Early Bactericidal Activity Trial of Nitazoxanide for Pulmonary Tuberculosis.

This study was conducted in treatment-naive adults with drug-susceptible pulmonary tuberculosis in Port-au-Prince, Haiti, to assess the safety, bactericidal activity, and pharmacokinetics of nitazoxanide (NTZ). This was a prospective phase II clinical trial in 30 adults with pulmonary tuberculosis. Twenty participants received 1 g of NTZ orally twice daily for 14 days. A control group of 10 participants received standard therapy over 14 days. The primary outcome was the change in time to culture positivity (TTP) in an automated liquid culture system. The most common adverse events seen in the NTZ group were gastrointestinal complaints and headache. The mean change in TTP in sputum over 14 days in the NTZ group was 3.2 h ± 22.6 h and was not statistically significant (P = 0.56). The mean change in TTP in the standard therapy group was significantly increased, at 134 h ± 45.2 h (P < 0.0001). The mean NTZ MIC for Mycobacterium tuberculosis isolates was 12.3 µg/ml; the mean NTZ maximum concentration (Cmax) in plasma was 10.2 µg/ml. Negligible NTZ levels were measured in sputum. At the doses used, NTZ did not show bactericidal activity against M. tuberculosis Plasma concentrations of NTZ were below the MIC, and its negligible accumulation in pulmonary sites may explain the lack of bactericidal activity. (This study has been registered at ClinicalTrials.gov under identifier NCT02684240.).

The effects of diet and sex in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease with no known cure. Approximately 90% of ALS cases are sporadic, suggesting there are multiple contributing factors that influence the disease risk, onset, and progression. Diet and sex are two factors that have been reported to alter ALS risk, onset and progression in humans and in animal models, providing potential modifiers of disease. Several epidemiological studies have identified diets that positively affect ALS patients, including various high-calorie fat or sugar-based diets, while animal models have been developed to test how these diets are working on a molecular level. These diets may offset the metabolic alterations that occur in ALS, such as hypermetabolism, lowered body mass index(BMI), and hyperlipidemia. Sex-dependent differences have also come forth from large-scale epidemiological studies as well as mouse-model studies. In addition, sex hormones have been shown to affect disease risk or progression. Herein, studies on the effects of diet and sex on ALS risk, onset, and progression will be reviewed. Understanding these diet- and sex-dependent outcomes may lead to optimized patient-specific therapies for ALS.

Trends in proportion of older HIV-infected people in care in Latin America and the Caribbean: a growing challenge.

We aimed to quantify the proportion of people receiving care for HIV-infection that are 50 years or older (older HIV patients) in Latin America and the Caribbean between 2000 and 2015 and to estimate the contribution to the growth of this population of people enrolled before (<50yo) and after 50 years old (yo) (⩾50yo). We used a series of repeated, cross-sectional measurements over time in the Caribbean, Central and South American network (CCASAnet) cohort. We estimated the percentage of patients retained in care each year that were older HIV patients. For every calendar year, we divided patients into two groups: those who enrolled before age 50 and after age 50. We used logistic regression models to estimate the change in the proportion of older HIV patients between 2000 and 2015. The percentage of CCASAnet HIV patients over 50 years had a threefold increase (8% to 24%) between 2000 and 2015. Most of the growth of this population can be explained by the increasing proportion of people that enrolled before 50 years and aged in care. These changes will impact needs of care for people living with HIV, due to multiple comorbidities and high risk of disability associated with aging.

[Psychological trauma as risk for delayed psychiatric disorders: epigenetic mechanisms]. / Psychotrauma als Risiko für spätere psychische Störungen : Epigenetische Mechanismen.

BACKGROUND: Psychological trauma is considered to be a risk factor for the development of a number of psychiatric disorders. Although 40-90% of the population is exposed to a traumatic event in their lifetime, only a small fraction of individuals will develop a disorder. In recent years, numerous studies described epigenetic changes, such as DNA methylation, histone modifications and non-coding RNA as potential biological mechanisms by which the environment can have long-term effects on an organism. METHODS AND RESULTS: This article reviews the accumulating evidence for the involvement of epigenetic factors in the development of psychiatric disorders associated with psychological trauma. Clinically the review focuses on posttraumatic stress disorder (PTSD) for which trauma is a diagnostic criterion. In this context, we specifically focus on studies that show trauma and disease-associated epigenetic changes in humans and animal models. Both tissue-specific as well as cross-tissue effects have been described and underline the global consequences of psychological trauma on the whole organism. In addition, possible epigenetic mechanisms are presented which could be responsible for the long-lasting effects of gene-environment interactions in psychiatric disorders. Finally, the review addresses how a better understanding of these epigenetic mechanisms could suggest avenues for possible future pharmacological and psychotherapeutic treatment approaches.

