701 Park Avenue Mail Code G5
Minneapolis MN 55415
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License #: 55697
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Delivery of an enzyme-IGFII fusion protein to the mouse brain is therapeutic for mucopolysaccharidosis type IIIB. - Proceedings of the National Academy of Sciences of the United States of America
Mucopolysaccharidosis type IIIB (MPS IIIB, Sanfilippo syndrome type B) is a lysosomal storage disease characterized by profound intellectual disability, dementia, and a lifespan of about two decades. The cause is mutation in the gene encoding Î±-N-acetylglucosaminidase (NAGLU), deficiency of NAGLU, and accumulation of heparan sulfate. Impediments to enzyme replacement therapy are the absence of mannose 6-phosphate on recombinant human NAGLU and the blood-brain barrier. To overcome the first impediment, a fusion protein of recombinant NAGLU and a fragment of insulin-like growth factor II (IGFII) was prepared for endocytosis by the mannose 6-phosphate/IGFII receptor. To bypass the blood-brain barrier, the fusion protein ("enzyme") in artificial cerebrospinal fluid ("vehicle") was administered intracerebroventricularly to the brain of adult MPS IIIB mice, four times over 2 wk. The brains were analyzed 1-28 d later and compared with brains of MPS IIIB mice that received vehicle alone or control (heterozygous) mice that received vehicle. There was marked uptake of the administered enzyme in many parts of the brain, where it persisted with a half-life of approximately 10 d. Heparan sulfate, and especially disease-specific heparan sulfate, was reduced to control level. A number of secondary accumulations in neurons [Î²-hexosaminidase, LAMP1(lysosome-associated membrane protein 1), SCMAS (subunit c of mitochondrial ATP synthase), glypican 5, Î²-amyloid, P-tau] were reduced almost to control level. CD68, a microglial protein, was reduced halfway. A large amount of enzyme also appeared in liver cells, where it reduced heparan sulfate and Î²-hexosaminidase accumulation to control levels. These results suggest the feasibility of enzyme replacement therapy for MPS IIIB.
Timing of antiretroviral therapy after diagnosis of cryptococcal meningitis. - The New England journal of medicine
Cryptococcal meningitis accounts for 20 to 25% of acquired immunodeficiency syndrome-related deaths in Africa. Antiretroviral therapy (ART) is essential for survival; however, the question of when ART should be initiated after diagnosis of cryptococcal meningitis remains unanswered.We assessed survival at 26 weeks among 177 human immunodeficiency virus-infected adults in Uganda and South Africa who had cryptococcal meningitis and had not previously received ART. We randomly assigned study participants to undergo either earlier ART initiation (1 to 2 weeks after diagnosis) or deferred ART initiation (5 weeks after diagnosis). Participants received amphotericin B (0.7 to 1.0 mg per kilogram of body weight per day) and fluconazole (800 mg per day) for 14 days, followed by consolidation therapy with fluconazole.The 26-week mortality with earlier ART initiation was significantly higher than with deferred ART initiation (45% [40 of 88 patients] vs. 30% [27 of 89 patients]; hazard ratio for death, 1.73; 95% confidence interval [CI], 1.06 to 2.82; P=0.03). The excess deaths associated with earlier ART initiation occurred 2 to 5 weeks after diagnosis (P=0.007 for the comparison between groups); mortality was similar in the two groups thereafter. Among patients with few white cells in their cerebrospinal fluid (<5 per cubic millimeter) at randomization, mortality was particularly elevated with earlier ART as compared with deferred ART (hazard ratio, 3.87; 95% CI, 1.41 to 10.58; P=0.008). The incidence of recognized cryptococcal immune reconstitution inflammatory syndrome did not differ significantly between the earlier-ART group and the deferred-ART group (20% and 13%, respectively; P=0.32). All other clinical, immunologic, virologic, and microbiologic outcomes, as well as adverse events, were similar between the groups.Deferring ART for 5 weeks after the diagnosis of cryptococcal meningitis was associated with significantly improved survival, as compared with initiating ART at 1 to 2 weeks, especially among patients with a paucity of white cells in cerebrospinal fluid. (Funded by the National Institute of Allergy and Infectious Diseases and others; COAT ClinicalTrials.gov number, NCT01075152.).
