Impaired leptin response to glucocorticoid as a chronic complication of diabetes

Leptin has anorectic, anti-obesity, and insulin-sensitizing properties. We recently reported subnormal responses to the leptin secretagogue dexamethasone in diabetes (DM). To determine whether this defect precedes or follows the occurrence of diabetes, we have studied 37 adults: 11 with type 2 DM diagnosed within 6 months prior to study, 16 with chronic (≥20 years) DM, and 10 healthy controls. After baseline measurements, subjects ingested dexamethasone (4 mg), followed by blood sampling 16 and 40 h later. Nadir plasma cortisol levels (<2.5 mg/dl) occurred 16 h after dexamethasone ingestion in all study groups; this period of maximal biological action of dexamethasone was associated with peak plasma leptin levels. The peak dexamethasone-stimulated plasma leptin responses (% baseline, ±SEM) were 188±18.7% among healthy controls, 180±13.8% among new DM patients, and 127±10.5% (P<0.01) in chronic DM patients. Following dexamethasone ingestion, plasma glucose remained stable in the control and new DM groups but increased by 240% in the chronic DM patients; in contrast, plasma insulin increased significantly in controls and new DM patients but not in patients with chronic DM. These results indicate that plasma leptin responses to secretagogue are preserved in newly diagnosed diabetes patients but markedly attenuated in patients with long-standing diabetes, who also were unable to augment insulin secretion during glucocorticoid treatment. Thus, defective glucocorticoid augmentation of plasma leptin, probably related to β-cell failure, may be a novel chronic complication of diabetes. Theoretically, such a defect could contribute to the obesity and insulin resistance associated with diabetes.     

Olmesartan attenuates the development of heart failure after experimental autoimmune myocarditis in rats through the modulation of ANG 1-7 mas receptor

Angiotensin-converting enzyme 2 (ACE-2) is a membrane-associated carboxy-peptidase catalyzes the conversion of the vasoconstrictor angiotensin (ANG)-II to the vasodilatory peptide ANG 1-7. In view of the expanding axis of the renin angiotensin system, we have investigated the cardioprotective effects of olmesartan (10mg/kg/day) in experimental autoimmune myocarditis. Olmesartan treatment effectively suppressed the myocardial protein expressions of inflammatory markers in comparison to the vehicle-treated rats. However, the protein and mRNA levels of ACE-2 and ANG 1-7, and its receptor Mas were upregulated in olmesartan treated group compared to vehicle-treated rats. Olmesartan medoxomil treatment significantly decreased the expression levels of phospho-p38 mitogen-activated protein kinase (MAPK), phospho-JNK, phospho-ERK and phospho-(MAPK) activated protein kinase-2 than with those of vehicle-treated rats. Moreover, vehicle-treated rats were shown to be up-regulated protein expressions of NADPH oxidase subunits (p47phox, p67phox and Nox-4), myocardial apoptotic markers and endoplasmic reticulum stress markers in comparison to those of normal and all these effects are expectedly down-regulated by an olmesartan. In addition, attenuated protein levels of phosphatidylinositol-3-kinase (PI3K) and phospho-Akt in the vehicle-treated EAM rats were prevented by olmesartan treatment. Our results suggest that beneficial effects of olmesartan treatment was more effective therapy in combating the inflammation, oxidative stress, apoptosis and signaling pathways associated with heart failure at least in part via the modulation of ANG 1-7 mas receptor.     

The abilities of improved schizophrenia patients to work and live independently in the community: a 10-year long-term outcome study from Mumbai, India

Background  

The outcome of first episode schizophrenia has several determinants. Socioecological factors, particularly living conditions, migration, community and culture, not only affect the level of risk but also the outcome. Mega cities around the world show a unique socioecological condition that has several challenges for mental health. The present study reports on the long-term status of patients with schizophrenia in such a mega city: Mumbai, India.     

Meta-analysis of randomized controlled trials on the safety and effectiveness of day-case laparoscopic cholecystectomy

Background:

Although day‐case laparoscopic cholecystectomy can save bed costs, its safety has to be established. The aim of this meta‐analysis is to assess the advantages and disadvantages of day‐case surgery compared with overnight stay in patients undergoing elective laparoscopic cholecystectomy.

Methods:

Randomized clinical trials addressing the above issue were identified from The Cochrane Library trials register, Medline, Embase, Science Citation Index Expanded and reference lists. Data were extracted from these trials by two independent reviewers. For each outcome the relative risk, weighted mean difference or standardized mean difference was calculated with 95 per cent confidence intervals based on available case analysis.