Association of PHB 1630 C>T and MTHFR 677 C>T polymorphisms with breast and ovarian cancer risk in BRCA1/2 mutation carriers: results from a multicenter study.

BACKGROUND: The variable penetrance of breast cancer in BRCA1/2 mutation carriers suggests that other genetic or environmental factors modify breast cancer risk. Two genes of special interest are prohibitin (PHB) and methylene-tetrahydrofolate reductase (MTHFR), both of which are important either directly or indirectly in maintaining genomic integrity. METHODS: To evaluate the potential role of genetic variants within PHB and MTHFR in breast and ovarian cancer risk, 4102 BRCA1 and 2093 BRCA2 mutation carriers, and 6211 BRCA1 and 2902 BRCA2 carriers from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA) were genotyped for the PHB 1630 C>T (rs6917) polymorphism and the MTHFR 677 C>T (rs1801133) polymorphism, respectively. RESULTS: There was no evidence of association between the PHB 1630 C>T and MTHFR 677 C>T polymorphisms with either disease for BRCA1 or BRCA2 mutation carriers when breast and ovarian cancer associations were evaluated separately. Analysis that evaluated associations for breast and ovarian cancer simultaneously showed some evidence that BRCA1 mutation carriers who had the rare homozygote genotype (TT) of the PHB 1630 C>T polymorphism were at increased risk of both breast and ovarian cancer (HR 1.50, 95%CI 1.10-2.04 and HR 2.16, 95%CI 1.24-3.76, respectively). However, there was no evidence of association under a multiplicative model for the effect of each minor allele. CONCLUSION: The PHB 1630TT genotype may modify breast and ovarian cancer risks in BRCA1 mutation carriers. This association need to be evaluated in larger series of BRCA1 mutation carriers.

Dental Caries Severity and Nutritional Status of Nigerian Preschool Children.

INTRODUCTION: Malnutrition in children is one of the most prevalent global health challenges, and malnourished children have a higher risk of death from childhood diseases. Early childhood caries (ECC) is the most common chronic disease of childhood. Complications from ECC such as pain, loss of tooth/teeth, and infection can undermine a child's nutrition and growth. AIM: This study aims to evaluate the severity of decay, missing, and filled tooth (dmft) by nutritional status using the z scores of the anthropometric measurements: height for age (HFA), weight for age (WFA), weight for height (WFH), and body mass index for age (BMIA) among children with ECC in Nigeria. STUDY DESIGN: This is a cross-sectional study conducted in 5 local government areas (LGAs) in Lagos State, Nigeria. A multistage sampling technique was used. RESULTS: A total of 273 cases of ECC were included in the analyses (mean age 4.19 ± 0.96 y). Overall, the mean dmft was 3.04 ± 2.28, and most (96%) were accounted for by untreated decay. The distribution of dmft within the different z score categories of BMIA (<-3 = severely wasted, -2 to -3 = wasted, -2 to +2 = normal, +2 to +3 = overweight and >+3 = obese) showed the highest dmft scores among the combined severely wasted and wasted groups, lowest among children with normal z scores, and intermediate in the overweight and obese groups. There was a significant negative correlation between BMIA z score, WFH z score, and dmft (r = -0.181, P < 0.05 and r = -0.143, P < 0.05, respectively). However, the correlations between HFA z score, WFA z score, and dmft were positive but not significant (r = 0.048, P = 0.44 and r = 0.022, P = 0.77, respectively). CONCLUSION: Our study showed an increased severity of dental caries among severely wasted or wasted children with ECC compared to those of normal or overweight. KNOWLEDGE TRANSFER STATEMENT: The results from this study will raise awareness among clinicians and policy makers on the need for a primary prevention program for early childhood caries in countries with high burden of malnutrition and limited resources. Also, it will help draw the attention of clinicians to the caries status of malnourished children that can be managed to improve the nutritional outcomes.

Genome-wide Gene-by-Sex Interaction Studies Identify Novel Nonsyndromic Orofacial Clefts Risk Locus.