Current status and future prospects of epidemiology and public health training and research in the WHO African region. - International journal of epidemiology
To date little has been published about epidemiology and public health capacity (training, research, funding, human resources) in WHO/AFRO to help guide future planning by various stakeholders.A bibliometric analysis was performed to identify published epidemiological research. Information about epidemiology and public health training, current research and challenges was collected from key informants using a standardized questionnaire.From 1991 to 2010, epidemiology and public health research output in the WHO/AFRO region increased from 172 to 1086 peer-reviewed articles per annum [annual percentage change (APC) = 10.1%, P for trend < 0.001]. The most common topics were HIV/AIDS (11.3%), malaria (8.6%) and tuberculosis (7.1%). Similarly, numbers of first authors (APC = 7.3%, P for trend < 0.001), corresponding authors (APC = 8.4%, P for trend < 0.001) and last authors (APC = 8.5%, P for trend < 0.001) from Africa increased during the same period. However, an overwhelming majority of respondents (>90%) reported that this increase is only rarely linked to regional post-graduate training programmes in epidemiology. South Africa leads in publications (1978/8835, 22.4%), followed by Kenya (851/8835, 9.6%), Nigeria (758/8835, 8.6%), Tanzania (549/8835, 6.2%) and Uganda (428/8835, 4.8%) (P < 0.001, each vs South Africa). Independent predictors of relevant research productivity were 'in-country numbers of epidemiology or public health programmes' [incidence rate ratio (IRR) = 3.41; 95% confidence interval (CI) 1.90-6.11; P = 0.03] and 'number of HIV/AIDS patients' (IRR = 1.30; 95% CI 1.02-1.66; P < 0.001).Since 1991, there has been increasing epidemiological research productivity in WHO/AFRO that is associated with the number of epidemiology programmes and burden of HIV/AIDS cases. More capacity building and training initiatives in epidemiology are required to promote research and address the public health challenges facing the continent.
HIV infection and the incidence of malaria among HIV-exposed children from Tanzania. - The Journal of infectious diseases
To determine whether human immunodeficiency virus (HIV) infection is associated with increased risk of malaria incidence and recurrence in children.Newborn infants of HIV-infected mothers were enrolled at 6 weeks and followed for 2 years. HIV status was assessed by enzyme-linked immunosorbant assay and confirmed by HIV DNA polymerase chain reaction. Malaria was defined as (1) physician-diagnosed clinical malaria; (2) probable malaria, in which laboratory testing is requested for parasitemia; and (3) blood smear-confirmed malaria. Cox proportional hazards models estimated hazard ratios (HRs) for development of first and second malaria episodes, and generalized estimating equation models estimated malaria rate differences per 100-child-years in relation to time-updated HIV status.Child HIV infection was associated with clinical (HR, 1.34; 95% confidence interval [CI], 1.12-1.61), probable (HR, 1.47; 95% CI, 1.19-1.81), and confirmed (HR, 1.67; 95% CI, 1.18-2.36) malaria episodes. Per 100 child-years, HIV-infected children experienced 88 (95% CI, 65-113), 36 (95% CI, 19-53), and 20 (95% CI, 9-31) more episodes of clinical, probable, and confirmed malaria episodes, respectively, than HIV-uninfected children. Among children with â‰¥1 malaria episodes, those with HIV infection developed second clinical (HR, 1.28; 95% CI, 1.04-1.57), probable (HR, 1.60; 95% CI, 1.26-2.14), and confirmed (HR, 2.27; 95% CI, 1.06-3.89) malaria sooner than HIV-uninfected children.HIV infection is a risk factor for the development of malaria. Proactive malaria disease prevention and treatment is warranted for all children, particularly those with HIV infection in settings of coendemicity.
