Polyphenolic acetates: A newer anti-Mycobacterial therapeutic option

The objective of our research project was screening of various highly specific substrates of Acetoxy Drug: Protein Transacytylase (M.TAase) for antimycobacterial activity. Mycobacterial culture was done in Middlebrook’s 7H9 media. Protein purification (Mycobacterial Tranacetylase, M.TAase) was done by ion exchange chromatography and its demonstration was done on SDS- polyacrylamide gel electrophoresis (SDS-PAGE) and western blot. Middlebrook’s 7H9 broth was procured from Becton Dickinson. CM-Sepharose, DEAE-Sepharose and Q-Sephharose were purchased from Amersham Pharmacia. Anti acetyl lysine polyclonal antibody was purchased from Cell Signaling. The Middlebrook 7H9 medium was used for M. smegmatis culture. The media was prepared according to the manufacturer’s instructions. The various Polyphenol acetate compounds were tested for their antimycobacterial activities. Minimal inhibitory concentrations (MIC) were calculated by Alamar blue dye assay method. The GST protein was used as a receptor protein and purified Mycobacterial Glutamine Synthetase (GS) as TAase for acetylation by DAMC. To demonstrate the TAase catalyzed acetylation of GST by DAMC, purified M.TAase (GS) was preincubated with GST and DAMC followed by western blot using anti acetyl lysine antibody, which avidly react with the acetylated proteins. The growth pattern of M. smegmatis was diminished under the influence of various polyphenolic acetates (PA) tested for their anti-mycobacterial activity. DAMC and DAMC-5-carboxylic acid was found to have MIC of 40μg/ml whereas DAMC-6-carboxylic acid was reported to have MIC value of 35μg/ml and for ellagic acid tetra acetate (EATA) it was 60μg/ml. Previous work in our lab has led to discovery of a novel enzyme acetoxy drug: protein transacetylase (TAase), catalyzing transfer of acetyl group from various polyphenolic peracetate (PA) to certain receptor proteins such as cytochromes P-450, NADPH cytochrome reductase, nitric oxide synthase (NOS) has been established in various eukaryotic as well as prokaryotic sources. PA(s) irreversible inhibitors of mammalian CYP linked MFO, possibly due to modification of cytochrome p- 450 by acetylation in a reaction catalysed by M.TAase (GS) utilizing PA(s) as a donor of acetyl groups. Accordingly, it was hypothesized that the CYP51 of mycobacteria involved in the cell wall sterol synthesis could possibly be modified by our PA(s) through the novel unknown action of GS as transacetylase leading to the death of mycobacterial cell by way of acetylation catalyzed by acetoxy drug: protein transacetylase (M.TAase or GS).Keywords: Transacetylase; Glutamine synthetase; Mycobacterium smegmatis; Polyphenolic acetates; Acetoxy drug: protein transacetylas

Polycystic kidney disease in patients on the renal transplant waiting list: trends in hematocrit and survival

BACKGROUND: The patient characteristics and mortality associated with autosomal dominant polycystic kidney disease (PKD) have not been characterized for a national sample of end stage renal disease (ESRD) patients on the renal transplant waiting list. METHODS: 40,493 patients in the United States Renal Data System who were initiated on ESRD therapy between 1 April 1995 and 29 June 1999 and later enrolled on the renal transplant waiting list were analyzed in an historical cohort study of the relationship between hematocrit at the time of presentation to ESRD and survival (using Cox Regression) in patients with PKD as a cause of ESRD. RESULTS: Hematocrit levels at presentation to ESRD increased significantly over more recent years of the study. Hematocrit rose in parallel in patients with and without PKD, but patients with PKD had consistently higher hemoglobin. PKD was independently associated with higher hematocrit in multiple linear regression analysis (p < 0.0001). In logistic regression, higher hematocrit was independently associated with PKD. In Cox Regression analysis, PKD was associated with statistically significant improved survival both in comparison with diabetic (hazard ratio, 0.64, 95% CI 0.53–0.77, p < 0.001) and non-diabetic (HR 0.68, 95% CI 0.56–0.82, p = 0.001) ESRD patients, adjusted for all other factors. CONCLUSIONS: Hematocrit at presentation to ESRD was significantly higher in patients with PKD compared with patients with other causes of ESRD. The survival advantage of PKD in ESRD persisted even adjusted for differences in hematocrit and in comparison with patients on the renal transplant waiting list

Kinetic exchange opinion model: solution in the single parameter map limit

We study a recently proposed kinetic exchange opinion model (Lallouache et. al., Phys. Rev E 82:056112, 2010) in the limit of a single parameter map. Although it does not include the essentially complex behavior of the multiagent version, it provides us with the insight regarding the choice of order parameter for the system as well as some of its other dynamical properties. We also study the generalized two- parameter version of the model, and provide the exact phase diagram. The universal behavior along this phase boundary in terms of the suitably defined order parameter is seen.Comment: 14 pages, 9 figure

