Is Gestational Diabetes Mellitus an Important Contributor to Metabolic Disorders in Trinidad and Tobago?

Objective. To investigate the incidence of Gestational Diabetes Mellitus at the Mt. Hope Women's Hospital and to describe its epidemiological pattern. Design. A retrospective observational study (Jan 2005 to Dec 2007). Setting. A teaching hospital of The University of the West Indies. Population/Sample. Pregnant women who gave birth. Methods. A sample size of 720. The variables analyzed were: age, ethnicity, BMI of mother, family history of diabetes; history of GDM, obstetric history, birth weight and APGAR score of infant. Main Outcome Measures. (1) Incidence of cases of GDM. (2) Impact of the measured variable. Chi-squares, odds ratios and logistic regression were performed. Results. The incidence of GDM was 4.31% (95% C.I. 2.31%, 6.31%). The proportion of GDM patients for the years 2005, 2006, and 2007 were 1.67%, 4.58%, and 6.67%, respectively. Age, Obesity Ethnicity, Family history of diabetes and a history of GDM were determined risk factors. Associations between GDM and (1) Mode of Delivery and (2) APGAR score of the baby were found. Discussion & Conclusion. There was an apparent increase in the incidence of GDM. Additional studies should be conducted to measure the occurrence of GDM in Trinidad and Tobago. Efforts to promote public awareness and a healthy lifestyle should be made to reverse this trend

GSI-I (Z-LLNle-CHO) inhibits γ-secretase and the proteosome to trigger cell death in precursor-B acute lymphoblastic leukemia

Gamma secretase inhibitors (GSIs) comprise a growing class of compounds that interfere with the membrane-bound Notch signaling protein and its downstream intra-nuclear transcriptional targets. As GSI-I (Z-LLNle-CHO) is also a derivative of a widely used proteosome inhibitor MG-132, we hypothesized that this compound might be active in precursor-B acute lymphoblastic leukemia (ALL) cell lines and patient samples. We found that GSI-I treatment of precursor-B ALL blasts induced apoptotic cell death within 18–24 h. With confirmation using RNA and protein analyses, GSI-I blocked nuclear accumulation of cleaved Notch1 and Notch2, and inhibited Notch targets Hey2 and Myc. Microarray analyses of 207 children with high-risk precursor-B ALL demonstrate that Notch pathway expression is a common feature of these neoplasms. However, microarray studies also implicated additional transcriptional targets in GSI-I-dependent cell death, including genes in the unfolded protein response, nuclear factor-κB and p53 pathways. Z-LLNle-CHO blocks both γ-secretase and proteosome activity, inducing more robust cell death in precursor-B ALL cells than either proteosome-selective or γ-secretase-selective inhibitors alone. Using Z-LLNle-CHO in a nonobese diabetes/severe combined immunodeficiency (NOD/SCID) precursor-B ALL xenograft model, we found that GSI-I alone delayed or prevented engraftment of B-lymphoblasts in 50% of the animals comprising the experimental group, suggesting that this compound is worthy of additional testing

HIV/TB Co-Infection in Mainland China: A Meta-Analysis

Background: TB and HIV co-epidemic is a major public health problem in many parts of the world, particularly in developing counties. We aimed to summarize the prevalence of TB and HIV co-infection in mainland China, using meta-analysis based on systematic review of published articles. Methods: We systematically reviewed published studies, from the MEDLINE and Chinese BioMedical Literature Databases, on the prevalence of HIV infection among TB patients and on the prevalence of TB among HIV/AIDS population until 15 April 2010, and quantitatively summarized the estimates using meta-analysis. Results: In total, 29 studies were included in this review, with consistently homogeneous results. TB patients, for whom the summary prevalence of HIV infection was 0.9 % (0.6%–1.4%) in mainland China, were found to be a potential target population for HIV screening. The prevalence of TB among HIV/AIDS population was 7.2 % (4.2%–12.3%), but this was much higher when the analyses were restricted to AIDS patients (22.8%). Significantly higher prevalence was observed for males and hospital-based studies. Conclusions: Our analyses indicated that the prevalence of HIV/TB co-infection in China deserves special attention, screening of TB among HIV/AIDS populations should be attached more importance, which would be much more helpful for treatment of both diseases

