Metabolically favorable remodeling of human adipose tissue by human adenovirus type 36

OBJECTIVE—Experimental infection of rats with human adenovirus type 36 (Ad-36) promotes adipogenesis and improves insulin sensitivity in a manner reminiscent of the pharmacologic effect of thiozolinediones. To exploit the potential of the viral proteins as a therapeutic target for treating insulin resistance, this study investigated the ability of Ad-36 to induce metabolically favorable changes in human adipose tissue.RESEARCH DESIGN AND METHODS—We determined whether Ad-36 increases glucose uptake in human adipose tissue explants. Cell-signaling pathways targeted by Ad-36 to increase glucose uptake were determined in the explants and human adipose–derived stem cells. Ad-2, a nonadipogenic human adenovirus, was used as a negative control. As a proof of concept, nondiabetic and diabetic subjects were screened for the presence of Ad-36 antibodies to ascertain if natural Ad-36 infection predicted improved glycemic control.RESULTS—Ad-36 increased glucose uptake by adipose tissue explants obtained from nondiabetic and diabetic subjects. Without insulin stimulation, Ad-36 upregulated expressions of several proadipogenic genes, adiponectin, and fatty acid synthase and reduced the expression of inflammatory cytokine macrophage chemoattractant protein-1 in a phosphotidylinositol 3-kinase (PI3K)-dependent manner. In turn, the activation of PI3K by Ad-36 was independent of insulin receptor signaling but dependent on Ras signaling recruited by Ad-36. Ad-2 was nonadipogenic and did not increase glucose uptake. Natural Ad-36 infection in nondiabetic and diabetic subjects was associated with significantly lower fasting glucose levels and A1C, respectively.CONCLUSIONS—Ad-36 proteins may provide novel therapeutic targets that remodel human adipose tissue to a more metabolically favorable profile.Obesity is associated with adverse metabolic profile of adipose tissue, including impaired adipogenesis, lower fatty acid synthase (FAS) and adiponectin, and increased secretion of inflammatory cytokines. Consequentially, this contributes to an increase in insulin resistance and a reduction in glucose uptake by the tissue (1–4). Although intentional weight loss could improve insulin resistance and attenuate the adverse metabolic profile, achieving meaningful fat loss and maintaining it long term is very challenging. Instead, a particularly appealing approach proposes to “remodel” the adipose tissue to a more favorable or healthy metabolic profile. For instance, the thiazolidinedione (TZD) class of drugs increases glucose uptake in response to insulin stimulation (5), induces peroxisome proliferator–activated receptor (PPAR)γ2, increases adipogenesis (6), activates phosphotidylinositol 3-kinase (PI3K) (7), reduces the release of inflammatory cytokines (8,9), and upregulates adiponectin secretion (10) and FAS expression (4) in adipose tissue. The metabolically beneficial effects of the TZDs and other remedial candidates, such as benzopyran-derived T33 (11), suggest that adipose tissue remodeling may be a pragmatic approach against the growing epidemic of diabetes. Among the other effects, expansion of adipose tissue by the TZDs appears to offer “storage space” for lipids (5,12) and offset ectopic lipid accumulation in muscle and liver, thereby contributing to insulin sensitivity.Recently, there is considerable interest in the role of adipose tissue expansion in improving insulin sensitivity. Medina-Gomez et al. (13) showed that PPARγ2 controls adipose tissue expansion and thereby improves insulin sensitivity in ob/ob mice. Kim et al. (14) achieved dramatic improvement in metabolic profile through expansion of adipose tissue in transgenic mice. Despite the massive increase in adiposity, the improved metabolic profile comprised of greater glucose disposal and adiponectin secretion; reduction in serum cholesterol, triglycerides, and inflammation; and induction of expression of PPARγ2 and its target genes (14).Human adenovirus type 36 (Ad-36) is another novel candidate for improving metabolic profile by expanding adipose tissue. Although Ad-36 increases adiposity (15–17), it enhances insulin sensitivity in experimentally infected rats (18) and reduces serum cholesterol and triglycerides (15–17). Indeed, a single inoculation of Ad-36 increased fat depot weight of rats by >60% but reduced the fasting insulin levels and homeostasis model assessment index by ∼50% for up to 7 months later (18), a robust and long-term effect that is reminiscent of TZDs. Moreover, Ad-36 upregulates PPARγ2 expression and induces differentiation and lipogenesis in human and rodent preadipocytes (19–23) and increases glucose uptake in rat adipocytes (22), even in the absence of insulin, which possibly contributes to its insulin-sensitizing effect.Harnessing certain properties of viruses for beneficial purposes has been creatively used for several years. For instance, even before the advent of antibiotics, the use of bacteriocidal properties of bacteriophage virus has been reported and had a recent resurgence in interest (rev. in 24). Furthermore, the first report of the oncolytic ability of a mutant adenovirus (25) was followed by numerous studies extending the use of oncolytic properties of various viruses. Herpes simplex virus, Newcastle disease virus, reovirus, and vaccinia virus were used for the treatment of various cancers (rev. in 26), alone or in combination with various synergistic drugs (27,28). The potential of Ad-36 proteins to enhance glucose disposal and improve adipose tissue metabolic profile could be exploited as therapeutic targets for humans, a natural host of the virus. To investigate this possibility, we first determined whether Ad-36 increases glucose uptake in primary adipose tissue explants obtained from healthy and diabetic subjects. Next, we elucidated the cellular signaling pathways involved in an Ad-36–induced increase in glucose uptake. Finally, as a proof of concept, nondiabetic and diabetic subjects were screened for the presence of Ad-36 antibodies to ascertain if natural infection with Ad-36 was a significant predictor of improved glycemic control.     

