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BackgroundIntestinal integrity is essential for proper nutrient absorption and tissue homeostasis, with damage leading to enteric protein loss, that is, protein-losing enteropathy (PLE). Recently, homozygous nonsense variants in the plasmalemma vesicle-associated protein gene (PLVAP) were reported in two patients with severe congenital PLE. PLVAP is the building block of endothelial cell (EC) fenestral diaphragms; its importance in barrier function is supported by mouse models of Plvap deficiency.ObjectiveTo genetically diagnose two first-degree cousins once removed, who presented with PLE at ages 22 and 2.5 years.MethodsFamily-based whole exome sequencing was performed based on an autosomal recessive inheritance model. In silicoanalyses were used to predict variant impact on protein structure and function.ResultsWe identified a rare homozygous variant (NM_031310.2:c.101T>C;p.Leu34Pro) in PLVAP, which co-segregated with the disease. Leu34 is predicted to be located in a highly conserved, hydrophobic, α-helical region within the protein’s transmembrane domain, suggesting Leu34Pro is likely to disrupt protein function and/or structure. Electron microscopy and PLVAP immunohistochemistry demonstrated apparently normal diaphragm morphology, predicted to be functionally affected.ConclusionsBiallelic missense variants in PLVAPcan cause an attenuated form of the PLE and hypertriglyceridaemia syndrome. Our findings support the role of PLVAP in the pathophysiology of PLE, expand the phenotypic and mutation spectrums and underscore PLVAP’s importance in EC barrier function in the gut.

Sepsis is a multifactorial syndrome with increasing incidence of morbidity and mortality. Identification of outcome predictors is therefore essential. Recently, elevated brain natriuretic peptide (BNP) levels have been observed in patients with septic shock. Little information is available concerning BNP levels in patients with critical illness, especially with sepsis. Therefore, this study aims to evaluate the role of BNP as a biomarker for long-term mortality in patients with sepsis.

Congenital pancreatic lipase (PNLIP) deficiency is a rare monoenzymatic form of exocrine pancreatic failure characterized by decreased absorption of dietary fat and greasy voluminous stools, but apparent normal development and an overall good state of health. While considered to be an autosomal recessive state affecting a few dozens of individuals world-wide and involving the PNLIPgene, no causative mutations for this phenotype were so far reported. Here, we report the identification of the homozygote missense mutation, Thr221Met [c.662C>T], in two brothers from a consanguineous family of Arab ancestry. The observed genotypes among the family members were concordant with an autosomal recessive mode of inheritance but moreover a clear segregation between the genotype state and the serum PNLIP activity was evident. Based on biophysical computational tools, we suggest the mutation disrupts the protein's stability and impairs its normal function. Although the role of PNLIP is well established, our observations provide genetic evidence that PNLIPmutations are causative for this phenotype.

Aldosterone is known to be involved in atherosclerosis and cardiovascular disease and blockade of its receptor was shown to improve cardiovascular function. It was, therefore, hypothesized that inhibition of aldosterone synthesis would also reduce atherosclerosis development.

Diabetes activates atherogenesis and macrophage foam cell formation. This study's goal was to determine whether insulin counteracts diabetes-induced macrophage foam cell formation, as well as to determine transcriptional mechanisms involved in this effect.

Oxidative stress is an important risk factor in the pathogenesis of atherosclerosis. Angiotensin-converting enzyme (ACE) inhibitors attenuate atherosclerosis and oxidative stress in animal models. Omapatrilat, a VasoPeptidase-inhibitor, selectively inhibits both Neutral-Endo-Peptidase (NEP) and ACE.

Oxidative stress is involved in the pathogenesis of atherosclerosis, and angiotensin II (AT-II) induces oxidative stress and enhances atherogenesis. Aldosterone, which has an important role in the pathology of heart failure, has recently been implicated as a mediator of AT-II biologic activities. In this study, we analyzed whether administration of the selective aldosterone blocker eplerenone to atherosclerotic apolipoprotein E–deficient (E0) mice would affect their oxidative status and atherogenesis. Apolipoprotein E–deficient mice were administered chow containing eplerenone (200 mg/kg/day) for 3 months. Blood pressure, serum and macrophage oxidative status, and aortic atherosclerotic lesion area were evaluated in mice treated with eplerenone compared with untreated mice. Eplerenone administration significantly decreased systolic and diastolic blood pressure by 12 and 11, respectively, compared with untreated mice. Serum susceptibility to lipid peroxidation decreased by as much as 26, and serum paraoxonase activity increased by 28 in eplerenone-treated mice compared with untreated mice. Peritoneal macrophages from eplerenone-treated mice contained reduced levels of lipid peroxides, and their macrophage oxidation of low-density lipoprotein (LDL) and superoxide ion release were significantly reduced (by 17 and 43, respectively), compared to untreated mice. Daily injections of AT-II (0.1 mL, 10−7M) during the final 3 weeks of the study in eplerenone-treated mice substantially attenuated the eplerenone-mediated reduction in macrophage superoxide release and LDL oxidation. Finally, the atherosclerotic lesion area in aortas of eplerenone-treated mice was significantly reduced (by 35) versus untreated mice, and this effect was reversed by AT-II. Administration of the selective aldosterone blocker eplerenone significantly reduced oxidative stress and atherosclerosis progression in E0mice. These data suggest that aldosterone could have a significant pro-oxidative role in the pathogenesis of atherosclerosis.