Risk loci identified through genome-wide association studies have explained about 25% of the phenotypic variations in nonsyndromic orofacial clefts (nsOFCs) on the liability scale. Despite the notable sex differences in the incidences of the different cleft types, investigation of loci for sex-specific effects has been understudied. To explore the sex-specific effects in genetic etiology of nsOFCs, we conducted a genome-wide gene × sex (GxSex) interaction study in a sub-Saharan African orofacial cleft cohort. The sample included 1,019 nonsyndromic orofacial cleft cases (814 cleft lip with or without cleft palate and 205 cleft palate only) and 2,159 controls recruited from 3 sites (Ethiopia, Ghana, and Nigeria). An additive logistic model was used to examine the joint effects of the genotype and GxSex interaction. Furthermore, we examined loci with suggestive significance (P < 1E-5) in the additive model for the effect of the GxSex interaction only. We identified a novel risk locus on chromosome 8p22 with genome-wide significant joint and GxSex interaction effects (rs2720555, p2df = 1.16E-08, pGxSex = 1.49E-09, odds ratio [OR] = 0.44, 95% CI = 0.34 to 0.57). For males, the risk of cleft lip with or without cleft palate at this locus decreases with additional copies of the minor allele (p < 0.0001, OR = 0.60, 95% CI = 0.48 to 0.74), but the effect is reversed for females (p = 0.0004, OR = 1.36, 95% CI = 1.15 to 1.60). We replicated the female-specific effect of this locus in an independent cohort (p = 0.037, OR = 1.30, 95% CI = 1.02 to 1.65), but no significant effect was found for the males (p = 0.29, OR = 0.86, 95% CI = 0.65 to 1.14). This locus is in topologically associating domain with craniofacially expressed and enriched genes during embryonic development. Rare coding mutations of some of these genes were identified in nsOFC cohorts through whole exome sequencing analysis. Our study is additional proof that genome-wide GxSex interaction analysis provides an opportunity for novel findings of loci and genes that contribute to the risk of nsOFCs.

Recovery of menses after functional hypothalamic amenorrhoea: if, when and why.

BACKGROUND: Prolonged amenorrhoea occurs as a consequence of functional hypothalamic amenorrhoea (FHA) which is most often induced by weight loss, vigorous exercise or emotional stress. Unfortunately, removal of these triggers does not always result in the return of menses. The prevalence and conditions underlying the timing of return of menses vary strongly and some women report amenorrhoea several years after having achieved and maintained normal weight and/or energy balance. A better understanding of these factors would also allow improved counselling in the context of infertility. Although BMI, percentage body fat and hormonal parameters are known to be involved in the initiation of the menstrual cycle, their role in the physiology of return of menses is currently poorly understood. We summarise here the current knowledge on the epidemiology and physiology of return of menses. OBJECTIVE AND RATIONALE: The aim of this review was to provide an overview of (i) factors determining the recovery of menses and its timing, (ii) how such factors may exert their physiological effects and (iii) whether there are useful therapeutic options to induce recovery. SEARCH METHODS: We searched articles published in English, French or German language containing keywords related to return of menses after FHA published in PubMed between 1966 and February 2020. Manuscripts reporting data on either the epidemiology or the physiology of recovery of menses were included and bibliographies were reviewed for further relevant literature. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) criteria served to assess quality of observational studies. OUTCOMES: Few studies investigate return of menses and most of them have serious qualitative and methodological limitations. These include (i) the lack of precise definitions for FHA or resumption of menses, (ii) the use of short observation periods with unsatisfactory descriptions and (iii) the inclusion of poorly characterised small study groups. The comparison of studies is further hampered by very inhomogeneous study designs. Consequently, the exact prevalence of resumption of menses after FHA is unknown. Also, the timepoint of return of menses varies strongly and reliable prediction models are lacking. While weight, body fat and energy availability are associated with the return of menses, psychological factors also have a strong impact on the menstrual cycle and on behaviour known to increase the risk of FHA. Drug therapies with metreleptin or naltrexone might represent further opportunities to increase the chances of return of menses, but these require further evaluation. WIDER IMPLICATIONS: Although knowledge on the physiology of return of menses is presently rudimentary, the available data indicate the importance of BMI/weight (gain), energy balance and mental health. The physiological processes and genetics underlying the impact of these factors on the return of menses require further research. Larger prospective studies are necessary to identify clinical parameters for accurate prediction of return of menses as well as reliable therapeutic options.

Four-year review of admissions to a South African regional hospital general surgery department.

