Impaired expression of mitochondrial and adipogenic genes in adipose tissue from a patient with acquired partial lipodystrophy (Barraquer-Simons syndrome): a case report

<p>Abstract</p> <p>Introduction</p> <p>Acquired partial lipodystrophy or Barraquer-Simons syndrome is a rare form of progressive lipodystrophy. The etiopathogenesis of adipose tissue atrophy in these patients is unknown.</p> <p>Case presentation</p> <p>This is a case report of a 44-year-old woman with acquired partial lipodystrophy. To obtain insight into the molecular basis of lipoatrophy in acquired partial lipodystrophy, we examined gene expression in adipose tissue from this patient newly diagnosed with acquired partial lipodystrophy. A biopsy of subcutaneous adipose tissue was obtained from the patient, and DNA and RNA were extracted in order to evaluate mitochondrial DNA abundance and mRNA expression levels.</p> <p>Conclusion</p> <p>The expression of marker genes of adipogenesis and adipocyte metabolism, including the master regulator <it>PPARγ</it>, was down-regulated in subcutaneous adipose tissue from this patient. Adiponectin mRNA expression was also reduced but leptin mRNA levels were unaltered. Markers of local inflammatory status were unaltered. Expression of genes related to mitochondrial function was reduced despite unaltered levels of mitochondrial DNA. It is concluded that adipogenic and mitochondrial gene expression is impaired in adipose tissue in this patient with acquired partial lipodystrophy.</p

Effects of Topically Administered Neuroprotective Drugs in Early Stages of Diabetic Retinopathy:Results of the EUROCONDOR Clinical Trial

The primary objective of this study was to assess whether the topical administration of two neuroprotective drugs (brimonidine and somatostatin) could prevent or arrest retinal neurodysfunction in patients with type 2 diabetes. For this purpose, adults aged between 45 and 75 years with a diabetes duration ≥5 years and an Early Treatment of Diabetic Retinopathy Study (ETDRS) level of ≤35 were randomly assigned to one of three arms: placebo, somatostatin, or brimonidine. The primary outcome was the change in implicit time (IT) assessed by multifocal electroretinography between baseline and at the end of follow-up (96 weeks). There were 449 eligible patients allocated to brimonidine (n = 152), somatostatin (n = 145), or placebo (n = 152). When the primary end point was evaluated in the whole population, we did not find any neuroprotective effect of brimonidine or somatostatin. However, in the subset of patients (34.7%) with preexisting retinal neurodysfunction, IT worsened in the placebo group (P < 0.001) but remained unchanged in the brimonidine and somatostatin groups. In conclusion, the topical administration of the selected neuroprotective agents appears useful in preventing the worsening of preexisting retinal neurodysfunction. This finding points to screening retinal neurodysfunction as a critical issue to identify a subset of patients in whom neuroprotective treatment might be of benefit

Cost-effectiveness analysis of antimuscarinics in the treatment of patients with overactive bladder in Spain: A decision-tree model

<p>Abstract</p> <p>Background</p> <p>Fesoterodine, a new once daily antimuscarinic, has proven to be an effective, safe, and well-tolerated treatment in patients with overactive bladder (OAB). To date, no analysis has evaluated the economic costs and benefits associated with fesoterodine, compared to antimuscarinics in Spain. The purpose of this analysis was to assess the economic value of OAB treatment with fesoterodine relative to extended release tolterodine and solifenacin, from the societal perspective.</p> <p>Methods</p> <p>The economic model was based on data from two 12-week, randomized, double-blind, and multicenter trials comparing fesoterodine and tolterodine extended released (ER). Treatment response rates for solifenacin were extracted from the published literature. Discontinuation and efficacy were based on the results of a 12-week multinational randomized clinical trial extrapolated to 52 weeks. Changes in health related quality of life were assessed with the King's Health Questionnaire, which was transformed into preference-based utility values. Medical costs included (expressed in € 2010) were antimuscarinics, physician visits, laboratory tests, incontinence pads and the costs of OAB-related comorbidities, fractures, skin infections, urinary tract infections, depression, and nursing home admissions associated with incontinence. Time lost from work was also considered. Univariate sensitivity analyses were also performed.</p> <p>Results</p> <p>At week 12, continents accounted for 50.6%, 40.6% and 47.2% of patients in the fesoterodine, tolterodine, and solifenacin groups, respectively. By week 52, the projected proportions of patients remaining on therapy were 33.1%, 26.5% and 30.8%, respectively. The projected quality- adjusted life years (QALY) gain (compared to baseline) over the 52-week simulation period were 0.01014, 0.00846 and 0.00957, respectively. The overall treatment cost was estimated at €1,937, €2,089 and €1,960 for fesoterodine, tolterodine and solifenacin, respectively. Therefore, treatment with fesoterodine resulted in similar overall costs and greater QALY gain than treatment with either tolterodine or solifenacin. Sensitivity analysis showed that these results were robust to all changes performed.</p> <p>Conclusions</p> <p>The results of this economic analysis suggest that fesoterodine is a cost-effective alternative to tolterodine and solifenacin for the treatment of patients with OAB in Spain. Fesoterodine provides additional health benefits while maintain a similar level of costs being a cost-effective treatment strategy from a societal perspective.</p

