Isoimmunization against CD36 can cause neonatal isoimmune thrombocytopenia (NITP), refractoriness to platelet transfusions, and post-transfusion purpura. Immunization against this glycoprotein (GP) should be considered in patients with apparent alloimmune platelet disorders not explained by immunization against recognized platelet-specific alloantigens, especially in persons of African, Asian, and, possibly, Mediterranean ancestry.

Mutations in CD36 / fatty acid translocase (FAT) gene are responsible for insulin resistance in the rat but contribution to human Type 2 diabetes is unknown. A nominal evidence for linkage of familial T2D at the CD36 locus led us to identify a rare nonsense mutation c.1079T>G (p.L360X) in one Caucasian pedigree presenting with autosomal dominant diabetes. Adiponectin levels, as marker of insulin sensitivity, were found to be significantly lower in the p.L360X variant carriers compared to homozygous for wild type CD36. Furthermore, expression studies of the truncated protein showed a defective binding of acetylated-LDL. Thus, our findings suggest a possible role for CD36 in the pathogenesis of T2D associated with reduced insulin sensitivity.

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Background Lynch syndrome is a rare familial cancer syndrome caused by pathogenic variants in the mismatch repair genes MLH1, MSH2, MSH6, or PMS2, that cause predisposition to various cancers, predominantly colorectal and endometrial cancer. Data are emerging that pathogenic variants in mismatch repair genes increase the risk of earlyonset aggressive prostate cancer. The IMPACT study is prospectively assessing prostate-specific antigen (PSA) screening in men with germline mismatch repair pathogenic variants. Here, we report the usefulness of PSA screening, prostate cancer incidence, and tumour characteristics after the first screening round in men with and without these germline pathogenic variants. MethodsThe IMPACT study is an international, prospective study. Men aged 40-69 years without a previous prostate cancer diagnosis and with a known germline pathogenic variant in the MLH1, MSH2, or MSH6 gene, and age-matched male controls who tested negative for a familial pathogenic variant in these genes were recruited from 34 genetic and urology clinics in eight countries, and underwent a baseline PSA screening. Men who had a PSA level higher than 3•0 ng/mL were offered a transrectal, ultrasound-guided, prostate biopsy and a histopathological analysis was done. All participants are undergoing a minimum of 5 years' annual screening. The primary endpoint was to determine the incidence, stage, and pathology of screening-detected prostate cancer in carriers of pathogenic variants compared with non-carrier controls. We used Fisher's exact test to compare the number of cases, cancer incidence, and positive predictive values of the PSA cutoff and biopsy between carriers and non-carriers and the differences between disease types (ie, cancer vs no cancer, clinically significant cancer vs no cancer). We assessed screening outcomes and tumour characteristics by pathogenic variant status. Here we present results from the first round of PSA screening in the IMPACT study. This study is registered with ClinicalTrials.gov, NCT00261456, and is now closed to accrual.

Cd36 is a small-molecular-weight integral membrane protein expressed in a diverse, but select, range of cell types. It has an equally diverse range of ligands and physiological functions, which has implicated Cd36 in a number of diseases including insulin resistance, diabetes, and, most notably, atherosclerosis. The protein is reported to reside in detergent-resistant microdomains within the plasma membrane and to form homoand hetero-intermolecular interactions. These data suggest that this class B scavenger receptor may gain functionality for ligand binding, and/or ligand internalization, by formation of protein complexes at the cell surface. Here, we have overexpressed Cd36 in insect cells, purified the recombinant protein to homogeneity, and analyzed its stability and solubility in a variety of nonionic and zwitterionic detergents. Octylglucoside conferred the greatest degree of stability, and by analytical ultracentrifugation we show that the protein is monomeric. A solid-phase ligand-binding assay demonstrated that the purified monomeric protein retains high affinity for acetylated and oxidized low-density lipoproteins. Therefore, no accessory proteins are required for interaction with ligand, and binding is a property of the monomeric fold of the protein. Thus, the highly purified and functional Cd36 should be suitable for crystallization in octylglucoside, and the in vitro ligand-binding assay represents a promising screen for identification of bioactive molecules targeting atherogenesis at the level of ligand binding.

Elevated circulating levels of acute phase proteins (APP) are associated with inflammation and inflammatory disorders such as cardiovascular disease. APP are mainly synthesised by hepatocytes and their transcription is induced by pro-inflammatory cytokines such as interleukin-1 (IL-1). The molecular mechanisms underlying the IL-1-induced expression of key transcription factors implicated in the regulation of APP are poorly understood. We have investigated this aspect using the CCAAT/enhancer binding protein-δ (C/EBPδ) as a model gene. IL-1 induced the expression of C/EBPδ mRNA and protein in the human hepatoma Hep3B cell line, a widely employed model system for studies on cytokine signalling in relation to the expression of APP. The IL-1-mediated induction of C/EBPδ expression was attenuated in the presence of pharmacological inhibitors against c-Jun N-terminal kinase (JNK) (curcumin and SP600125), casein kinase 2 (CK2) (apigenin) and nuclear factor-κB (NF-κB) (NF-κB activation inhibitor). RNA interference assays showed significant attenuation of the IL-1-induced expression of C/EBPδ following knockdown of the p50 and p65 subunits of NF-κB. IL-1 induced NF-κB DNA binding and activation by this transcription factor and this was attenuated by curcumin and apigenin. Taken together, these results suggest a potentially crucial role for NF-κB in the IL-1-induced expression of C/EBPδ, and thereby downstream APP genes regulated by this transcription factor.

We found low rates of baseline TST documentation and postexposure screening among exposed HCWs. Compliance with initiating postexposure isoniazid prophylaxis among HCWs was fair, but only a small fraction of those who started prophylaxis completed the recommended course of therapy. These findings suggest substantial opportunities to implement administrative measures to enhance LTBI management among HCWs.

The spontaneously hypertensive rat (SHR) is a model of human essential hypertension. Increased blood pressure in SHR is associated with other risk factors associated with cardiovascular disease, including insulin resistance and dyslipidemia. DNA microarray studies identified over 200 differentially expressed genes and ESTs between SHR and normotensive control rats. These clones represent candidate genes that may underlie previously detected QTLs in SHR. This study made use of the publication of two whole-genome maps to identify positional QTL candidates. Radiation hybrid (RH) mapping was used to determine the chromosomal locations of 70 rat genes and ESTs from this dataset. Most of the locations are novel, but in five cases we identified a definitive map location for genes previously mapped by somatic cell hybrids and/or linkage analysis. Genes for which the mouse genome map location was already determined mapped to syntenic segments in the rat genome map, except for two rat genes whose map locations confirmed previous findings. Where synteny comparisons could be made only with the human, 74% of the genes mapped in this study lay in a conserved syntenic segment. Chromosomal localisation of these mouse and human orthologs to syntenic segments produces a high level of confidence in the data presented in this study. The data provide new map locations for rat genes and will aid efforts to advance the rat genome map. The data may also be used to prioritize candidate QTL genes in SHR and other rat strains on the basis of their map location.