Therapeutic potential of sulindac against ischemia-reperfusion-induced myocardial infarction in diabetic and nondiabetic rats

BACKGROUND

Diabetes mellitus is an independent risk factor for cardiovascular disease and is also associated with increased susceptibility to cardiovascular complications. It has been suggested that alterations in glucose metabolism and glucose flux via the aldose reductase pathway make the diabetic heart more sensitive to ischemic-reperfusion injury. Previous studies have found sulindac to have inhibitory and anti-inflammatory effects on aldose reductase. The use of aldose reductase inhibitors for the protection of ischemic myocardium is still in an exploratory state.

OBJECTIVES

To evaluate the therapeutic potential of sulindac in an in vivo rat model of acute ischemia (30 min) and reperfusion (4 h) in diabetic and nondiabetic rats.

METHODS

Diabetes was induced in rats by administering streptozotocin (45 mg/kg, intravenously). Myocardial infarction was induced by occlusion of the left anterior descending coronary artery for 30 min followed by 4 h of reperfusion. Infarct size was measured using the staining agent 2,3,5-triphenyltetrazolium chloride. A lead II electrocardiogram was monitored at various intervals throughout the experiment. Sorbitol dehydrogenase levels in heart tissue, as well as lipid peroxide levels in serum and heart tissue, were estimated spectrophotometrically.

RESULTS

Infarct size was increased in diabetic rats in comparison with normal rats. Pretreatment with sulindac significantly reduced infarct size, lipid peroxidation and sorbitol dehydrogenase levels in both diabetic and nondiabetic rats. The degree of cardioprotection was greater in diabetic rats than in nondiabetic rats.

CONCLUSIONS

The present study indicates that the observed cardioprotection provided by sulindac in terms of reducing infarct size in normal rats may be due to its combined antioxidant and anti-inflammatory activities. The inhibition of aldose reductase may be responsible for the enhanced cardioprotection observed in diabetic rats treated with sulindac.     

Coinduction of granulocyte-macrophage colony-stimulating factor release and lymphokine-activated killer cell susceptibility in monocytes by interleukin-2 via interleukin-2 receptor beta

Human monocytes express interleukin-2 receptor beta (IL-2R beta) constitutively; however, the function of these receptors has not been fully delineated. We discovered that IL-2R beta directs two biologic activities in human monocytes, the release of granulocyte-macrophage colony-stimulating factor (GM-CSF) and increased susceptibility to lysis by lymphokine-activated killer cells (LAK) cells. Human monocytes were purified from peripheral blood mononuclear cells by plastic adherence and anti-CD2 plus complement lysis. By a 5-hour 51Cr-release assay, monocytes cultured in IL-2 were found to gain increasing susceptibility to LAK cells with time and this effect was dose dependent. Maximal susceptibility was obtained with a 4-day culture in 1,000 U/mL of IL-2. Monocytes were also found to release GM-CSF in response to IL-2 using a CSF-dependent cell line, Mo7e. Because IL-2- induced GM-CSF release coincides with LAK lysis of IL-2-cultured monocytes, we treated monocytes with anti-GM-CSF and anti-IL-2R beta to determine whether GM-CSF release and LAK susceptibility were dependent or independent events. We found that both phenomena were inhibited by either antibody. Therefore, we conclude that IL-2-induced release of GM- CSF is mediated by IL-2R beta, which then acts to modulate the susceptibility of monocytes to lysis by LAK cells.     

Study of treatment outcomes of multidrug-resistant tuberculosis under programmatic conditions and factors influencing the outcomes in Hyderabad District

BackgroundTreatment outcomes for Multidrug-Resistant Tuberculosis (MDR TB) is generally poor. The study aims to know about the treatment outcomes of MDR-TB under programmatic conditions in Hyderabad District and to analyze the factors influencing the treatment outcomes.MethodsThis is a retrospective study in which 377 patients of Hyderabad district, Telangana state who were diagnosed with MDR TB and registered at Drug Resistance TB Treatment site of Government General & Chest Hospital, Hyderabad from 4th quarter 2008 to 4th quarter 2013 were included in the study. Impact of Demographic factors (age, sex; Nutritional status (BMI); Co-morbid condition (Diabetes, HIV, Hypothyroidism); Programmatic factors (time delay in the initiation of treatment); Initial Resistance pattern on the outcomes were studied and analyzed.ResultsThe treatment outcomes of Multidrug-Resistant Tuberculosis under Programmatic Conditions were: 57% cured, 21.8% died, 19.6% defaulted, 1.1% failed and 0.5% switched to XDR. Age, Sex, BMI had a statistically significant impact on treatment outcomes. Hypothyroidism and Delay in the initiation of treatment >1 a month had an impact on the outcomes though not statistically significant. NO impact on treatment outcomes was found when Rifampicin resistance & INH sensitive patients were compared with those resistant to both INH and Rifampicin.ConclusionTo reduce MDR-TB transmission in the community, improvement of treatment outcomes, via ensuring adherence, paying special attention to elderly patients is required. The Programmatic Management of Drug Resistance Tuberculosis (PMDT) should seriously think of providing Nutritional support to patients with low BMI to improve outcomes. In the programmatic conditions if we could address the problems like delay in initiation of treatment and proper management of comorbidities like HIV, Diabetes, Hypothyroidism would definitely improve the treatment outcomes.     