Interferon-gamma release assays for diagnosing mycobacterium tuberculosis infection in renal dialysis patients. - Clinical journal of the American Society of Nephrology : CJASN
End-stage renal disease (ESRD) patients are at high risk for tuberculosis (TB). IFN-gamma release assays that assess immune responses to specific TB antigens offer potential advantages over tuberculin skin testing (TST) in screening such patients for Mycobacterium tuberculosis infection. This study sought to determine whether IFN-gamma release assay results are more closely associated with recent TB exposure than TST results.Prospective cohort investigation of patients at a hemodialysis center with a smear-positive case of TB. Patients without a history of TB underwent initial and repeat testing with TST, and with the IFN-gamma assays QuantiFERON-TB Gold (QFT-G) and ELISPOT test. Outcome measures included the prevalence of positive test results, identification of factors associated with positive results, and test result discordance.A total of 100 (47% foreign born; median age, 55 yr; age range, 18 to 83 yr) of 124 eligible patients were enrolled. Twenty-six persons had positive TST results, 21 had positive QFT-G results, and 27 had positive ELISPOT results. Patients with TB case contact were likely to have a positive QFT-G result (P = 0.02) and ELISPOT results (P = 0.04), whereas TB case contact was not associated with positive TST results (P = 0.7). Positive TST results were associated with foreign birth (P = 0.04) and having had a TST in the previous year (P = 0.04).Positive IFN-gamma assay results were more closely associated with recent TB exposure than were positive TST results. QFT-G and ELISPOT might offer a better method for detecting TB infection in ESRD patients.
Adherence to highly active antiretroviral therapy assessed by pharmacy claims predicts survival in HIV-infected South African adults. - Journal of acquired immune deficiency syndromes (1999)
It is unclear how adherence to highly active antiretroviral therapy (HAART) may best be monitored in large HIV programs in sub-Saharan Africa where it is being scaled up. We aimed to evaluate the association between HAART adherence, as estimated by pharmacy claims, and survival in HIV-1-infected South African adults enrolled in a private-sector AIDS management program. Of the 6288 patients who began HAART between January 1999 and August 2004, 3805 (61%) were female and 6094 (97%) were black African. HAART adherence was >or=80% for 3298 patients (52%) and 100% for 1916 patients (30%). Women were significantly more likely to have adherence>or=80% than men (54% vs 49%, P<0.001). The median (interquartile range) follow-up time was 1.8 (1.37-2.5) years. As of 1 September 2004, 222 patients had died-a crude mortality rate of 3.5%. In a multivariate Cox regression model, adherence<80% was associated with lower survival (relative hazard 3.23; 95% confidence interval: 2.37-4.39). When medication adherence was divided into 5 strata with a width of 20% each, each stratum had lower survival rates than the adjacent, higher-adherence stratum. Among other variables tested, only baseline CD4+ T-cell count was significantly associated with decreased survival in multivariate analysis (relative hazard 5.13; 95% confidence interval: 3.42-7.72, for CD4+ T-cell count
200 cells/microL). Pharmacy-based records may be a simple and effective population-level tool for monitoring adherence as HAART programs in Africa are scaled up.
Rapid detection of isoniazid and rifampin resistance mutations in Mycobacterium tuberculosis complex from cultures or smear-positive sputa by use of molecular beacons. - Journal of clinical microbiology
The slow-growing nature of Mycobacterium tuberculosis complex hinders the improvement of turnaround time for phenotypic drug susceptibility testing. We designed a set of molecular beacons for the detection of isoniazid and rifampin resistance mutations in M. tuberculosis complex organisms from cultures or from N-acetyl-l-cysteine-NaOH-treated, smear-positive specimens. The performance of the molecular beacons was characterized by studying a total of 196 clinical isolates (127 drug-resistant isolates and 69 drug-susceptible isolates). For detection of isoniazid resistance, the sensitivity and specificity of the assay were 82.7 and 100%, and the positive predictive value (PPV) and negative predictive value (NPV) at a resistance prevalence of 10% were 100 and 98.11%, respectively. For detection of rifampin resistance, the sensitivity and specificity of the assay were 97.5 and 100%, and the PPV and NPV at a resistance prevalence of 2.0% were 100 and 99.95%, respectively.
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