Chemical screening and identification of high cordycepin containing cultured isolate(s) of medicinal Chinese caterpillar mushroom, Ophiocordyceps sinensis (Berk.) G.H. Sung et al

Forty isolates of Ophiocordyceps sinensis collected from Himalayan alpine meadows of Uttarakhand, India, and cultivated on Jhangora (Echinochloa crusgalli) grains were screened to identify the isolate(s) of high cordycepin content. The cultured mycelia were extracted with 50% methanol-chloroform and analyzed by HPTLC using chloroform:methanol (6:1 v/v) as mobile phase and densitometry scanning at 263 nm. Cordycepin varied from 0.002% to 0.029% was detected in twenty-one isolates. Compared to natural O. sinensis (0.004%, 0.006%), cordycepin was determined to be enhanced in twelve cultured samples.     

Statin therapy significantly reduces risk of ventricular tachyarrhythmias in patients with an implantable cardioverter defibrillator

A few observational studies have shown the protective effect of statins on preventing ventricular tachycardia/ventricular fibrillation (VT/VF). However, the disparate study results prompt further exploration of this concept. We performed a meta-analysis to assess whether statin therapy is associated with a decrease in the incidence or recurrence of VT/VF in patients with an implantable cardioverter-defibrillator (ICD).The MEDLINE(?) and Cochrane databases were searched from 1980 to July 2009 for studies examining the effect of statins on VT/VF in recipients of ICDs. We retrieved all prospective cohort studies that examined this association. The endpoint was defined as appropriate ICD therapy for VT/VF. The quality of individual studies was assessed using the Newcastle Ottawa Scale.Seven prospective cohort studies met our inclusion criteria with a total of 2278 patients with a mean follow-up of 19.7 months. Pooled analysis of the eligible studies revealed that statin therapy was associated with a 45% reduction in the risk of developing VT/VF in recepients of ICDs [pooled odds ratio (pOR): 0.55; 95% confidence interval: 0.34-0.90; heterogeneity I(2) = 81%, P = 0.02]. In a subgroup analysis, the magnitude of the risk reduction in patients with ischemic cardiomyopathy was 54% (pOR: 0.46, P = 0.05). Sensitivity analysis including studies with higher methodological qualities alone showed a significant protective effect (pOR: 0.48, P = 0.01). There was no evidence of publication bias in the analysis.Our meta-analysis suggests an association between the use of statin and a reduction in the VT/VF occurrence in recipients of ICDs, mainly in patients with ischemic cardiomyopathy.     