Cardiac fibrosis in aging mice

Dystrophic cardiac calcinosis (DCC), also called epicardial and myocardial fibrosis and mineralization, has been detected in mice of a number of laboratory inbred strains, most commonly C3H/HeJ and DBA/2J. In previous mouse breeding studies between these DCC susceptible and the DCC-resistant strain C57BL/6J, 4 genetic loci harboring genes involved in DCC inheritance were identified and subsequently termed Dyscalc loci 1 through 4. Here, we report susceptibility to cardiac fibrosis, a sub-phenotype of DCC, at 12 and 20 months of age and close to natural death in a survey of 28 inbred mouse strains. Eight strains showed cardiac fibrosis with highest frequency and severity in the moribund mice. Using genotype and phenotype information of the 28 investigated strains, we performed genome-wide association studies (GWAS) and identified the most significant associations on chromosome (Chr) 15 at 72 million base pairs (Mb) (P < 10(-13)) and Chr 4 at 122 Mb (P < 10(-11)) and 134 Mb (P < 10(-7)). At the Chr 15 locus, Col22a1 and Kcnk9 were identified. Both have been reported to be morphologically and functionally important in the heart muscle. The strongest Chr 4 associations were located approximately 6 Mb away from the Dyscalc 2 quantitative trait locus peak within the boundaries of the Extl1 gene and in close proximity to the Trim63 and Cap1 genes. In addition, a single-nucleotide polymorphism association was found on chromosome 11. This study provides evidence for more than the previously reported 4 genetic loci determining cardiac fibrosis and DCC. The study also highlights the power of GWAS in the mouse for dissecting complex genetic traits.The authors thank Jesse Hammer and Josiah Raddar for technical assistance. Research reported in this publication was supported by the Ellison Medical Foundation, Parker B. Francis Foundation, and the National Institutes of Health (R01AR055225 and K01AR064766). Mouse colonies were supported by the National Institutes of Health under Award Number AG025707 for the Jackson Aging Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The Jackson Laboratory Shared Scientific Services were supported in part by a Basic Cancer Center Core Grant from the National Cancer Institute (CA34196).This is the author accepted manuscript. The final version is available from Springer via http://dx.doi.org/10.1007/s00335-016-9634-

The Heart Is an Early Target of Anthrax Lethal Toxin in Mice: A Protective Role for Neuronal Nitric Oxide Synthase (nNOS)

Anthrax lethal toxin (LT) induces vascular insufficiency in experimental animals through unknown mechanisms. In this study, we show that neuronal nitric oxide synthase (nNOS) deficiency in mice causes strikingly increased sensitivity to LT, while deficiencies in the two other NOS enzymes (iNOS and eNOS) have no effect on LT-mediated mortality. The increased sensitivity of nNOS−/− mice was independent of macrophage sensitivity to toxin, or cytokine responses, and could be replicated in nNOS-sufficient wild-type (WT) mice through pharmacological inhibition of the enzyme with 7-nitroindazole. Histopathological analyses showed that LT induced architectural changes in heart morphology of nNOS−/− mice, with rapid appearance of novel inter-fiber spaces but no associated apoptosis of cardiomyocytes. LT-treated WT mice had no histopathology observed at the light microscopy level. Electron microscopic analyses of LT-treated mice, however, revealed striking pathological changes in the hearts of both nNOS−/− and WT mice, varying only in severity and timing. Endothelial/capillary necrosis and degeneration, inter-myocyte edema, myofilament and mitochondrial degeneration, and altered sarcoplasmic reticulum cisternae were observed in both LT-treated WT and nNOS−/− mice. Furthermore, multiple biomarkers of cardiac injury (myoglobin, cardiac troponin-I, and heart fatty acid binding protein) were elevated in LT-treated mice very rapidly (by 6 h after LT injection) and reached concentrations rarely reported in mice. Cardiac protective nitrite therapy and allopurinol therapy did not have beneficial effects in LT-treated mice. Surprisingly, the potent nitric oxide scavenger, carboxy-PTIO, showed some protective effect against LT. Echocardiography on LT-treated mice indicated an average reduction in ejection fraction following LT treatment in both nNOS−/− and WT mice, indicative of decreased contractile function in the heart. We report the heart as an early target of LT in mice and discuss a protective role for nNOS against LT-mediated cardiac damage

Correlations Between Gene Expression and Mercury Levels in Blood of Boys With and Without Autism

Gene expression in blood was correlated with mercury levels in blood of 2- to 5-year-old boys with autism (AU) compared to age-matched typically developing (TD) control boys. This was done to address the possibility that the two groups might metabolize toxicants, such as mercury, differently. RNA was isolated from blood and gene expression assessed on whole genome Affymetrix Human U133 expression microarrays. Mercury levels were measured using an inductively coupled plasma mass spectrometer. Analysis of covariance (ANCOVA) was performed and partial correlations between gene expression and mercury levels were calculated, after correcting for age and batch effects. To reduce false positives, only genes shared by the ANCOVA models were analyzed. Of the 26 genes that correlated with mercury levels in both AU and TD boys, 11 were significantly different between the groups (P(Diagnosis*Mercury) ≤ 0.05). The expression of a large number of genes (n = 316) correlated with mercury levels in TD but not in AU boys (P ≤ 0.05), the most represented biological functions being cell death and cell morphology. Expression of 189 genes correlated with mercury levels in AU but not in TD boys (P ≤ 0.05), the most represented biological functions being cell morphology, amino acid metabolism, and antigen presentation. These data and those in our companion study on correlation of gene expression and lead levels show that AU and TD children display different correlations between transcript levels and low levels of mercury and lead. These findings might suggest different genetic transcriptional programs associated with mercury in AU compared to TD children

