Common variants of SLAMF1 and ITLN1 on 1q21 are associated with type 2 diabetes in Indian population

Though multiple studies link chromosomal regions 1q21-q23 and 20q13 with type 2 diabetes, fine mapping of these regions is yet to confirm gene(s) explaining the linkages. These candidate regions remain unexplored in Indians, which is a high-risk population for type 2 diabetes. Hypothesizing regulatory regions to have a more important role in complex disorders, we examined association of 207 common variants in proximal promoter and untranslated regions of genes on 1q21-23 and 20q13 with type 2 diabetes in 2115 North Indians. Further, top signals were replicated in an independent group of 2085 North Indians. Variants-rs11265455-SLAMF1 (odds ratios (OR)=1.32, P=1.1 × 10(-3)), rs1062827-F11R (OR=1.36, P=1.7 × 10(-3)) and rs12565932-F11R (OR=1.35, P=1.8 × 10(-3)) were top signals for association with type 2 diabetes whereas rs1333062-ITLN1 (OR=1.28, P=3.4 × 10(-3)) showed strongest association in body mass index-stratified analysis. Replication of these four variants confirmed associations of rs11265455-SLAMF1 (OR=1.27, P=9.1 × 10(-3)) and rs1333062-ITLN1 (OR=1.25, P=1.1 × 10(-3)) with type 2 diabetes. Meta-analysis further corroborated the association of rs11265455-SLAMF1 (OR random effect=1.29, P random effect=3.9 × 10(-5)) and rs1333062-ITLN1 (OR random effect=1.19, P random effect=1.8 × 10(-4)). In conclusion, the study demonstrates that variants of SLAMF1 and ITLN1, both implicated in inflammation, are associated with type 2 diabetes in Indians.     

Age-Dependent IgG Subclass Responses to Plasmodium falciparum EBA-175 Are Differentially Associated with Incidence of Malaria in Mozambican Children

Plasmodium falciparum blood-stage antigens such as merozoite surface protein 1 (MSP-1), apical membrane antigen 1 (AMA-1), and the 175-kDa erythrocyte binding antigen (EBA-175) are considered important targets of naturally acquired immunity to malaria. However, it is not clear whether antibodies to these antigens are effectors in protection against clinical disease or mere markers of exposure. In the context of a randomized, placebo-controlled trial of intermittent preventive treatment in infants conducted between 2002 and 2004, antibody responses to Plasmodium falciparum blood-stage antigens in a cohort of 302 Mozambican children were evaluated by immunofluorescence antibody test and enzyme-linked immunosorbent assay at 5, 9, 12, and 24 months of age. We found that IgG subclass responses to EBA-175 were differentially associated with the incidence of malaria in the follow-up period. A double amount of cytophilic IgG1 or IgG3 was associated with a significant decrease in the incidence of malaria (incidence rate ratio [IRR] = 0.49, 95% confidence interval [CI] = 0.25 to 0.97, and P = 0.026 and IRR = 0.44, CI = 0.19 to 0.98, and P = 0.037, respectively), while a double amount of noncytophilic IgG4 was significantly correlated with an increased incidence of malaria (IRR = 3.07, CI = 1.08 to 8.78, P = 0.020). No significant associations between antibodies to the 19-kDa fragment of MSP-1 (MSP-1₁₉) or AMA-1 and incidence of malaria were found. Age, previous episodes of malaria, present infection, and neighborhood of residence were the main factors influencing levels of antibodies to all merozoite antigens. Deeper understanding of the acquisition of antibodies against vaccine target antigens in early infancy is crucial for the rational development and deployment of malaria control tools in this vulnerable population.     

Current concepts and management strategies in chronic kidney disease-mineral and bone disorder

ABSTRACT: The term renal osteodystrophy describes the pathological changes in bone structure in chronic kidney disease (CKD); however, this term fails to describe adequately the adverse changes in mineral and hormonal metabolism in CKD that have grave consequences for patient survival. CKD-mineral and bone disorder (CKD-MBD) is a broader, newly defined term that should be used instead of renal osteodystrophy to define the mineral, bone, hormonal, and calcific cardiovascular abnormalities that are seen in CKD. The new paradigm in the management of renal bone disease is to "think beyond the bones" and strive to improve cardiovascular outcomes and survival. This means treating other aspects of the disease process that go beyond merely controlling parathyroid hormone levels. Primary physicians need to take a proactive approach to the management of CKD-MBD because the disorder begins early in the course of CKD, well before a patient is referred to a nephrologist. This review outlines the evidence behind the understanding of CKD-MBD, its implications for overall mortality, and the latest recommendations for management of CKD-MBD in patients with predialysis CKD.     

