Prevalence and functionality of paucimorphic and private MC4R mutations in a large, unselected European British population, scanned by meltMADGE

Identification of unknown mutations has remained laborious, expensive, and only viable for studies of selected cases. Population-based "reference ranges" of rarer sequence diversity are not available. However, the research and diagnostic interpretation of sequence variants depends on such information. Additionally, this is the only way to determine prevalence of severe, moderate, and silent mutations and is also relevant to the development of screening programs. We previously described a system, meltMADGE, suitable for mutation scanning at the population level. Here we describe its application to a population-based study of MC4R (melanocortin 4 receptor) mutations, which are associated with obesity. We developed nine assays representing MC4R and examined a population sample of 1,100 subjects. Two "paucimorphisms" were identified (c.307G>A/p.Val103Ile in 27 subjects and c.-178A>C in 22 subjects). Neither exhibited any anthropometric effects, whereas there would have been >90% power to detect a body mass index (BMI) effect of 0.5 kg/m(2) at P=0.01. Two "private" variants were also identified. c.335C>T/p.Thr112Met has been previously described and appears to be silent. A novel variant, c.260C>A/p.Ala87Asp, was observed in a subject with a BMI of 31.5 kg/m(2) (i.e., clinically obese) but not on direct assay of a further 3,525 subjects. This mutation was predicted to be deleterious and analysis using a cyclic AMP (cAMP) responsive luciferase reporter assay showed substantial loss of function of the mutant receptor. This population-based mutation scan of MC4R suggests that there is no severe MC4R mutation with high prevalence in the United Kingdom, but that obesity-causing MC4R mutation at 1 in 1,100 might represent one of the commonest autosomal dominant disorders in man.     

Physicochemical aspects of inorganic nanoparticles stabilized in N-vinyl caprolactam based microgels for various applications

The vinyl caprolactam (VCL) based microgel system has become the center of great attention due to its versatile properties. Copolymerization of VCL with an ionic monomer imparts pH responsive properties into the microgel system in addition to thermo-sensitivity. Stimuli responsive behavior of VCL-based microgels makes them prospective and appealing candidates for practical applications covering the fields of drug delivery, catalysis and optical devices. In the last few years, VCL-based microgels have been used as microreactors and stabilizers for the synthesis and stabilization of inorganic nanoparticles to obtain hybrid microgels. The present review article provides a summary of the present-day progress of fabrication, stabilization, categorization and analysis of VCL-based microgels and their hybrids with different morphologies. The stimuli responsive properties and applications of VCL-based hybrid microgels have been reviewed critically. The remaining problems which need to be addressed have been pointed out for further advancement in this field.

The present review provides recent research progress of fabrication, stabilization, characterization and applications of N-vinyl caprolactam based microgels loaded with inorganic nanoparticles.     

p53 alpha-Helix mimetics antagonize p53/MDM2 interaction and activate p53

Overexpression or hyperactivation of MDM2 contributes to functional inactivation of wild-type p53 in nearly 50% of tumors. Inhibition of p53 by MDM2 depends on binding between an NH(2)-terminal (residues 16-28) p53 alpha-helical peptide and a hydrophobic pocket on MDM2, presenting an attractive target for development of inhibitors against tumors expressing wild-type p53. Here we report that novel p53 alpha-helical peptide mimics based on a terphenyl scaffold can inhibit MDM2-p53 binding in vitro and activate p53 in vivo. Several active compounds have been identified that inhibit MDM2-p53 binding in an ELISA assay with IC(50) of 10 to 20 micromol/L and induce p53 accumulation and activation in cell culture at 15 to 40 micromol/L. These results suggest that p53 alpha-helical mimetics based on the terphenyl scaffold may be developed into potent p53 activators.     

Kidney disease other than renal crisis in patients with diffuse scleroderma

OBJECTIVE: To determine the frequency and severity of kidney abnormalities in patients with diffuse scleroderma. METHODS: All patients with diffuse scleroderma seen at the University of Pittsburgh between 1972 and 1993 were included in the study. Kidney function tests were routinely obtained as part of the Pittsburgh Scleroderma Outcome Study. Additional kidney tests were obtained as part of the 1992 biannual outcome assessment. Patients who had kidney abnormalities including a serum creatinine > 1.2 mg/dl or proteinuria prior to 1993 were identified. The clinical setting and longterm outcome of kidney disease were evaluated. RESULTS: Renal crisis occurred in 129/675 (19.5%) patients. Kidney function abnormalities or proteinuria were present in 173 (26%); 48% had no abnormalities. Most patients had other explanations for the abnormality. Only 12 (2%) of the 675 patients with diffuse scleroderma had no explanation for the elevated creatinine level. Most patients with proteinuria had toxicity from D-penicillamine. No explanations for proteinuria were found in 16 (2%) of this cohort. Thus, a total of only 28 (4%) of these 675 patients had an unknown cause for their kidney dysfunction or proteinuria. None of these patients, who were followed for a mean of 10 years after onset of scleroderma, have developed chronic renal insufficiency that progressed to dialysis. CONCLUSION: Patients with diffuse scleroderma without renal crisis rarely have significant increases in serum creatinine or proteinuria that cannot be explained by other etiologies. These patients with scleroderma should be carefully evaluated for non-scleroderma causes of kidney disease.     

Neonatal Myocardial Infarction: Case Report and Review of the Literature

Myocardial infarction in a neonate is rare. We describe the case of a full‐term male who presented with respiratory distress. A chest radiograph demonstrated cardiomegaly. An electrocardiogram revealed ST segment changes suggestive of ischemia. Cardiac enzymes were elevated and an echocardiogram revealed a regional wall motion abnormality. Cardiac catheterization was performed demonstrating occlusion of the ramus intermedius branch of the left main coronary artery. The patient decompensated, requiring extracorporeal membrane oxygenation (ECMO). The infant was able to be decannulated from ECMO support in 5 days and was ultimately discharged on hospital day 25. We review this case as well as the literature on neonatal myocardial infarction.     

Recent advances in the genetics of severe childhood obesity.

Childhood obesity is becoming a global epidemic. Twin studies suggest a heritability of fat mass, and disorders of energy balance that arise from genetic defects have been identified. In the past three years, five single gene disorders resulting in early onset obesity have been characterised. The discovery of these genetic defects has biological and clinical implications which are greater than the rarity of the individual diseases might suggest.     

Hepatitis E virus infection in the liver transplant recipients:Clinical presentation and management

Hepatitis E virus(HEV) is an emerging pathogen and an increasingly recognized cause of graft hepatitis, especially in the post-orthotopic liver transplantation immunocompromised population. The exact incidence and prevalence of HEV infection in this population remains unclear but is certainly greater than historical estimates. Identifying acute HEV infection in this population is imperative for choosing the right course of management as it is very difficult to distinguish histologically from acute rejection on liver biopsy. Current suggested approach to manage acute HEV involves modifying immunosuppression, especially discontinuing calcineurin inhibitors which are the preferred immunosuppressive agents post-orthotopic liver transplantation. The addition of ribavirin monotherapy has shown promising success rates in clearing HEV infection and is used commonly in reported cases.