BACKGROUND: There are limited published data describing surgical admissions at a regional hospital level in the South African (SA) context. OBJECTIVES: To retrospectively review data from an electronic discharge summary  database at a regional SA hospital from 2012 to 2016 to describe the burden of surgical disease by analysing characteristics of the patients admitted. METHODS: All discharge summary records for the 4-year period were reviewed after extraction from a database created for the surgery department. Admissions were classified into 5 types: (i) elective surgery or investigations (ESI); (ii) trauma; (iii) burns; (iv) non-traumatic surgical emergencies (NTSE); and (v) unplanned readmission within 30 days. Other variables reviewed were demographic data, the International Statistical Classification of Diseases and Related Health Problems - Version 10 (ICD-10) diagnosis; area of origin; and outcome (death, tertiary referral, discharge). Data were subgrouped into 12-month periods to facilitate trend analysis. RESULTS: Discharge summaries (N=9 805) over the 4-year study period were assessed and 9 799 were included in the analysis. All data were entered by the attending medical personnel. A total of 5 647 male patients (57.6%) and 4 152 female patients (42.4%) were admitted, with a mean age of 43.3 years (95% confidence interval (CI) 43.0 - 43.8) and a mean length of stay of 4.9 days (95% CI 4.7 - 5.1). Male patients comprised a larger proportion of trauma (83.7%) and burn (63.9%) admissions. The mean length of stay ranged from 3.5 days for elective patients to 9.1 days for burn patients. The most common diagnoses for emergency admissions were appendicitis, peripheral vascular disease and peptic ulcer disease. Common diagnoses for elective admissions were gallstone disease, inguinal hernia, anal fistulas/fissures, and ventral and incisional hernia. The most common cancer diagnoses were of the colorectum, oesophagus, breast and stomach. The overall mortality rate was 2.2%, and highest by subtype was burn patients (6.3%). Trend analysis showed a statistically significant increase in admission for NTSE (p=0.019), trauma (p<0.001) and 30-day readmission rates (p<0.001), with a decrease in admissions for ESI (p=0.001) over the 4 years. CONCLUSIONS: A precise understanding of the burden of disease profile is essential for national, provincial and district budgeting and resource allocation. Ongoing surveillance such as that performed in the study provides this critical information.

Diagnostic yield of active case finding for tuberculosis at human immunodeficiency virus testing in Haiti.

SETTING: The Groupe Haïtien d'étude du Sarcome de Kaposi et des Infections Opportunistes (GHESKIO) Centres, Port-au-Prince, Haiti, facilitate "test and treat" strategies by screening all patients for tuberculosis (TB) at human immunodeficiency virus (HIV) testing.OBJECTIVE: 1) To determine the proportion of patients with chronic cough at HIV testing diagnosed with TB, stratified by HIV test results; and 2) to evaluate the additional diagnostic yield of Xpert® MTB/RIF vs. sputum microscopy.DESIGN: We conducted a retrospective cohort analysis including all adults tested for HIV at GHESKIO from August 2014 to July 2015.RESULTS: Of 29 233 adult patients tested for HIV, 2953 (10%) were diagnosed as HIV-positive. Chronic cough lasting ≥2 weeks was reported by 1116 (38%) HIV-positive patients; 984 (88%) were tested and 265 (27%) were diagnosed with TB. Chronic cough was reported by 5985 (23%) HIV-negative patients; 5654 (94%) were tested and 1179 (21%) were diagnosed with TB. Of all bacteriologically confirmed cases, 27% were smear-negative and Xpert-positive. Among all TB patients, 81% were HIV-negative.CONCLUSIONS: Screening for TB at HIV testing was high-yield, among both HIV-infected and HIV-negative individuals. Testing for both diseases should be conducted among patients who present with chronic cough at HIV testing.

Blood transcriptomic markers of Mycobacterium tuberculosis load in sputum.

BACKGROUND: Peripheral blood transcriptome signatures that distinguish active pulmonary tuberculosis (TB) from control groups have been reported, but correlations of these signatures with sputum mycobacterial load are incompletely defined. METHODS: We assessed the performance of published TB transcriptomic signatures in Haiti, and identified transcriptomic biomarkers of TB bacterial load in sputum as measured by Xpert® MTB/RIF molecular testing. People in Port au Prince, Haiti, with untreated pulmonary TB (n = 51) formed the study cohort: 19 people with low and 32 with high sputum Mycobacterium tuberculosis load. Peripheral whole blood transcriptomes were generated using RNA sequencing. RESULTS: Twenty of the differentially expressed transcripts in TB vs. no TB were differentially expressed in people with low vs. high sputum mycobacterial loads. The difference between low and high bacterial load groups was independent of radiographic severity. In a published data set of transcriptomic response to anti-tuberculosis treatment, this 20-gene subset was more treatment-responsive at 6 months than the full active TB signature. CONCLUSION: We identified genes whose transcript levels in the blood distinguish active TB with high vs. low M. tuberculosis loads in the sputum. These transcripts may reveal mechanisms of mycobacterial control of M. tuberculosis during active infection, as well as identifying potential biomarkers for bacterial response to anti-tuberculosis treatment.