Plasma cathepsin L: A prognostic marker for pancreatic cancer

AIM: To assess the prognostic significance of cathepsin L, a cysteine protease that degrades the peri-tumoral tissue, in patients with pancreatic cancer.METHODS: Plasma samples from 127 pancreatic cancer patients were analyzed for cathepsin L levels by ELISA. Out of these patients, 25 underwent surgery and their paraffin-embedded tissue was analyzed for cathepsin L expression by immunohistochemistry. Survival of patients and clinicopathological parameters was correlated with cathepsin L expression in plasma and tissue using appropriate statistical analysis.RESULTS: The mean (± SD) cathepsin L in plasma samples of pancreatic cancer patients was 5.98 ± 2.5 ng/mL that was significantly higher compared to the levels in healthy controls (3.83 ± 0.45) or chronic pancreatitis patients (3.97 ± 1.06). Using ROC curve, a cut-off level of 5.0 ng/mL was decided for survival analysis. Elevated plasma levels of cathepsin L were found to be associated with poor prognosis (P = 0.01) in multivariate analysis. The plasma levels of the protease decreased after surgery. Though no significant correlation was seen between plasma and tissue expression of this protease, a trend did emerge that high cathepsin L expression in tissue correlated with its high levels in plasma.CONCLUSION: Cathepsin L levels in plasma of pancreatic cancer patients may be used as a potential prognostic marker for the disease.     

Neonatal brachial plexus palsy: Incidence,prevalence, and temporal trends

Epidemiological knowledge of the incidence, prevalence, and temporal changes of neonatal brachial plexuses palsy (NBPP) should assist the clinician, avert unnecessary interventions, and help formulate evidence-based health policies. A summary of 63 publications in the English language with over 17 million births and 24,000 NBPPs is notable for six things. First, the rate of NBPP in the US and other countries is comparable: 1.5 vs. 1.3 per 1000 total births, respectively. Second, the rate of NBPP may be decreasing: 0.9, 1.0 and 0.5 per 1,000 births for publications before 1990, 1990–2000, and after 2000, respectively. Third, the likelihood of not having concomitant shoulder dystocia with NBPP was 76% overall, though it varied by whether the publication was from the US (78%) vs. other countries (47%). Fourth, the likelihood of NBPP being permanent (lasting at least 12 months) was 10–18% in the US-based reports and 19–23% in other countries. Fifth, in studies from the US, the rate of permanent NBPP is 1.1–2.2 per 10,000 births and 2.9–3.7 per 10,000 births in other nations. Sixth, we estimate that approximately 5000 NBPPs occur every year in the US, of which over 580–1050 are permanent, and that since birth, 63,000 adults have been afflicted with persistent paresis of their brachial plexus. The exceedingly infrequent nature of permanent NBPP necessitates a multi-center study to improve our understanding of the antecedent factors and to abate the long-term sequela.     

FLRT2 and FLRT3 Cooperate in Maintaining the Tangential Migratory Streams of Cortical Interneurons during Development

Neuron migration is a hallmark of nervous system development that allows gathering of neurons from different origins for assembling of functional neuronal circuits. Cortical inhibitory interneurons arise in the ventral telencephalon and migrate tangentially forming three transient migratory streams in the cortex before reaching the final laminar destination. Although migration defects lead to the disruption of inhibitory circuits and are linked to aspects of psychiatric disorders such as autism and schizophrenia, the molecular mechanisms controlling cortical interneuron development and final layer positioning are incompletely understood. Here, we show that mouse embryos with a double deletion of FLRT2 and FLRT3 genes encoding cell adhesion molecules exhibit an abnormal distribution of interneurons within the streams during development, which in turn, affect the layering of somatostatin+ interneurons postnatally. Mechanistically, FLRT2 and FLRT3 proteins act in a noncell-autonomous manner, possibly through a repulsive mechanism. In support of such a conclusion, double knockouts deficient in the repulsive receptors for FLRTs, Unc5B and Unc5D, also display interneuron defects during development, similar to the FLRT2/FLRT3 mutants. Moreover, FLRT proteins are chemorepellent ligands for developing interneurons in vitro, an effect that is in part dependent on FLRT-Unc5 interaction. Together, we propose that FLRTs act through Unc5 receptors to control cortical interneuron distribution in a mechanism that involves cell repulsion.SIGNIFICANCE STATEMENT Disruption of inhibitory cortical circuits is responsible for some aspects of psychiatric disorders such as schizophrenia or autism. These defects include interneuron migration during development. A crucial step during this process is the formation of three transient migratory streams within the developing cortex that determine the timing of interneuron final positioning and the formation of functional cortical circuits in the adult. We report that FLRT proteins are required for the proper distribution of interneurons within the cortical migratory streams and for the final laminar allocation in the postnatal cortex. These results expand the multifunctional role of FLRTs during nervous system development in addition to the role of FLRTs in axon guidance and the migration of excitatory cortical neurons.