Results:

Five trials with 215 patients randomized to the day‐case group and 214 to the overnight‐stay group were included in the review. Four of the five trials were of low risk of bias. The trials recruited 49·1 per cent of patients presenting for cholecystectomy. There was no significant difference between day case and overnight stay with respect to morbidity, prolongation of hospital stay, readmission rates, pain, quality of life, patient satisfaction, and return to normal activity and work. In the day‐case group 80·5 per cent of patients were discharged on the day of surgery.

Conclusion:

Day‐case laparoscopic cholecystectomy is a safe and effective treatment for symptomatic gallstones. Copyright © 2008 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.     

Genetic polymorphisms of CYP2D6 increase the risk for recurrence of breast cancer in patients receiving tamoxifen as an adjuvant therapy

Purpose

Tamoxifen is used in the treatment of breast cancer to prevent recurrences. It is converted to its active metabolite endoxifen by CYP2D6 enzyme. This study was conducted to evaluate the influence of CYP2D6 genetic polymorphisms on the recurrence of breast cancer in patients receiving treatment with tamoxifen as an adjuvant hormonal therapy.

Methods

Breast cancer patients (n?=?141) on adjuvant tamoxifen and not on any concomitant CYP2D6 inhibitors were recruited for the study. Patient characteristics and treatment history were obtained. Five milliliters of venous blood was collected for genotyping CYP2D6 alleles *1, *2, *4, *5 and *10. CYP2D6 activity score was calculated to determine the phenotype based on genotype. The activity scores were compared between patients with recurrence and patients with no recurrence of breast cancer.

Results

Of the 141 patients recruited for the study, genotyping was done for 132 of them. CYP2D6 activity score ??0.5 is associated with a statistically significant increased risk of recurrence (OR??12.37; 95?% CI??3.23, 47.33; p?p?p?p?=?0.006) for activity score ??0.5.

Conclusion

Reduced CYP2D6 activity is associated with poor treatment outcomes, in terms of increased risk of recurrence and shorter recurrence free survival, in breast cancer patients on adjuvant tamoxifen therapy.     

Physical chemical and biological characterization of a new bacteriocin produced by Bacillus cereus NS02

ObjectiveTo screen the bacteriocinogenic isolate from buffalo milk and to characterize it on physical, chemical and biological aspects for the application in biopreservation.MethodsBacillus cereus (B. cereus) was isolated and assessed for its baceteriocinogenic activity. Bacteriocin was produced and purified by ammonium sulphate precipitation, dialysis and gel filtration chromatography. Purified bacteriocin was used to check its antimicrobial activity against food borne bacteria. Effect and stability of bacteriocin was determined with the respect to temperature, pH, enzymes, organic solvents and chemicals. Bacteriocin was also subjected to SDS PAGE analysis to determine its molecular weight. In addition, functional groups exist in the bacteriocin was determined by FTIR analysis.ResultsB. cereus was identified by 16S rRNA sequence analysis. Bacteriocin showed increased activity against all the bacteria used and its activity unit was found to be 51, 200 AU/mL. It was stable to high temperature (100 °C) and wide range of pH (3-10), sensitive to proteolytic enzymes and resistant to nonproteolytic enzymes. It was low molecular weight (3.5 – 6 KDa) protein and FTIR study revealed the presence of amide group and NH stretching.ConclusionsBacteriocin produced in this study possesses the highest antimicrobial activity against both gram positive and gram negative bacteria thereby it has immense application as biopreservative agent. FTIR proved its peptide nature.     

Bioreducible hyaluronic acid conjugates as siRNA carrier for tumor targeting

The successful clinical translation of siRNA-based therapeutics requires efficient carrier systems that can specifically deliver siRNA within the cytosol of the target cells. Although numerous polymeric nanocarriers forming ionic complexes with siRNA have been investigated for cancer therapy, their poor stability and lack of tumor targetability have impeded their in vivo applications. To surmount these limitations, we synthesized a novel type of biodegradable hyaluronic acid-graft-poly(dimethylaminoethyl methacrylate) (HPD) conjugate that can form complexes with siRNA and be chemically crosslinked via the formation of the disulfide bonds under facile conditions. The crosslinked siRNA-HPD (C-siRNA-HPD) complexes exhibited high stability in a 50% serum solution, as compared to the uncrosslinked siRNA-HPD (U-siRNA-HPD) complexes and free siRNA. Both the C-siRNA-HPD and U-siRNA-HPD complexes were efficiently taken up by the CD44-overexpressing melanoma cells (B16F10), but not by the normal fibroblast cells (NIH3T3). When the RFP-expressing B16F10 cells were treated with the complexes or free siRNA, the C-siRNA-HPD complexes showed the highest decrease in RFP expression. In vivo studies demonstrated the selective accumulation of C-siRNA-HPD complexes at the tumor site after their systemic administration into tumor-bearing mice, resulting in an efficient gene silencing effect. Overall, these results suggest that the HPD conjugate could be used as an efficient carrier for the tumor-targeted delivery of siRNA.