Oxidative stress is thought to play an important role in atherogenesis. The present study demonstrated, for the first time, that macrophages (originally derived from blood monocytes) isolated from aortas of the atherosclerotic apolipoprotein E deficient (E°) mice or from human carotid artery, are oxidized as they contain lipid peroxides and oxysterols. The major oxysterol in arterial macrophages was found to be 7-ketocholesterol (51% of total oxysterols). To find out whether lipid peroxidation of monocytes occurs in vivo already in the blood, we analyzed the oxidative state of monocytes derived from E° mice in comparison to monocytes from control mice. Cellular lipid peroxides and total oxysterols were four and sevenfold higher respectively, in monocytes derived from E° mice in comparison to monocytes from control mice. The results of the present study thus demonstrated the presence of lipid-peroxidized monocytes already in the blood, which are further oxidized in the arterial wall after their conversion into macrophages. The arterial oxidized macrophages could be considered key contributors to foam cell formation, the hallmark of early atherosclerosis.

AbstractOxidative stress and inflammatory processes are of major importance in atherogenesis because they stimulate oxidized LDL (Ox-LDL)-induced macrophage cholesterol accumulation and foam cell formation, the hallmark of early atherosclerosis. Under oxidative stress, both blood monocytes and plasma lipoproteins invade the arterial wall, where they are exposed to atherogenic modifications. Oxidative stress stimulates endothelial secretion of monocyte chemoattractant protein 1 (MCP-1) and of macrophage colony stimulating factor (M-CSF), leading to monocyte adhesion and differentiation, respectively. LDL binds to extracellular matrix (ECM secreted by endothelial cells, smooth muscle cells and macrophages) proteoglycans, in a process that contributes to the enhanced susceptibility of the lipoprotein to oxidation by arterial wall macrophages. ECM-retained Ox-LDL is taken up by activated macrophages via their scavenger receptors. This leads to cellular cholesterol accumulation and enhanced atherogenesis. Protection of LDL against oxidation by antioxidants that can act directly on the LDL, or indirectly on the cellular oxidative machinery, or conversion of Ox-LDL to a non-atherogenic particle by HDL-associated paraoxonase (PON-1), can contribute to attenuation of atherosclerosis.

Extracellular matrix (ECM), which was shown to be secreted by arterial wall cells, is a major part of the atherosclerotic lesion. ECM can contribute to low density lipoprotein (LDL) retention which can then lead to macrophage foam cell formation, the hallmark of early atherogenesis. The present study demonstrated that in addition to the known ability of endothelial cells and smooth muscle cells to produce ECM, macrophages can also secrete an ECM layer. The macrophage derived ECM was shown to contain the proteoglycans chondroitin sulfate, heparan sulfate and dermatan sulfate. Macrophage derived ECM can bind native LDL, as well as oxidized LDL (3 fold more than native LDL), and this binding is significantly increased in the presence of lipoprotein lipase. Glycosaminoglycans from the ECM (mainly chondroitin sulfate and heparan sulfate) participate in the binding of Ox-LDL to the macrophage derived ECM. These observations suggest that ECM is produced also by macrophages, and it can contribute to a specific and local delivery of atherogenic LDL to macrophages, leading to cellular cholesterol accumulation and foam cell formation.

No relevant conflicts of interest to declare.

Introduction: Immature platelet fraction (IPF) is a new laboratory parameter, representing a fraction of young platelets in peripheral blood count which is known to correlate with thrombopoiesis. IPF can be reported in absolute numbers or expressed as percentage (IPF%) of total platelet count. IPF% can be used to differentiate individuals at higher risk for bleeding among patients suffering from immune thrombocytopenia and to predict recovery of blood counts after stem cell transplantation (SCT). Moreover, IPF% was also reported to predict the development of sepsis in patients admitted to the general intensive care unit. This study was aimed to prospectively evaluate the value of IPF% as a predictor of clinical outcome and/or mortality in patients susceptible to sepsis.