Fibroblast Growth Factor-9 Enhances M2 Macrophage Differentiation and Attenuates Adverse Cardiac Remodeling in the Infarcted Diabetic Heart

Inflammation has been implicated as a perpetrator of diabetes and its associated complications. Monocytes, key mediators of inflammation, differentiate into pro-inflammatory M1 macrophages and anti-inflammatory M2 macrophages upon infiltration of damaged tissue. However, the inflammatory cell types, which propagate diabetes progression and consequential adverse disorders, remain unclear. The current study was undertaken to assess monocyte infiltration and the role of fibroblast growth factor-9 (FGF-9) on monocyte to macrophage differentiation and cardioprotection in the diabetic infarcted heart. Db/db diabetic mice were assigned to sham, myocardial infarction (MI), and MI+FGF-9 groups. MI was induced by permanent coronary artery ligation and animals were subjected to 2D transthoracic echocardiography two weeks post-surgery. Immunohistochemical and immunoassay results from heart samples collected suggest significantly increased infiltration of monocytes (Mean +/- SEM; MI: 2.02% +/- 0.23% vs. Sham 0.75% +/- 0.07%; p \u3c 0.05) and associated pro-inflammatory cytokines (TNF-alpha, MCP-1, and IL-6), adverse cardiac remodeling (Mean +/- SEM; MI: 33% +/- 3.04% vs. Sham 2.2% +/- 0.33%; p \u3c 0.05), and left ventricular dysfunction (Mean +/- SEM; MI: 35.4% +/- 1.25% vs. Sham 49.19% +/- 1.07%; p \u3c 0.05) in the MI group. Importantly, treatment of diabetic infarcted myocardium with FGF-9 resulted in significantly decreased monocyte infiltration (Mean +/- SEM; MI+FGF-9: 1.39% +/- 0.1% vs. MI: 2.02% +/- 0.23%; p \u3c 0.05), increased M2 macrophage differentiation (Mean +/- SEM; MI+FGF-9: 4.82% +/- 0.86% vs. MI: 0.85% +/- 0.3%; p \u3c 0.05) and associated anti-inflammatory cytokines (IL-10 and IL-1RA), reduced adverse remodeling (Mean +/- SEM; MI+FGF-9: 11.59% +/- 1.2% vs. MI: 33% +/- 3.04%; p \u3c 0.05), and improved cardiac function (Fractional shortening, Mean +/- SEM; MI+FGF-9: 41.51% +/- 1.68% vs. MI: 35.4% +/- 1.25%; p \u3c 0.05). In conclusion, our data suggest FGF-9 possesses novel therapeutic potential in its ability to mediate monocyte to M2 differentiation and confer cardiac protection in the post-MI diabetic heart

Efficacy and safety of tadalafil in ureteric stent related symptoms: a double blind, prospective, randomised study

Background: Is tadalafil effective and safe in ureteric stent related symptoms? The objective of this trial is to study the efficacy and safety of tadalafil and compare it with tamsulosin in relieving ureteric stent related symptoms by using ureteral stent symptom questionnaire.Methods: Total 144 patients with dj stent symptoms were randomized into two groups with 72 patients in each. Group A patients were given tadalafil 5mg and Group B, tamsulosin 0.4mg for 2 weeks. Ureteral stent symptom questionnaire was filled on 7th day and on 21st day after stent insertion. Statistically significant difference between groups was determined by the t-test, Mann-Whitney U-test, Pearson Chi-square test or Fisher's exact test. Comparison between quantitative time related variables was done by Wilcoxon Signed Rank test. All the statistical tests were two-sided and were performed at a significance level of α=.05.Results: Tamsulosin was found more effective then tadalafil in decreasing mean urinary index (p=0.004). Tadalafil caused significant decrease in body pain (p=0.006) and improvement in general health index score, work performance and sex score (P value= 0.041, <0.001 and <0.015 respectively) as compared to tamsulosin. Additional problems score improvement and analgesic use were found comparable in 2 groups (p value =0.193, 0.070 respectively). Adverse effect with both the drugs were minimal, mild to moderate and self-limiting.Conclusions: Tadalafil found more effective then Tamsulosin in relieving body pain, sexual symptoms and improving general health and work performance but less effective in improvement of urinary symptoms