Goal-Based Selection of Visual Representations for Big Data Analytics

The H2020 TOREADOR Project adopts a model-driven architecture to streamline big data analytics and make it widely available to companies as a service. Our work in this context focuses on visualization, in particular on how to automate the translation of the visualization objectives declared by the user into a suitable visualization type. To this end we first define a visualization context based on seven prioritizable coordinates for assessing the user's objectives and describing the data to be visualized; then we propose a skyline-based technique for automatically translating a visualization context into a set of suitable visualization types. Finally, we evaluate our approach on a real use case excerpted from the pilot applications of TOREADOR

Potential role of differential medication use in explaining excess risk of cardiovascular events and death associated with chronic kidney disease: A cohort study

<p>Abstract</p> <p>Background</p> <p>Patients with chronic kidney disease (CKD) are less likely to receive cardiovascular medications. It is unclear whether differential cardiovascular drug use explains, in part, the excess risk of cardiovascular events and death in patients with CKD and coronary heart disease (CHD).</p> <p>Methods</p> <p>The ADVANCE Study enrolled patients with new onset CHD (2001-2003) who did (N = 159) or did not have (N = 1088) CKD at entry. The MDRD equation was used to estimate glomerular filtration rate (eGFR) using calibrated serum creatinine measurements. Patient characteristics, medication use, cardiovascular events and death were ascertained from self-report and health plan electronic databases through December 2008.</p> <p>Results</p> <p>Post-CHD event ACE inhibitor use was lower (medication possession ratio 0.50 vs. 0.58, P = 0.03) and calcium channel blocker use higher (0.47 vs. 0.38, P = 0.06) in CKD vs. non-CKD patients, respectively. Incidence of cardiovascular events and death was higher in CKD vs. non-CKD patients (13.9 vs. 11.5 per 100 person-years, P < 0.001, respectively). After adjustment for patient characteristics, the rate of cardiovascular events and death was increased for eGFR 45-59 ml/min/1.73 m²(hazard ratio [HR] 1.47, 95% CI: 1.10 to 2.02) and eGFR < 45 ml/min/1.73 m²(HR 1.58, 95% CI: 1.00 to 2.50). After further adjustment for statins, β-blocker, calcium channel blocker, ACE inhibitor/ARB use, the association was no longer significant for eGFR 45-59 ml/min/1.73 m²(HR 0.82, 95% CI: 0.25 to 2.66) or for eGFR < 45 ml/min/1.73 m²(HR 1.19, 95% CI: 0.25 to 5.58).</p> <p>Conclusions</p> <p>In adults with CHD, differential use of cardiovascular medications may contribute to the higher risk of cardiovascular events and death in patients with CKD.</p

Ideal and actual involvement of community pharmacists in health promotion and prevention: a cross-sectional study in Quebec, Canada

<p>Abstract</p> <p>Background</p> <p>An increased interest is observed in broadening community pharmacists' role in public health. To date, little information has been gathered in Canada on community pharmacists' perceptions of their role in health promotion and prevention; however, such data are essential to the development of public-health programs in community pharmacy. A cross-sectional study was therefore conducted to explore the perceptions of community pharmacists in urban and semi-urban areas regarding their ideal and actual levels of involvement in providing health-promotion and prevention services and the barriers to such involvement.</p> <p>Methods</p> <p>Using a five-step modified Dillman's tailored design method, a questionnaire with 28 multiple-choice or open-ended questions (11 pages plus a cover letter) was mailed to a random sample of 1,250 pharmacists out of 1,887 community pharmacists practicing in Montreal (Quebec, Canada) and surrounding areas. It included questions on pharmacists' ideal level of involvement in providing health-promotion and preventive services; which services were actually offered in their pharmacy, the employees involved, the frequency, and duration of the services; the barriers to the provision of these services in community pharmacy; their opinion regarding the most appropriate health professionals to provide them; and the characteristics of pharmacists, pharmacies and their clientele.</p> <p>Results</p> <p>In all, 571 out of 1,234 (46.3%) eligible community pharmacists completed and returned the questionnaire. Most believed they should be very involved in health promotion and prevention, particularly in smoking cessation (84.3%); screening for hypertension (81.8%), diabetes (76.0%) and dyslipidemia (56.9%); and sexual health (61.7% to 89.1%); however, fewer respondents reported actually being very involved in providing such services (5.7% [lifestyle, including smoking cessation], 44.5%, 34.8%, 6.5% and 19.3%, respectively). The main barriers to the provision of these services in current practice were lack of: time (86.1%), coordination with other health care professionals (61.1%), staff or resources (57.2%), financial compensation (50.8%), and clinical tools (45.5%).</p> <p>Conclusions</p> <p>Although community pharmacists think they should play a significant role in health promotion and prevention, they recognize a wide gap between their ideal and actual levels of involvement. The efficient integration of primary-care pharmacists and pharmacies into public health cannot be envisioned without addressing important organizational barriers.</p