Quality of life of very young spina bifida patients after initial surgical treatment

Objective

The objectives of this study were to assess the quality of life (QOL) of operated patients with spina bifida (SB) in their initial years and to elucidate the factors affecting the QOL and the timing of proposed interventions.

Patients and methods

We studied 18 patients operated on for SB, aging 3?years or more at the time of assessment. The quality of life score was calculated for all the patients by the parental-administered questionnaire method. The impact of all these factors on the social and school lives of these patients was studied.

Results

Eleven patients were having neurogenic bladder. Thirteen patients were having stool problems which ranged from mild to severe constipation and soiling. Five patients were having lower limb deformities interfering with normal ambulation. Ten patients were able to walk on their own without any help, four patients were using either crutches or help of the caregiver for ambulation while the remaining four patients were non-ambulatory. Twelve patients were attending school. The calculated QOL scores ranged from 2 to 15. The Barthel Index (BI) ranged from 15 to 100. The QOL questionnaire score and BI were showing significant positive correlation.

Conclusions

The patients operated on for SB commonly have the neurological sequelae. The QOL score identifies the important problems in the initial years after surgery which can help in initiating and maintaining rehabilitative services in these patients. The treatment of urinary and fecal incontinence very early in life will allow these children to have a normal social and school life.     

A semi-structured clinical interview for psychosis sub-groups (SCIPS): development and psychometric properties

Background

Clinical sub-groups of schizophrenia, namely drug related, traumatic, anxiety and stress sensitivity sub-types, have been proposed for use in research, training and practice. They were developed on the basis of clinical observation but have not yet been used in research or clinical practice to any great extent.

Aims

To develop a semi-structured clinical interview for psychosis sub-groups (SCIPS) and determine the best diagnostic criteria with the highest inter-rater reliability, test–retest reliability and concurrent validity for sub-grouping patients with schizophrenia according to a newly developed classification scheme.

Methods

The SCIPS was developed based upon discussion with the clinician researchers who had developed and were using the sub-groups. Kappa coefficients were calculated between two independent diagnostic assessments with the SCIPS (for inter-rater reliability and test–retest reliability, n?=?20) and between the SCIPS diagnosis and the sub-groupings as determined independently with highest achievable validity (for concurrent validity, n?=?21) for patients with schizophrenia. These inter-rater reliability and concurrent validity were compared among five different sets of diagnostic criteria to determine which was most reliable and valid.

Results

A set of diagnostic criteria with the highest inter-rater reliability and concurrent validity was determined. Kappa coefficients (95% confidence interval) for the inter-rater reliability and concurrent validity were 0.93 (0.66–1.20) and 0.73 (0.47–1.00), respectively, with these diagnostic criteria.

Conclusions

The SCIPS is a promising tool with which to sub-group patients with schizophrenia according to this recently developed classification scheme. The semi-structured interview achieves acceptable inter-rater and test–retest reliability and concurrent validity.     

Acceptable terminology and subgroups in schizophrenia

There is general agreement that "the group of schizophrenias" comprises a very heterogeneous group of patients with diverse problems. Schizophrenia itself is a highly stigmatised term and yet has continued in use for nearly one hundred years. The development of cognitive behaviour therapy for psychosis and psychosocial epidemiological research has led to increased interest in finding alternative ways of conceptualisation. This study investigated attitudes of patients, care coordinators and consultant psychiatrists to the term, schizophrenia, and to psychosocial alternatives. It found that 63% of patients expressed negative attitudes to schizophrenia compared to 19% to the alternatives. However, concordance between the terms selected by patients, psychiatrists and care coordinators with those of the researchers was low. Such terms and subgroups may be more acceptable to patients but further work is needed on establishing their reliability and validity.