Increased hepatobiliary and fecal cholesterol excretion upon activation of the liver X receptor is independent of ABCA1

The ATP-binding cassette transporter ABCA1 is essential for high density lipoprotein (HDL) formation and considered rate-controlling for reverse cholesterol transport. Expression of the Abca1 gene is under control of the liver X receptor (LXR). We have evaluated effects of LXR activation by the synthetic agonist T0901317 on hepatic and intestinal cholesterol metabolism in C57BL/6J and DBA/1 wild-type mice and in ABCA1-deficient DBA/1 mice. In wild-type mice, T0901317 increased expression of Abca1 in liver and intestine, which was associated with a similar to60% rise in HDL. Biliary cholesterol excretion rose 2.7-fold upon treatment, and fecal neutral sterol output was increased by 150-300%. Plasma cholesterol levels also increased in treated Abca1(-/-) mice (+120%), but exclusively in very low density lipoprotein-sized fractions. Despite the absence of HDL, hepatobiliary cholesterol output was stimulated upon LXR activation in Abca1(-/-) mice, leading to a 250% increase in the biliary cholesterol/phospholipid ratio. Most importantly, fecal neutral sterol loss was induced to a similar extent (+300%) by the LXR agonist in DBA/1 wild-type and Abca1(-/-) mice. Expression of Abcg5 and Abcg8, recently implicated in biliary excretion of cholesterol and its intestinal absorption, was induced in T0901317-treated mice. Thus, activation of LXR in mice leads to enhanced hepatobiliary cholesterol secretion and fecal neutral sterol loss independent of (ABCA1-mediated) elevation of HDL and the presence of ABCA1 in liver and intestine

Does antiretroviral therapy use affect the accuracy of HIV rapid diagnostic assays? Experience from a demographic health and surveillance site in rural South Africa

Rapid diagnostic tests (RDTs) are the mainstay of HIV diagnosis in the developing world but might have poor sensitivity among individuals taking antiretroviral therapy (ART). We leveraged a home-based HIV testing program linked to clinical data to compare the sensitivity of RDTs between individuals using versus not using ART. Field workers tested 6802 individuals using 2 HIV RDTs, which were compared to a single HIV immunoassay tested on dried blood spots. Approximately 5% (371/6802) tested positive by immunoassay, of whom 157 (42%) were currently on ART. The sensitivity of the Abon RDT among those never versus currently on ART was 91.6% (95% CI 88.3–94.3) and 96.6% (95% CI 88.3–94.3), respectively, and 95.4% (95% CI 92.8–97.3) versus 99.3% (95% CI 95.2–99.7) for the Advanced Quality assay. We report similar sensitivity of RDTs in ART-naïve and ART-experienced individuals, which mitigates concerns about their use among treated individuals in population-based epidemiologic surveys and those transferring care

Encephalomeningocele cases over 10 years in Thailand: a case series

BACKGROUND: Encephalomeningocele, especially in the frontoethmoidal region, is a form of neural tube defect which affects patients in Southeast Asia more commonly than in Western countries. Its underlying cause is not known but teratogenic environmental agents are suspected. However, nutritional deficiency, as in spina bifida, cannot be excluded. METHODS: This study reports 21 cases of meningocele (without brain tissue in the lesion) and encephalomeningocele (with brain tissue) that were admitted to our hospital for surgical corrections in the period of ten years, from 1990 to 1999. Clinicopathological findings, as well as occupations of family members and prenatal exposures to infectious agents or chemicals were reviewed and analyzed. RESULTS: The most commonly involved area was the frontoethmoidal region, found in 20 cases. The combined pattern between nasoethmoidal and nasoorbital defects was found most frequently (11 from 21 cases) and had more associated abnormalities. Encephalomeningocele had more related abnormalities than meningocele with proportions of 0.6 and 0.3, respectively. CONCLUSIONS: Here, we confirmed that genetic defects are not likely to be the single primary cause of this malformation. However, we could not draw any conclusions on etiologic agents. We suggest that case control studies and further investigation on the role of nutritional deficiencies, especially folic acid, in the pathogenesis of encephalomeningocele are necessary to clarify the underlying mechanisms

Findings from home-based HIV testing and facilitated linkage after scale-up of test and treat in rural South Africa: young people still missing

Objectives: The aim of the study was to estimate rates of linkage to HIV care and antiretroviral treatment (ART) initiation after the introduction of home‐based HIV counselling and testing (HBHCT) and telephone‐facilitated support for linkage in rural South Africa. / Methods: A population‐based prospective cohort study was carried out in KwaZulu Natal, South Africa. All residents aged ≥ 15 years were eligible for HBHCT. Those who tested positive and were not in care were referred for ART at one of 11 public‐sector clinics. Individuals who did not attend the clinic within 2 weeks were sent a short message service (SMS) reminder; those who had not attended after a further 2 weeks were telephoned by a nurse counsellor, to discuss concerns and encourage linkage. Kaplan–Meier methods were used to estimate the proportion of newly diagnosed individuals linking to care and initiating ART. / Results: Among 38 827 individuals visited, 26% accepted HBHCT. Uptake was higher in women than in men (30% versus 20%, respectively), but similar in people aged < 30 years and ≥ 30 years (28% versus 26%, respectively). A total of 784 (8%) tested HIV positive, of whom 427 (54%) were newly diagnosed. Within 6 months, 31% of women and 18% of men < 30 years old had linked to care, and 29% and 16%, respectively, had started ART. Among those ≥ 30 years, 41% of women and 38% of men had linked to care within 6 months, and 41% and 35%, respectively, had started ART. / Conclusions: Despite facilitated linkage, rates of timely linkage to care and ART initiation after HBHCT were very low, particularly among young men. Innovations are needed to provide effective HIV care and prevention interventions to young people, and thus maximize the benefits of universal test and treat