Outcomes across the tuberculosis care continuum among adolescents in Haiti.

Setting: GHESKIO (Groupe Haitien d'Etude du Sarcome de Kaposi et des Infections Opportunistes) clinic, Port-au-Prince, Haiti. Objective: To evaluate tuberculosis (TB) care continuum outcomes among adolescents. Design: Among a retrospective cohort of 10-24 year olds diagnosed with active TB, we report completion of the following steps of the TB care continuum stratified by human immunodeficiency virus (HIV) status: diagnosis of microbiologically confirmed TB, initiation of anti-tuberculosis treatment, retention in care at 2 months on anti-tuberculosis treatment, and TB treatment success. Factors associated with attrition at each step were identified using multivariable regression. Results: A total of 1005 adolescents were diagnosed with active TB; 74 (7%) were HIV-positive at the time of TB diagnosis. HIV-positive patients had poorer outcomes than non-HIV-infected patients: 73% vs. 85% initiated anti-tuberculosis treatment (P < 0.01), 46% vs. 74% were retained in care at 2 months (P < 0.01), and 41% vs. 68% achieved TB treatment success (P < 0.01). Among those who initiated treatment, same-day initiation resulted in less treatment failure. Attrition before treatment initiation was associated with female sex and HIV coinfection. Attrition after treatment initiation was associated with age ⩾16 years and HIV coinfection. Conclusion: Outcomes across the TB care continuum are suboptimal among adolescents, with only two thirds of patients achieving treatment success. Interventions tailored to adolescents are needed to improve retention in care, particularly for those who are co-infected with HIV.

Contexte : Centre de santé, Groupe Haitien d'Etude du Sarcome de Kaposi et des Infections Opportunistes, Port-au-Prince, Haïti.Objectif : Evaluer les résultats tout au long de la prise en charge de la tuberculose (TB) parmi les adolescents.Schéma : Parmi une cohorte rétrospective d'adolescents âgés de 10­24 ans ayant eu un diagnostic de TB active, nous rapportons le déroulement des étapes suivantes des soins de la TB stratifiés par statut virus de l'immunodéficience humaine (VIH) : diagnostic de TB confirmée par microbiologie ; mise en route du traitement de la TB ; rétention en soins à 2 mois sous traitement de TB ; et succès du traitement de TB. Les facteurs associés à l'attrition à chaque étape ont été identifiés grâce à une régression logistique multivariée.Résultats: Des 1005 adolescents qui ont eu un diagnostic de TB active, 74 (7%) ont été positifs au VIH au moment du diagnostic de TB. Les patients VIH positifs ont eu des résultats plus médiocres comparés aux patients non infectés par le VIH : 73% contre 85% ont mis en route le traitement de TB (P < 0,01), 46% contre 74% sont restés sous traitement à 2 mois (P < 0,01) et 41% contre 68% ont achevé le traitement avec succès (P < 0,01). Parmi ceux qui ont mis en route le traitement, une prise dès le premier jour a abouti à moins d'échec du traitement. L'attrition avant le début du traitement a été associée au sexe féminin et à la coinfection à VIH. L'attrition après mise en route du traitement a été associée à un âge ⩾16 ans et à la coinfection à VIH.Conclusion : Les résultats au niveau de la continuité des soins de TB sont sousoptimaux parmi les adolescents, dont seulement deux tiers achèvent le traitement avec succès. Des interventions adaptées aux adolescents sont requises pour améliorer la rétention en soins, particulièrement pour ceux qui sont coinfectés par le VIH.