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

The Changing Face of Death in Trinidad and Tobago, before and after Independence

Objectives: The aim of this study is to compare the changing patterns of mortality in adults and infants during the pre-independence period 1953–1962 with the post-independence period 1962–2006 thus providing evidence for the burden of disease and the impact of independence on the state of health of the nation. Methods: The study examined data from 1953–2006, collected under statutory regulations by the Central Statistical Office. Results: While the population doubled during the study period, the standardized death rate improved from 16.4 to 4.5, infant mortality also declined from 70 per 1000 live births to 10.5 per 1000 live births. Mortality from selected infectious diseases also declined, however, mortality from chronic diseases continued to increase. Deaths associated with HIV increased during the 1990s, reaching a peak of 42 per 100 000 population in 2001 before declining. Conclusion: Like the developed world, some developing countries have experienced similar transitions in the patterns of disease occurrence and thus will need to develop strategies to effectively cope with these new challenges. Keywords: Burden of disease, epidemiological transition, GDP, infant mortality, mortality "La faz Cambiante de la Muerte en Trinidad y Tobago, antes y después de la Independencia" RESUMEN Objetivos: El objetivo de este estudio es comparar los patrones cambiantes de mortalidad en adultos y niños durante el periodo de pre-independencia de 1953–1962 y el periodo de la post-independencia de 1962–2006, y brindar así evidencia en relación con la carga de enfermedades y el impacto de la independencia sobre el estado de salud de la nación. Métodos: El estudio examinó los datos de 1953–2006, recogidos bajo regulaciones obligatorias por la Oficina Central de Estadísticas. Resultados: Aunque la población se duplicó durante el periodo de estudio, la tasa de mortalidad estandarizada mejoró de 16.4 a 4.5, la mortalidad infantil también disminuyó de 70 por 1000 nacidos vivos a 10.5 por 1000 nacidos vivos. La mortalidad por enfermedades infecciosas seleccionadas también disminuyó. Sin embargo, la mortalidad de las enfermedades crónicas continuó aumentando. Las muertes asociadas con el VIH aumentaron durante los años 90, alcanzando un pico de 42 por 100 000 de población en 2001 antes de disminuir. Conclusión: Al igual que el mundo desarrollado, algunos países en desarrollo han experimentado transiciones similares en los patrones de manifestación de las enfermedades, y por ende necesitarán desarrollar estrategias para hacer frente a estos nuevos desafíos de manera efectiva. Palabras claves: carga de enfermedad, transición epidemiológica, producto interno bruto (PIB), mortalidad infantil, mortalida

The occurrence of left ventricular hypertrophy in normotensive individuals in a community setting in North-East Trinidad

Romel Bacchus, Kristianna Singh, Ijaz Ogeer, Kameel MungrueDepartment Paraclinical Sciences, Public Health and Primary Care Unit, Faculty of Medical Sciences, University of the West Indies, EWMSC, Mt Hope TrinidadObjective: The purpose of this study is to determine primarily the occurrence of left ventricular hypertrophy (LVH) in normotensive Trinidadians.Design and methods: Enrolment into the study required participants to have normal blood pressure (&le;140/90) using the JNC 7 (The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure) classification, free of type 2 diabetes, as well as no existing LVH. Upon entry into the study, participants were first screened for LVH using a standard 12-lead electrocardiogram (ECG), using the Sokolow&ndash;Lyon index and the Cornell index. ECHO was used to confirm or refute the diagnosis of LVH.Results: A total of 209 patients met the criteria for entry into the study. Of these, 63.6% had LVH using Cornell criteria and 68.2% using LVH by Sokolow&ndash;Lyon criteria. Subsequently, ECHO confirmed the diagnosis in 2.9% using American Society of Echocardiography criteria and 1.5% using World Health Organization criteria. Thus the estimated prevalence of LVH in normotensive individuals was approximately 3%.Conclusion: The estimated prevalence of LVH in normotensive individuals appears to be relatively high if an ECG is the single investigation performed, which is common in our setting and may also be common in the developing world. However, using ECHO, the prevalence of LVH approaches a value similarly reported in the literature. Therefore, these findings raise two important issues: 1) the use of criteria such as the Cornell and Sokolow&ndash;Lyon voltage criteria established in the developed world from populations of vastly different ethnic backgrounds may not be widely applicable, and 2) all individuals suspected of having LVH should have an ECHO.Keywords: hypertension, normotensive, echocardiography, Sokolow&ndash;Lyo