Measuring the Quality of Data Collection in a Large Observational Cohort of HIV and AIDS

The aim of this study was to examine the quality of data collection by studying the validity of collected data. Data were extracted from the clinic charts of two anonymous outpatients by 38 data collectors. A standard for the data to be collected was determined (168 items). The validity was measured by comparing the collected items with the standard; in this way, the percentages of the collected items that were ‘correct’ could be calculated. The percentage ‘correct’ was higher for clinic chart 1 (mean: 83% correct, SD 7%) than for clinic chart 2 (mean: 78% correct, SD 8%). All categories contained incorrectly collected data. These data were divided into missing data, incorrect start-stop dates, and surplus collected data. Almost all start-stop dates would change into ‘correct’ if ‘monthyear’ was considered correct (instead of the standard ‘daymonthyear’). Not all data collectors used specific protocols, and sources other than the written comments were not always checked. This study shows that a high proportion of data was correctly collected. However, the collection of start-stop dates was not optimal, and the collected data included surplus and missing data. Data collectors should be more knowledgeable about HIV disease and trained in the use of difficult protocols, so that they can better recognize what data to collect and how it should be collected. Among physicians, there should be more agreement about what information to record in the charts, to facilitate data extraction for data collectors

The Pharmacogenetics of Statin Therapy on Clinical Events: No Evidence that Genetic Variation Affects Statin Response on Myocardial Infarction

Background: The pharmacogenetic effect on cardiovascular disease reduction in response to statin treatment has only been assessed in small studies. In a pharmacogenetic genome wide association study (GWAS) analysis within the Genomic Investigation of Statin Therapy (GIST) consortium, we investigated whether genetic variation was associated with the response of statins on cardiovascular disease risk reduction. Methods: The investigated endpoint was incident myocardial infarction (MI) defined as coronary heart disease death and definite and suspect non-fatal MI. For imputed single nucleotide polymorphisms (SNPs), regression analysis was performed on expected allelic dosage and meta-analysed with a fixed-effects model, inverse variance weighted meta-analysis. All SNPs with p-values <5.0 × 10(−4) in stage 1 GWAS meta-analysis were selected for further investigation in stage-2. As a secondary analysis, we extracted SNPs from the Stage-1 GWAS meta-analysis results based on predefined hypotheses to possibly modifying the effect of statin therapy on MI. Results: In stage-1 meta-analysis (eight studies, n = 10,769, 4,212 cases), we observed no genome-wide significant results (p < 5.0 × 10(−8)). A total of 144 genetic variants were followed-up in the second stage (three studies, n = 1,525, 180 cases). In the combined meta-analysis, no genome-wide significant hits were identified. Moreover, none of the look-ups of SNPs known to be associated with either CHD or with statin response to cholesterol levels reached Bonferroni level of significance within our stage-1 meta-analysis. Conclusion: This GWAS analysis did not provide evidence that genetic variation affects statin response on cardiovascular risk reduction. It does not appear likely that genetic testing for predicting effects of statins on clinical events will become a useful tool in clinical practice

Huntingtin gene repeat size variations affect risk of lifetime depression

Huntington disease (HD) is a severe neuropsychiatric disorder caused by a cytosine-adenine-guanine (CAG) repeat expansion in the HTT gene. Although HD is frequently complicated by depression, it is still unknown to what extent common HTT CAG repeat size variations in the normal range could affect depression risk in the general population. Using binary logistic regression, we assessed the association between HTT CAG repeat size and depression risk in two well-characterized Dutch cohorts─the Netherlands Study of Depression and Anxiety and the Netherlands Study of Depression in Older Persons─including 2165 depressed and 1058 non-depressed persons. In both cohorts, separately as well as combined, there was a significant non-linear association between the risk of lifetime depression and HTT CAG repeat size in which both relatively short and relatively large alleles were associated with an increased risk of depression (β = −0.292 and β = 0.006 for the linear and the quadratic term, respectively; both P < 0.01 after adjustment for the effects of sex, age, and education level). The odds of lifetime depression were lowest in persons with a HTT CAG repeat size of 21 (odds ratio: 0.71, 95% confidence interval: 0.52 to 0.98) compared to the average odds in the total cohort. In conclusion, lifetime depression risk was higher with both relatively short and relatively large HTT CAG repeat sizes in the normal range. Our study provides important proof-of-principle that repeat polymorphisms can act as hitherto unappreciated but complex genetic modifiers of depression