Marco de Referencia: El centro du Groupe Haitien d'Etude du Sarcome de Kaposi et des Infections Opportunistes de Port-au-Prince, en Haití.Objetivo: Evaluar los resultados del proceso asistencial continuo de la tuberculosis (TB) en los adolescentes.Método: En una cohorte retrospectiva de jóvenes de 10­24 años de edad con diagnóstico de TB activa, se comunican los resultados logrados en las siguientes etapas del proceso asistencial continuo de la TB, estratificados según la situación frente al virus de la inmunodeficiencia humana (VIH): diagnóstico de TB confirmada microbiológicamente; inicio del tratamiento antituberculoso; retención en la atención a los 2 meses del tratamiento; y el éxito del tratamiento antituberculoso. Se determinaron los factores asociados con el abandono en cada etapa mediante un modelo de regresión multivariante.Resultados: Se diagnosticó TB activa en 1005 adolescentes; 74 de ellos (7%) eran positivos frente al VIH en el momento del diagnóstico de TB. Los pacientes positivos frente al VIH presentaron desenlaces más desfavorables que los pacientes sin infección por el VIH (73% contra 85% inició el tratamiento antituberculoso, P < 0,01; 46% contra 74% continuaba en la atención a los 2 meses, P < 0,01; y 41% contra 68% alcanzó un tratamiento antituberculoso exitoso, P < 0,01). Los jóvenes que iniciaron tratamiento el mismo día de la consulta presentaron menos fracasos terapéuticos. El abandono antes de iniciar el tratamiento se asoció con el sexo femenino y la coinfección por el VIH. El abandono después de haber iniciado el tratamiento se asoció con la edad ⩾16 años y la coinfección por el VIH.Conclusión: Los resultados a lo largo de la continuidad asistencial de la TB son deficientes en los adolescentes, pues solo dos tercios de ellos alcanzan el éxito terapéutico. Se precisan intervenciones adaptadas a los adolescentes que mejoren la retención en los servicios de atención, sobre todo en los pacientes coinfectados por el VIH.

Calcium and sodium transport and vitamin D metabolism in the spontaneously hypertensive rat.

Serum ionized calcium levels are lower and immunoreactive parathyroid hormone levels are higher in the spontaneously hypertensive (SH) rat than in the normotensive Wistar-Kyoto (WKy) control. We postulated that there is either a defect in the regulation of vitamin D metabolism by parathyroid hormone or that the gut target organ for vitamin D in the SH rat is unresponsive. To test these hypotheses we measured serum concentrations of vitamin D metabolites and intestinal transport of calcium and sodium. Compared with that of WKy controls, in vitro calcium transport by duodenal sacs of the SH rat was decreased (P less than 0.001) at 5 wk, before the development of hypertension, and at 12 wk, after hypertension was well established. When measured in vivo in the most proximal 20 cm of small intestine, maximum velocity (Vmax) for calcium transport was decreased (P less than 0.05) and net absorption of sodium and water was increased (P less than 0.05) in SH rats as compared with WKy rats. Vmax for calcium transport was also decreased (P less than 0.05) in the most distal 20 cm of small intestine of SH rats, but net sodium and water transport were the same in SH and WKy rats. At 12 wk, serum concentration of 1,25-dihydroxycholecalciferol [1,25-(OH)2D3] was the same in both SH and WKy groups, but its precursor, 25-hydroxycholecalciferol, was increased (P less than 0.05) in the SH rat. We conclude that in the SH rat: (a) the concentration of 1,25-(OH)2D3 is inappropriately low in relation to the elevated immunoreactive parathyroid hormone and the depressed calcium absorption, suggesting a defect in the regulation of vitamin D metabolism; and (b) the depressed calcium absorption, in the setting of normal concentrations of [1,25-(OH)2D3], demonstrates unresponsiveness of the gut to vitamin D and may explain in part the low serum ionized calcium found in earlier studies. The presence of these abnormalities before we found a significant difference in blood pressure suggests that they may be causal, not secondary, to the hypertension.

Impact of Early Consumption of High-Fat Diet on the Mesolimbic Dopaminergic System.

Increasing evidence suggest that consumption of high-fat diet (HFD) can impact the maturation of brain circuits, such as during adolescence, which could account for behavioral alterations associated with obesity. In the present study, we used behavioral sensitization to amphetamine to investigate the effect of periadolescent HFD exposure (pHFD) in rats on the functionality of the dopamine (DA) system, a central actor in food reward processing. pHFD does not affect responding to an acute injection, however, a single exposure to amphetamine is sufficient to induce locomotor sensitization in pHFD rats. This is paralleled by rapid neurobiological adaptations within the DA system. In pHFD-exposed animals, a single amphetamine exposure induces an increase in bursting activity of DA cells in the ventral tegmental area (VTA) as well as higher DA release and greater expression of (tyrosine hydroxylase, TH) in the nucleus accumbens (NAc). Post-synaptically, pHFD animals display an increase in NAc D2 receptors and c-Fos expression after amphetamine injection. These findings highlight the vulnerability of DA system to the consumption of HFD during adolescence that may support deficits in reward-related processes observed in obesity.

Diagnostic yield of active case finding for tuberculosis and HIV at the household level in slums in Haiti.

