Disruption of positive selection of thymocytes causes autoimmunity

To differentiate into T cells, immature thymocytes must engage, through their antigen-specific T-cell receptor, peptides derived from self proteins presented by cortical epithelial cells in the thymus, a process called positive selection. Despite this requirement for self-recognition during development, mature T cells do not normally show autoreactivity. Mice injected in the thymus with procainamide-hydroxylamine, a metabolite of procainamide, develop autoimmune features resembling drug-induced lupus. Here, we show that when thymocytes undergo positive selection in the presence of procainamide-hydroxylamine, they fail to establish unresponsiveness to low affinity selecting self antigens, resulting in systemic autoimmunity.     

Disruption of adiponectin causes insulin resistance and neointimal formation

The adipocyte-derived hormone adiponectin has been proposed to play important roles in the regulation of energy homeostasis and insulin sensitivity, and it has been reported to exhibit putative antiatherogenic properties in vitro. In this study we generated adiponectin-deficient mice to directly investigate whether adiponectin has a physiological protective role against diabetes and atherosclerosis in vivo. Heterozygous adiponectin-deficient (adipo(+/-)) mice showed mild insulin resistance, while homozygous adiponectin-deficient (adipo(-/-)) mice showed moderate insulin resistance with glucose intolerance despite body weight gain similar to that of wild-type mice. Moreover, adipo(-/-) mice showed 2-fold more neointimal formation in response to external vascular cuff injury than wild-type mice (p = 0.01). This study provides the first direct evidence that adiponectin plays a protective role against insulin resistance and atherosclerosis in vivo.     

Plasminogen activator in nephrotic syndrome

Plasminogen activators were studied in blood urine in 207 patients with nephrotic syndrome of different etiological forms. The blood plasminogen activator activity was decreased in chronic glomerulonephritis, SLE, systemic vasculities as result of great level of inhibitors (L2M), penetration of enzymes to abdominal and pleural transudates, excretion to urine. The blood plasminogen activator activity and urokinase level in chronic glomerulonephritis was dependent on the degree of nephrotic syndrome. The plasminogen activator in amyloidosis was sharply elevated because of permanent irritability of endothelial wall by amyloid mass. Venous occlusion caused the release of plasminogen activator to blood only in more favourable clinical course of nephrotic syndrome.     

Disruption of the somitic molecular clock causes abnormal vertebral segmentation

Somites are the precursors of the vertebral column. They segment from the presomitic mesoderm (PSM) that is caudally located and newly generated from the tailbud. Somites form in synchrony on either side of the embryonic midline in a reiterative manner. A molecular clock that operates in the PSM drives this reiterative process. Genetic manipulation in mouse, chick and zebrafish has revealed that the molecular clock controls the activity of the Notch and WNT signaling pathways in the PSM. Disruption of the molecular clock impacts on somite formation causing abnormal vertebral segmentation (AVS). A number of dysmorphic syndromes manifest AVS defects. Interaction between developmental biologists and clinicians has lead to groundbreaking research in this area with the identification that spondylocostal dysostosis (SCD) is caused by mutation in Delta-like 3 (DLL3), Mesoderm posterior 2 (MESP2), and Lunatic fringe (LFNG); three genes that are components of the Notch signaling pathway. This review describes our current understanding of the somitic molecular clock and highlights how key findings in developmental biology can impact on clinical practice.     

Posterior reversible encephalopathy syndrome associated with nephrotic syndrome

Kabicek and colleagues described a case of nephritic-syndrome-associated posterior reversible encephalopathy syndrome (PRES) (Kabicek, et al. 2010). This adds to the accumulating evidence that PRES can be associated with disorders other than hypertension. However, we wonder how the authors would explain the neuroimaging findings unsuggestive of vasogenic oedema. PRES (also named reversible posterior leukoencephalopathy syndrome, RPLS) represents a clinicoradiological syndrome characterized by vasogenic oedema as revealed by apparent diffusion coefficient (ADC) map of diffusion-weighted imaging (DWI) (Bartynski, 2008). The pathogenesis of PRES has been suggested to be autoregulation failure and endothelial dysfunction (Sharma, et al.). ...     

Renal leptin in experimental nephrotic syndrome

Leptin is a fat derived hormone involved in the regulation of metabolism and body composition. The kidney is the principle organ responsible for elimination of circulating leptin. Our aim is to evaluate if the nephrotic kidneys participate in the metabolism of leptin by comparing the serum leptin level in renal veins and in their renal arteries and to study the relationship between leptin and lipoprotein levels in healthy and nephrotic rats. Methods: Rats were divided into two equal groups: group 1 in which experimental nephrotic syndrome was produced by injecting them intraperitoneally with a supernatant of the homogenized mixture of their own kidney (obtained by previous unilateral nephrectomy) and complete Freund’s adjuvant. Another group constituted the control group. Leptin and lipid profile were estimated in blood samples of renal veins and renal arteries. There was a highly significant increase in leptin and lipid profile levels in the nephrotic rats compared with the normal group. There was a high significant decrease in leptin in the renal venous blood compared with its level in the renal arterial blood of normal and nephrotic rats. This work has stressed the involvement of kidney and the nephrotic renal tissue in the process of leptin metabolism and lipogenesis.     

Disruption of klotho gene causes an abnormal energy homeostasis in mice

klotho mice, which genetically lack klotho gene expression, are characterized with various systemic phenotypes resembling human aging, and also with growth retardation. Here we show that klotho mice have a barely detectable amount of the white adipose tissue but their brown adipose tissue (BAT) is comparably preserved. Glucose tolerance and insulin sensitivity in klotho mice are increased compared to those in wild-type mice as revealed by intraperitoneal glucose and insulin tolerance tests. Uncoupling protein-1 gene expression of BAT and body temperature in klotho mice are lower than those in wild-type mice, suggesting that klotho mice have less energy expenditure than wild-type mice. Histological examination suggests that klotho mice possess less energy storage than wild-type mice with respect to glycogen in the liver and lipid in BAT. All these changes of parameters for energy homeostasis in klotho mice are very similar to those reported under food-restricted conditions. However, the amount of food intake is not different between klotho and wild-type mice when normalized for body weight. The present study elucidates the importance of klotho gene expression for the maintenance of normal energy homeostasis.