Impact of Vitamin D Supplementation on Arterial Vasomotion, Stiffness and Endothelial Biomarkers in Chronic Kidney Disease Patients

Background: Cardiovascular events are frequent and vascular endothelial function is abnormal in patients with chronic kidney disease (CKD). We demonstrated endothelial dysfunction with vitamin D deficiency in CKD patients; however the impact of cholecalciferol supplementation on vascular stiffness and vasomotor function, endothelial and bone biomarkers in CKD patients with low 25-hydroxy vitamin D [25(OH)D] is unknown, which this study investigated. Methods: We assessed non-diabetic patients with CKD stage 3/4, age 17–80 years and serum 25(OH)D ,75 nmol/L. Brachial artery Flow Mediated Dilation (FMD), Pulse Wave Velocity (PWV), Augmentation Index (AI) and circulating blood biomarkers were evaluated at baseline and at 16 weeks. Oral 300,000 units cholecalciferol was administered at baseline and 8-weeks. Results: Clinical characteristics of 26 patients were: age 50614 (mean61SD) years, eGFR 41611 ml/min/1.73 m2, males 73%, dyslipidaemia 36%, smokers 23% and hypertensives 87%. At 16-week serum 25(OH)D and calcium increased (43616 to 84629 nmol/L, p,0.001 and 2.3760.09 to 2.4260.09 mmol/L; p = 0.004, respectively) and parathyroid hormone decreased (10.868.6 to 7.464.4; p = 0.001). FMD improved from 3.163.3% to 6.163.7%, p = 0.001. Endothelial biomarker concentrations decreased: E-Selectin from 566662123 to 525662058 pg/mL; p = 0.032, ICAM-1, 3.4560.01 to 3.1061.04 ng/mL; p = 0.038 and VCAM-1, 54633 to 42633 ng/mL; p = 0.006. eGFR, BP, PWV, AI, hsCRP, von Willebrand factor and Fibroblast Growth Factor-23, remained unchanged. Conclusion: This study demonstrates for the first time improvement of endothelial vasomotor and secretory functions with vitamin D in CKD patients without significant adverse effects on arterial stiffness, serum calcium or FGF-23. Trial Registration: ClinicalTrials.gov NCT0200571

Massive stars as thermonuclear reactors and their explosions following core collapse

Nuclear reactions transform atomic nuclei inside stars. This is the process of stellar nucleosynthesis. The basic concepts of determining nuclear reaction rates inside stars are reviewed. How stars manage to burn their fuel so slowly most of the time are also considered. Stellar thermonuclear reactions involving protons in hydrostatic burning are discussed first. Then I discuss triple alpha reactions in the helium burning stage. Carbon and oxygen survive in red giant stars because of the nuclear structure of oxygen and neon. Further nuclear burning of carbon, neon, oxygen and silicon in quiescent conditions are discussed next. In the subsequent core-collapse phase, neutronization due to electron capture from the top of the Fermi sea in a degenerate core takes place. The expected signal of neutrinos from a nearby supernova is calculated. The supernova often explodes inside a dense circumstellar medium, which is established due to the progenitor star losing its outermost envelope in a stellar wind or mass transfer in a binary system. The nature of the circumstellar medium and the ejecta of the supernova and their dynamics are revealed by observations in the optical, IR, radio, and X-ray bands, and I discuss some of these observations and their interpretations.Comment: To be published in " Principles and Perspectives in Cosmochemistry" Lecture Notes on Kodai School on Synthesis of Elements in Stars; ed. by Aruna Goswami & Eswar Reddy, Springer Verlag, 2009. Contains 21 figure

Heart rate variability and target organ damage in hypertensive patients

Background: We evaluated the association between linear standard Heart Rate Variability (HRV) measures and vascular, renal and cardiac target organ damage (TOD). Methods: A retrospective analysis was performed including 200 patients registered in the Regione Campania network (aged 62.4 ± 12, male 64%). HRV analysis was performed by 24-h holter ECG. Renal damage was assessed by estimated glomerular filtration rate (eGFR), vascular damage by carotid intima-media thickness (IMT), and cardiac damage by left ventricular mass index. Results: Significantly lower values of the ratio of low to high frequency power (LF/HF) were found in the patients with moderate or severe eGFR (p-value < 0.001). Similarly, depressed values of indexes of the overall autonomic modulation on heart were found in patients with plaque compared to those with a normal IMT (p-value <0.05). These associations remained significant after adjustment for other factors known to contribute to the development of target organ damage, such as age. Moreover, depressed LF/HF was found also in patients with left ventricular hypertrophy but this association was not significant after adjustment for other factors. Conclusions: Depressed HRV appeared to be associated with vascular and renal TOD, suggesting the involvement of autonomic imbalance in the TOD. However, as the mechanisms by which abnormal autonomic balance may lead to TOD, and, particularly, to renal organ damage are not clearly known, further prospective studies with longitudinal design are needed to determine the association between HRV and the development of TOD