SETTING: Haiti has the highest burden of tuberculosis (TB) in the Americas, with an estimated prevalence of 254 per 100 000 population. The Haitian Group for the Study of Kaposi's Sarcoma and Opportunistic Infections (Groupe Haïtien d'Etude du Sarcome de Kaposi et des Infections Opportunistes, GHESKIO) conducted active case finding (ACF) for TB at the household level in nine slums in Port-au-Prince. OBJECTIVE: We report on the prevalence of undiagnosed TB detected through GHESKIO's ACF campaign. DESIGN: From 1 August 2014 to 31 July 2015, we conducted a retrospective cohort analysis using GHESKIO's ACF campaign data. All individuals who reported chronic cough (cough 2 weeks) were tested for TB at GHESKIO, and those aged 10 years were included in the analyses. RESULTS: Of 104 097 individuals screened in the community, 5598 (5%) reported chronic cough and satisfied the study inclusion criteria. A total of 1110 (20%) were diagnosed with active TB disease (prevalence of 1066/100 000). Of the 5472 (98%) patients tested for human immunodeficiency virus (HIV), 528 (10%) were HIV-positive; 143 (3%) patients were diagnosed with both diseases. CONCLUSION: Household-level screening for cough with TB and HIV testing for symptomatic patients was a high-yield strategy, leading to the detection of a prevalence of undiagnosed disease exceeding national estimates by more than four-fold for TB, and by five-fold for HIV.

Childhood cryptosporidiosis is associated with a persistent systemic inflammatory response.

Cryptosporidiosis in young children prompts local inflammation in the intestinal tract. We studied a cohort of young children with cryptosporidiosis to determine whether systemic inflammatory responses occur and, if so, to evaluate whether inflammation persists after infection. Cryptosporidiosis was associated with increased levels of interleukin-8 and tumor necrosis factor- alpha systemically, which persisted at 6 months after enrollment. The level of intestinal tumor necrosis factor- alpha was elevated at enrollment, but elevated levels did not persist. Worsening of malnutrition, particularly stunting, was observed after infection. The association of cryptosporidiosis, inflammation, and stunting in children with cryptosporidiosis warrants further evaluation.

Serum mannose-binding lectin deficiency is associated with cryptosporidiosis in young Haitian children.

BACKGROUND: Mannose-binding lectin (MBL) is a component of the innate immune response and binds microbial surfaces through carbohydrate recognition domains. MBL deficiency may contribute to susceptibility to a variety of infectious diseases, particularly in young children. MBL binds to the Cryptosporidium sporozoite and may be important in resistance to cryptosporidiosis. METHODS: We studied the association of serum MBL levels and cryptosporidiosis in a case-control study of young Haitian children with cryptosporidiosis versus children who were control subjects. RESULTS: Ninety-nine children were enrolled, as follows: 49 children with cryptosporidiosis, 41 healthy controls, and 9 children with diarrhea from other causes. Case children were more malnourished than controls, and 49% had persistent or chronic diarrhea. At enrollment, mean serum MBL levels were markedly lower in children with cryptosporidiosis (P = .002), as was the number of children with an MBL deficiency of < or = 70 ng/mL (P = .005). In multivariate analysis, the association of cryptosporidiosis and MBL deficiency persisted (P = .002; adjusted odds ratio, 22.4), as did the association of cryptosporidiosis with general malnutrition. The subset of children with cryptosporidiosis and MBL deficiency were more likely to be male (P = .025). CONCLUSIONS: MBL may be an important component of innate immune protection against Cryptosporidium infection in young children. Additional studies are necessary to determine whether MBL intestinal losses, deficient epithelial expression, and/or genetic polymorphisms in the MBL gene contribute to MBL deficiency in cryptosporidiosis and other enteric infections in young children.

Immunocytochemical detection of cholecystokinin and corticotrophin-releasing hormone neuropeptides in the hypothalamic paraventricular nucleus of the jerboa (Jaculus orientalis): modulation by immobilisation stress.