Fluorescent in vivo tracking of hematopoietic cells. Part I. Technical considerations

We report a new technology for in vivo tracking of hematopoietic cells, using fluorescent lipophilic probes. Because the probe is irreversibly bound in the lipids of the cell membrane; substantial numbers of dye molecules can be incorporated per cell and thus substantial signal to noise can be achieved. Although this technology can be used for all hematopoietic cells, these first findings are reported on red blood cells (RBCs) owing to the importance of the membrane to RBC function and integrity. We demonstrated that labeling 10% of the RBCs of a rabbit and reinjecting them into the animal makes possible the tracking of these cells at various times after injection. Furthermore, the labeling appears not to affect in vivo cell lifetime or cellular volume changes in response to hypotonic shock. The single cell fluorescence intensity of the labeled RBCs remains relatively constant for 60 days, and an immune response appears not to be generated against labeled cells. That labeled RBCs have lifetime kinetics in vivo, as shown in other studies, indicates that the membranes are functioning normally and are unaltered by the labeling technology. The technology we present is also applicable to white blood cells, bone marrow, and platelets.     

Complete 360° circumferential gonioscopic optical coherence tomography imaging of the iridocorneal angle

Clinically, gonioscopy is used to provide en face views of the ocular angle. The angle has been imaged with optical coherence tomography (OCT) through the corneoscleral limbus but is currently unable to image the angle from within the ocular anterior chamber. We developed a novel gonioscopic OCT system that images the angle circumferentially from inside the eye through a custom, radially symmetric, gonioscopic contact lens. We present, to our knowledge, the first 360° circumferential volumes (two normal subjects, two subjects with pathology) of peripheral iris and iridocorneal angle structures obtained via an internal approach not typically available in the clinic.OCIS codes: (170.4500) Optical coherence tomography, (170.0110) Imaging systems, (170.4470) Ophthalmology     

Sphingolipids Mediate Differential Echinocandin Susceptibility in Candida albicans and Aspergillus nidulans

The cell wall synthesis-inhibiting echinocandins, including caspofungin and micafungin, play important roles in the treatment of candidiasis and aspergillosis. Previous studies revealed that, in the haploid yeast Candida glabrata, sphingolipid biosynthesis pathway mutations confer caspofungin reduced susceptibility (CRS) but micafungin increased susceptibility (MIS). Here, we describe one Candida albicans strain (of 10 tested) that similarly yields CRS-MIS mutants at relatively high frequency. Mutants demonstrated increased levels of long-chain bases (sphingolipid pathway intermediates) and, unique to this strain, loss of His104/Pro104 heterozygosity in the TSC13-encoded enoyl reductase. CRS-MIS was similarly observed in a C. albicans homozygous fen1Δ fen12Δ laboratory strain and in diverse wild-type strains following exogenous long-chain-base treatment. Analogous to these results, CRS-MIS was demonstrated in an Aspergillus nidulans basA mutant encoding defective sphingolipid C₄-hydroxylase and in its wild-type parent exposed to long-chain bases. Sphingolipids likely modulate echinocandin interaction with their Fks membrane target in all susceptible fungi, with potential implications for optimizing therapy with existing antifungals and the development of novel agents.     

Predictors of changes in disease activity among children with juvenile dermatomyositis enrolled in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Legacy Registry

Determinants of changes in disease activity among patients with juvenile dermatomyositis (JDM) are unknown. Our objective was to develop predictive models to predict changes in disease activity using the CARRA Legacy Registry. The CARRA Legacy Registry included 658 subjects with definite or probably JDM with 297 subjects with a one follow-up visit after baseline, and we studied the 65 subjects with active disease at baseline. Linear regression models were used to build risk scores for changes in disease activity adjusted for baseline disease activity, age, sex, and disease duration. Disease activity improved from baseline to 6-month follow-up as measured by patient/parent global health score (median 4; p = 0.008), patient pain score (median 2; p = 0.014), physician global (median 4; p < 0.001), and Childhood Myositis Assessment Scale (CMAS) (median 41, p < 0.001). Anti-nuclear antibodies (p = 0.013) and hydroxychloroquine use (p = 0.045) were significant predictors of less improvement in patient/parent global and baseline patient/parent global. Anti-nuclear antibodies (p = 0.001) and V/shawl sign (p = 0.005) were significant predictors of less improvement in patient pain (R-square improved from 0.29 for adjustors alone to 0.46 for the full model). Small joint arthritis (p < 0.01) predicted less improvement and dysphagia/dysphonia (p = 0.033) predicted greater improvement in CMAS and baseline CMAS (R-square improved from 0.73 for adjustors alone to 0.86 for the full model). Disease characteristics can help identify patients who are less likely to improve over time. Risk scores to predict future changes in disease activity could be used to trigger more aggressive treatment earlier in the disease course.     

Auricular Retentive Prosthetic Conformer Post Brent's Stage III Surgery in Microtia Repair: A Clinical Report

Auricular reconstruction is an interdisciplinary approach where multiple specialties play a vital role in the treatment provided to the patient. This article provides a comprehensive interpretation of the process carried out for the fabrication of a custom‐made prosthetic conformer for the management of postoperative contraction of a skin graft after ear reconstruction surgery—Brent stage III. The prosthesis is used as a precautionary measure and is simple, effective, and economical.