Functional validation of a novel isoform of Na<SUP>+</SUP>/H<SUP>+</SUP> antiporter from Pennisetum glaucum for enhancing salinity tolerance in rice

Salt stress is an environmental factor that severely impairs plant growth and productivity. We have cloned a novel isoform of a vacuolar Na+/H+ antiporter from Pennisetum glaucum (PgNHX1) that contains 5 transmembrane domains in contrast to AtNHX1 and OsNHX1 which have 9 transmembrane domains. Recently we have shown that PgNHX1 could confer high level of salinity tolerance when overexpressed in Brassica juncea. Here, we report the functional validation of this antiporter in crop plant rice. Overexpression of PgNHX1 conferred high level of salinity tolerance in rice. Transgenic rice plants overexpressing PgNHX1 developed more extensive root system and completed their life cycle by setting flowers and seeds in the presence of 150 mM NaCl. Our data demonstrate the potential of PgNHX1 for imparting enhanced salt tolerance capabilities to salt-sensitive crop plants for growing in high saline areas

Drug utilization study in diabetic patients seeking medical treatment in a north Indian rural medical college hospital

Background: Diabetes Mellitus is a chronic disease and its life-long management causes burden on lifestyle and financial condition of the patients. Drug utilization studies provide useful insights into the current prescribing practices.Methods: To evaluate the drug utilization pattern of anti-diabetic drugs in diabetic patients. A prospective observational study was carried out in adult diabetic patients visiting the Wards and Outpatient Department of General Medicine of a tertiary care hospital. The demographic data and utilization of different classes of anti-diabetic agents as well as individual drugs were analyzed.Results: In 125 patients (Male-65, Female-60), a total of 379 drugs (average 3.032±2.05) were used per day, out of which 76 (20.05%) were rational fixed dose combinations (FDCs) and 261 (68.86%) were prescribed from National List of Essential Medicines (NLEM) 2015. The number of drugs prescribed to be ingested was 326 (86.01%) and 63 (16.62%) were injectables.Conclusions: It was found that the prescription tendencies of the doctors were quite rational. More improvement can be done by sensitizing them to prescribe more drugs from NLEM. The limitations in the affordability of rural population should be taken care of while prescribing drugs for this chronic disease

Regulation of PTEN/Akt Pathway Enhances Cardiomyogenesis and Attenuates Adverse Left Ventricular Remodeling following Thymosin beta 4 Overexpressing Embryonic Stem Cell Transplantation in the Infarcted Heart

Thymosin beta 4 (T beta 4), a small G-actin sequestering peptide, mediates cell proliferation, migration, and angiogenesis. Whether embryonic stem (ES) cells, overexpressing T beta 4, readily differentiate into cardiac myocytes in vitro and in vivo and enhance cardioprotection following transplantation post myocardial infarction (MI) remains unknown. Accordingly, we established stable mouse ES cell lines, RFP-ESCs and T beta 4-ESCs, expressing RFP and an RFP-T beta 4 fusion protein, respectively. In vitro, the number of spontaneously beating embryoid bodies (EBs) was significantly increased in T beta 4-ESCs at day 9, 12 and 15, compared with RFP-ESCs. Enhanced expression of cardiac transcriptional factors GATA-4, Mef2c and Txb6 in T beta 4-EBs, as confirmed with real time-PCR analysis, was accompanied by the increased number of EB areas stained positive for sarcomeric alpha-actin in T beta 4-EBs, compared with the RFP control, suggesting a significant increase in functional cardiac myocytes. Furthermore, we transplanted T beta 4-ESCs into the infarcted mouse heart and performed morphological and functional analysis 2 weeks after MI. There was a significant increase in newly formed cardiac myocytes associated with the Notch pathway, a decrease in apoptotic nuclei mediated by an increase in Akt and a decrease in levels of PTEN. Cardiac fibrosis was significantly reduced, and left ventricular function was significantly augmented in the T beta 4-ESC transplanted group, compared with controls. It is concluded that genetically modified T beta 4-ESCs, potentiates their ability to turn into cardiac myocytes in vitro as well as in vivo. Moreover, we also demonstrate that there was a significant decrease in both cardiac apoptosis and fibrosis, thus improving cardiac function in the infarcted heart