The hypothalamic response to an environmental stress implicates the corticotrophin-releasing hormone (CRH) neuroendocrine system of the hypothalamic parvicellular paraventricular nucleus (PVN) in addition to other neuropeptides coexpressed within CRH neurones and controlling the hypothalamo-pituitary-adrenal (HPA) axis activity as well. Such neuropeptides are vasopressin, neurotensin and cholecystokinin (CCK). It has previously been demonstrated that the majority of the CRH neuronal population coexpresses CCK after a peripheral stress in rats. In the present study, we explored such neuroendocrine plasticity in the jerboa in captivity as another animal model. In particular, we studied CCK and CRH expression within the hypothalamic PVN by immunocytochemistry in control versus acute immobilisation stress-submitted jerboas. The results show that CCK- and CRH-immunoreactive neuronal systems are located in the hypothalamic parvicellular PVN. The number of CCK-immunoreactive neurones within the PVN was significantly increased (138% increase) in stressed animals compared to controls. Similarly, the number of CRH-containing neurones was higher in stressed jerboas (128%) compared to controls. These results suggest that the neurogenic stress caused by immobilisation stimulates CCK as well as CRH expression in jerboas, which correlates well with previous data obtained in rats using other stressors. The data obtained also suggest that, in addition to CRH, CCK is another neuropeptide involved in the response to stress in jerboa, acting by controlling HPA axis activity. Because CCK is involved in the phenotypical plasticity of CRH-containing neurones in response to an environmental stress, we also explored their coexpression by double immunocytochemistry within the PVN and the median eminence (i.e. the site of CRH and CCK corelease in the rat) following jerboa immobilisation. The results show that CCK is not coexpressed within CRH neurones in either control or stressed jerboa, suggesting differences between jerboas and rats in the neuroendocrine regulatory mechanisms of the stress response involving CRH and CCK. The adaptative physiological mechanisms to environmental conditions might vary from one mammal species to another.

[Enteric parasites and AIDS in Haiti: utility of detection and treatment of intestinal parasites in family members]. / Parasites intestinaux et sida en Haïti: faut-il déparasiter l'entourage familial?

Intestinal parasites and human immunodeficiency virus (HIV) are major health problems in Haiti. Both entities are known to interact strongly with cell-mediated immunity. The purpose of this study undertaken in Port-au-Prince, Haiti was to evaluate the risk of enteric parasite transmission between HIV-infected patients and family members. Routine examination of stool specimens for parasites was conducted in 90 HIV-infected undergoing treatment for intestinal disorders due mainly to Cryptosporidium sp. (62%) and 123 healthy family member volunteers. A stool sample preserved in 10% formalin solution was examined to detect protozoa (MIF, modified Ziehl-Neelsen stain, Uvibio fluorescence technique, Weber stain) and helminth ova (Bailenger technique). In addition to Cryptosporidium sp., 14 parasitic species were identified: 6 Rhizopoda, 3 Flagellata (including Giardia duodenalis), 1 Coccidia (Cyclospora cayetanensis), 3 Nematoda (mainly Ascaris lumbricoides) and 1 Cestoda (Hymenolepis nana). This is the first time that 5 protozoa, i.e., Blastocystis hominis, Entamoeba hartmanni, E. polecki, Chilomastix mesnili, and Enteromonas hominis, have been reported in Haiti. As expected, enteric parasites were less common in HIV-infected subjects undergoing medical treatment (11.1%) than in uninfected family members (41.5%) (p = 0.0000). Multiple intestinal parasitism (infection by 2 to 4 parasites) was observed in 19.5% of family members. The findings of this study indicate that detecting and treating intestinal parasites in subjects living in close contact with HIV-infected patients as well as informing family members of the importance of personal hygiene in Haiti are highly recommended measures to preserve the health of AIDS patients.

Transgenics identify distal 5'- and 3'-sequences specifying gonadotropin-releasing hormone expression in adult mice.

GnRH neurons play a critical role in regulating gonadotropin secretion, but their scattered distribution has prevented detailed understanding of their molecular and cellular properties in vivo. Using GnRH promoter-driven transgenics we have examined here the role of 5'- and 3'-murine GnRH sequences in specifying GnRH expression in the adult mouse. Transgenic mice bearing a lacZ construct incorporating 5.5 kb of 5'-, all the introns and exons, and 3.5 kb of 3'-murine GnRH sequence were found to express beta-galactosidase (betagal) immunoreactivity in approximately 85% of all GnRH neurons. Deletion of GnRH sequence 3' to exon II had no effect upon transgene expression in the GnRH population (89%) but resulted in the appearance of ectopic betagal immunoreactivity in several regions of the brain. The production of additional mice in which 5'-elements were deleted to leave only -2.1 kb of sequence resulted in an approximately 40% reduction in the number of GnRH neurons expressing betagal. Mice in which further deletion of 400 bp allowed only -1.7 kb of 5'-sequence to remain exhibited a complete absence of betagal immunoreactivity within GnRH and other neurons. These results suggest that elements 3' to exon II of the GnRH gene have little role in enabling GnRH expression within the GnRH phenotype but, instead, are particularly important in repressing the GnRH gene in non-GnRH neurons. In contrast, elements located between -2.1 and -1.7 kb of distal 5'-sequence appear to be critical for the in vivo activation of GnRH expression within GnRH neurons in the adult brain.