, ethambutol and streptomycin, six (6.8%) were resistant to one drug, and one multidrug-resistant strain was found. CONCLUSIONS: Fine-needle aspiration is simple, cost-effective and non-invasive and can be performed by trained staff. Combined with rapid molecular diagnostic tests, fine-needle aspirates could improve the diagnosis of TB and provide valuable information for appropriate treatment and drug resistance
Breaking the barriers to access a low cost intra-dermal rabies vaccine through innovative "pooling strategy"
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Diagnostic accuracy of molecular amplification tests for human African trypanosomiasis-systematic review
No full textBACKGROUND: A range of molecular amplification techniques have been developed for the diagnosis of Human African Trypanosomiasis (HAT); however, careful evaluation of these tests must precede implementation to ensure their high clinical accuracy. Here, we investigated the diagnostic accuracy of molecular amplification tests for HAT, the quality of articles and reasons for variation in accuracy. METHODOLOGY: Data from studies assessing diagnostic molecular amplification tests were extracted and pooled to calculate accuracy. Articles were included if they reported sensitivity and specificity or data whereby values could be calculated. Study quality was assessed using QUADAS and selected studies were analysed using the bivariate random effects model. RESULTS: 16 articles evaluating molecular amplification tests fulfilled the inclusion criteria: PCR (n = 12), NASBA (n = 2), LAMP (n = 1) and a study comparing PCR and NASBA (n = 1). Fourteen articles, including 19 different studies were included in the meta-analysis. Summary sensitivity for PCR on blood was 99.0% (95% CI 92.8 to 99.9) and the specificity was 97.7% (95% CI 93.0 to 99.3). Differences in study design and readout method did not significantly change estimates although use of satellite DNA as a target significantly lowers specificity. Sensitivity and specificity of PCR on CSF for staging varied from 87.6% to 100%, and 55.6% to 82.9% respectively. CONCLUSION: Here, PCR seems to have sufficient accuracy to replace microscopy where facilities allow, although this conclusion is based on multiple reference standards and a patient population that was not always representative. Future studies should, therefore, include patients for which PCR may become the test of choice and consider well designed diagnostic accuracy studies to provide extra evidence on the value of PCR in practice. Another use of PCR for control of disease could be to screen samples collected from rural areas and test in reference laboratories, to spot epidemics quickly and direct resources appropriately
Incidence of treatment-limiting toxicity with Stavudine-based antiretroviral therapy in Cambodia: a retrospective cohort study
No full textBACKGROUND: Although stavudine (D4T) remains frequently used in low-income countries in Asia, associated long-term toxicity data are scarce. The aim of this study was to determine the long-term incidence of severe D4T-toxicity (requiring drug substitution) and associated risk factors in HIV-infected Cambodians up to six years on antiretroviral treatment (ART). METHODOLOGY/PRINCIPAL FINDINGS: This is a retrospective analysis of an observational cohort, using data from an ART program with systematic monitoring for D4T-toxicity. Probabilities of time to D4T substitution due to suspected D4T toxicity (treatment-limiting D4T toxicity) were calculated, a risk factor analysis was performed using multivariate Cox regression modelling. Out of 2581 adults initiating a D4T-containing regimen, D4T was replaced in 276 (10.7%) patients for neuropathy, 14 (0.5%) for lactic acidosis and 957 (37.1%) for lipoatrophy. The main early side effect was peripheral neuropathy (7.0% by 1 year). After the first year, lipoatrophy became predominant, with a cumulative incidence of 56.1% and 72.4% by 3 and 6 years respectively. Older age (aHR 1.8; 95%CI: 1.4-2.3) and lower baseline haemoglobin (aHR 1.7; 95%CI: 1.4-2.2) were associated with the occurrence of neuropathy. Being female (aHR 3.8; 95%CI: 1.1-12.5), a higher baseline BMI (aHR 12.6; 95%CI: 3.7-43.1), and TB treatment at ART initiation (aHR 8.6; 95%CI: 2.7-27.5) increased the likelihood of lactic acidosis. Lipoatrophy was positively associated with female gender (aHR 2.3; 95%CI: 2.0-2.6), an older age (aHR 1.3; 95%CI: 1.1-1.4), and a CD4 count <200 cells/microL (aHR 1.3; 95%CI: 1.1-1.5). CONCLUSIONS: Stavudine-based treatment regimens in low-income countries are associated with significant long-term toxicities, predominantly lipoatrophy. Close clinical monitoring for toxicity with timely D4T substitution is recommended. Phasing-out of stavudine should be implemented, as costs allows
Rapid screening and diagnostic tests for human schistosomiasis in endemic areas (Protocol)
No full textRisk factors for obstetric fistula: a clinical review
No full textObstetric fistula is the presence of a hole between a woman's genital tract and either the urinary or the intestinal tract. Better knowledge of the risk factors for obstetric fistula could help in preventing its occurrence. The purpose of this study was to assess the characteristics of obstetric fistula patients. We conducted a search of the literature to identify all relevant articles published during the period from 1987-2008. Among the 19 selected studies, 15 were reports from sub-Saharan Africa and 4 from the Middle East. Among the reported fistula cases, 79.4% to 100% were obstetrical while the remaining cases were from other causes. Rectovaginal fistulae accounted for 1% to 8%, vesicovaginal fistulae for 79% to 100% of cases, and combined vesicovaginal and rectovaginal fistulae were reported in 1% to 23% of cases. Teenagers accounted for 8.9% to 86% of the obstetrical fistulae patients at the time of treatment. Thirty-one to 67% of these women were primiparas. Among the obstetric fistula patients, 57.6% to 94.8% of women labor at home and are secondarily transferred to health facilities. Nine to 84% percent of these women delivered at home. Many of the fistula patients were shorter than 150 cm tall (40-79.4%). The mean duration of labor among the fistula patients ranged from 2.5 to 4 days. Twenty to 95.7% of patients labored for more than 24 h. Operative delivery was eventually performed in 11% to 60% of cases. Obstetric fistula was associated with several risk factors, and they appear to be preventable. This knowledge should be used in strengthening the preventive strategy both at the health facility and at the community level