Branch Retinal Vein Occlusion: Pathogenesis, Visual Prognosis, and Treatment Modalities

In branch retinal vein occlusion (BRVO), abnormal arteriovenous crossing with vein compression, degenerative changes of the vessel wall and abnormal hematological factors constitute the primary mechanism of vessel occlusion. In general, BRVO has a good prognosis: 50–60% of eyes are reported to have a final visual acuity (VA) of 20/40 or better even without treatment. One important prognostic factor for final VA appears to be the initial VA. Grid laser photocoagulation is an established treatment for macular edema in a particular group of patients with BRVO, while promising results for this condition are shown by intravitreal application of steroids or new vascular endothelial growth factor inhibitors. Vitrectomy with or without arteriovenous sheathotomy combined with removal of the internal limiting membrane may improve vision in eyes with macular edema which are unresponsive to or ineligible for laser treatment

A microarray study of MPP(+)-treated PC12 Cells: Mechanisms of toxicity (MOT) analysis using bioinformatics tools

BACKGROUND: This paper describes a microarray study including data quality control, data analysis and the analysis of the mechanism of toxicity (MOT) induced by 1-methyl-4-phenylpyridinium (MPP(+)) in a rat adrenal pheochromocytoma cell line (PC12 cells) using bioinformatics tools. MPP(+ )depletes dopamine content and elicits cell death in PC12 cells. However, the mechanism of MPP(+)-induced neurotoxicity is still unclear. RESULTS: In this study, Agilent rat oligo 22K microarrays were used to examine alterations in gene expression of PC12 cells after 500 μM MPP(+ )treatment. Relative gene expression of control and treated cells represented by spot intensities on the array chips was analyzed using bioinformatics tools. Raw data from each array were input into the NCTR ArrayTrack database, and normalized using a Lowess normalization method. Data quality was monitored in ArrayTrack. The means of the averaged log ratio of the paired samples were used to identify the fold changes of gene expression in PC12 cells after MPP(+ )treatment. Our data showed that 106 genes and ESTs (Expressed Sequence Tags) were changed 2-fold and above with MPP(+ )treatment; among these, 75 genes had gene symbols and 59 genes had known functions according to the Agilent gene Refguide and ArrayTrack-linked gene library. The mechanism of MPP(+)-induced toxicity in PC12 cells was analyzed based on their genes functions, biological process, pathways and previous published literatures. CONCLUSION: Multiple pathways were suggested to be involved in the mechanism of MPP(+)-induced toxicity, including oxidative stress, DNA and protein damage, cell cycling arrest, and apoptosis

A Literature Review of Empirical Studies of Philanthropy: Eight Mechanisms that Drive Charitable Giving

The authors present an overview of the academic literature on charitable giving based on a literature review of more than 500 articles. They structure their review around the central question of why people donate money to charitable organizations. They identify eight mechanisms as the most important forces that drive charitable giving: (a) awareness of need; (b) solicitation; (c) costs and benefits; (d) altruism; (e) reputation; (f) psychological benefits; (g) values; (h) efficacy. These mechanisms can provide a basic theoretical framework for future research explaining charitable giving

Regulation of Fn14 Receptor and NF-κB Underlies Inflammation in Meniere’s Disease

Meniere’s disease (MD) is a rare disorder characterized by episodic vertigo, sensorineural hearing loss, tinnitus, and aural fullness. It is associated with a fluid imbalance between the secretion of endolymph in the cochlear duct and its reabsorption into the subarachnoid space, leading to an accumulation of endolymph in the inner ear. Epidemiological evidence, including familial aggregation, indicates a genetic contribution and a consistent association with autoimmune diseases (AD). We conducted a case–control study in two phases using an immune genotyping array in a total of 420 patients with bilateral MD and 1,630 controls. We have identified the first locus, at 6p21.33, suggesting an association with bilateral MD [meta-analysis leading signal rs4947296, OR = 2.089 (1.661–2.627); p = 1.39 × 10−09]. Gene expression profiles of homozygous genotype-selected peripheral blood mononuclear cells (PBMCs) demonstrated that this region is a trans-expression quantitative trait locus (eQTL) in PBMCs. Signaling analysis predicted several tumor necrosis factor-related pathways, the TWEAK/Fn14 pathway being the top candidate (p = 2.42 × 10−11). This pathway is involved in the modulation of inflammation in several human AD, including multiple sclerosis, systemic lupus erythematosus, or rheumatoid arthritis. In vitro studies with genotype-selected lymphoblastoid cells from patients with MD suggest that this trans-eQTL may regulate cellular proliferation in lymphoid cells through the TWEAK/Fn14 pathway by increasing the translation of NF-κB. Taken together; these findings suggest that the carriers of the risk genotype may develop an NF-κB-mediated inflammatory response in MD