Absence of miR-146a in Podocytes Increases Risk of Diabetic Glomerulopathy via Up-regulation of ErbB4 and Notch-1.

Podocyte injury is an early event in diabetic kidney disease and is a hallmark of glomerulopathy. MicroRNA-146a (miR-146a) is highly expressed in many cell types under homeostatic conditions, and plays an important anti-inflammatory role in myeloid cells. However, its role in podocytes is unclear. Here, we show that miR-146a expression levels decrease in the glomeruli of patients with type 2 diabetes (T2D), which correlates with increased albuminuria and glomerular damage. miR-146a levels are also significantly reduced in the glomeruli of albuminuric BTBR ob/ob mice, indicating its significant role in maintaining podocyte health. miR-146a-deficient mice (miR-146a-/-) showed accelerated development of glomerulopathy and albuminuria upon streptozotocin (STZ)-induced hyperglycemia. The miR-146a targets, Notch-1 and ErbB4, were also significantly up-regulated in the glomeruli of diabetic patients and mice, suggesting induction of the downstream TGFß signaling. Treatment with a pan-ErbB kinase inhibitor erlotinib with nanomolar activity against ErbB4 significantly suppressed diabetic glomerular injury and albuminuria in both WT and miR-146a-/- animals. Treatment of podocytes in vitro with TGF-ß1 resulted in increased expression of Notch-1, ErbB4, pErbB4, and pEGFR, the heterodimerization partner of ErbB4, suggesting increased ErbB4/EGFR signaling. TGF-ß1 also increased levels of inflammatory cytokine monocyte chemoattractant protein-1 (MCP-1) and MCP-1 induced protein-1 (MCPIP1), a suppressor of miR-146a, suggesting an autocrine loop. Inhibition of ErbB4/EGFR with erlotinib co-treatment of podocytes suppressed this signaling. Our findings suggest a novel role for miR-146a in protecting against diabetic glomerulopathy and podocyte injury. They also point to ErbB4/EGFR as a novel, druggable target for therapeutic intervention, especially because several pan-ErbB inhibitors are clinically available.

Frequency of functional constipation in 3 different populations and its causative factors.

OBJECTIVE: To assess the frequency of constipation and its causative factors in 3 different populations, namely, the hospitalized patients admitted at Civil Hospital Karachi, their attendants and medical students. METHOD: A sample size of 200 was divided into 3 groups: hospitalized patients, their attendants and medical students. Frequency of constipation was expected to be greater in patients, so 100 subjects were taken from this population; while from the other 2 populations only 50 subjects were taken. The subjects were diagnosed as constipated on the basis of Rome III criteria for functional constipation and their dietary habits and physical activity were also assessed. RESULTS: The frequency of functional constipation was found to be 53% in hospitalized patients, 52% in their attendants and 34% in medical students. Among the constipated individuals, 50.94% of hospitalized patients, 46.15% of attendants and 29.41% of medical students took laxatives for relief of their symptoms. Constipation was most prevalent among the age group of 18 to 30 years in all the 3 populations. CONCLUSION: Constipation was fairly common in all 3 populations. Male to female ratio is almost equal. Physical inactivity and low fiber intake were prominent risk factors for constipation.

Sinus Venosus Atrial Septal Defect: A Challenging Diagnosis.

Sinus venosus atrial septal defect (SVASD) is a rare adult congenital heart disease which permits shunting of blood from the systemic to the pulmonary circulation and is commonly associated with anomalous pulmonary venous return. We report a case of a 27-year-old man with a history of premature birth and unilateral cryptorchidism who was admitted for syncope. Electrocardiogram (ECG) demonstrated atrial fibrillation (AF)and S1Q3T3 pattern along with an incomplete right bundle branch block. Transthoracic echocardiography (TTE) suggested the presence of right ventricular pressure and volume overload and severe right ventricular and right atrial enlargement. The agitated saline study was negative suggesting no inter-atrial communication. Transesophageal echocardiography (TEE) demonstrated a superior SVASD and raised the possibility of an anomalous pulmonary venous connection. Chest computed tomography identified the right superior pulmonary vein connection to the superior vena cava. The diagnosis of SVASD poses multiple challenges from the variety of symptoms to the selection of appropriate imaging and the complexity of surgical treatment.

CD11b activation suppresses TLR-dependent inflammation and autoimmunity in systemic lupus erythematosus.

Genetic variations in the ITGAM gene (encoding CD11b) strongly associate with risk for systemic lupus erythematosus (SLE). Here we have shown that 3 nonsynonymous ITGAM variants that produce defective CD11b associate with elevated levels of type I interferon (IFN-I) in lupus, suggesting a direct link between reduced CD11b activity and the chronically increased inflammatory status in patients. Treatment with the small-molecule CD11b agonist LA1 led to partial integrin activation, reduced IFN-I responses in WT but not CD11b-deficient mice, and protected lupus-prone MRL/Lpr mice from end-organ injury. CD11b activation reduced TLR-dependent proinflammatory signaling in leukocytes and suppressed IFN-I signaling via an AKT/FOXO3/IFN regulatory factor 3/7 pathway. TLR-stimulated macrophages from CD11B SNP carriers showed increased basal expression of IFN regulatory factor 7 (IRF7) and IFN-ß, as well as increased nuclear exclusion of FOXO3, which was suppressed by LA1-dependent activation of CD11b. This suggests that pharmacologic activation of CD11b could be a potential mechanism for developing SLE therapeutics.