Evidence for a potent antiinflammatory effect of rosiglitazone

We have recently demonstrated a potent antiinflammatory effect of troglitazone, an agonist of peroxisome proliferator-activated receptor gamma (PPARgamma) and a partial agonist of PPARalpha in both the nondiabetic obese and diabetic obese subjects. We have now investigated the antiinflammatory actions of rosiglitazone, a selective PPARgamma agonist. Eleven nondiabetic obese subjects and 11 obese diabetic subjects were each given 4 mg of rosiglitazone daily for a period of 6 wk. Fasting blood samples were obtained at 0, 1, 2, 4, 6, and 12 wk (6 wk after the cessation of rosiglitazone). Eight obese subjects and five obese diabetic subjects were also included in the study as control groups. Fasting blood samples were obtained from the control groups at 0, 1, 2, 4, and 6 wk only. Nuclear factor kappaB (NFkappaB)-binding activity in mononuclear cells, plasma monocyte chemoattractant protein-1 (MCP-1), TNF-alpha, soluble intercellular adhesion molecule-1, C-reactive protein (CRP), and serum amyloid A (SAA) were measured. Blood glucose concentration changed significantly at 6 wk only in the obese diabetic subjects after rosiglitazone treatment for 6 wk, whereas insulin concentration decreased significantly at 6 wk in both groups. NFkappaB-binding activity in mononuclear cell nuclear extract fell in both obese and obese diabetic subjects (P < 0.02). Rosiglitazone treatment resulted in a reduction in plasma MCP-1 and CRP in both groups (P < 0.05). Plasma TNF-alpha and SAA concentrations were inhibited significantly in the obese group (P < 0.05) but not in the obese diabetic subjects. NFkappaB-binding activity and plasma MCP-1, CRP, SAA, and TNF-alpha did not change in the obese and obese diabetic control groups. We conclude that rosiglitazone, a selective PPARgamma agonist, exerts an antiinflammatory effect at the cellular and molecular level, and in plasma. These observations may have implications for atherogenesis in the long term in subjects treated with rosiglitazone and possibly other thiazolidinediones.     

Superiority of Higher-Volume Fresh Feces Compared to Lower-Volume Frozen Feces in Fecal Microbiota Transplantation for Recurrent Clostridioides Difficile Colitis

Digestive Diseases and Sciences - To compare the clinical outcomes of different protocols for fecal microbiota transplantation (FMT) in two community hospitals with similar patient demographics....     

Wnt8a and Wnt3a cooperate in the axial stem cell niche to promote mammalian body axis extension

Background: Vertebrate body axis extension occurs in a head‐to‐tail direction from a caudal progenitor zone that responds to interacting signals. Wnt/β‐catenin signaling is critical for generation of paraxial mesoderm, somite formation, and maintenance of the axial stem cell pool. Body axis extension requires Wnt8a in lower vertebrates, but in mammals Wnt3a is required, although the anterior trunk develops in the absence of Wnt3a. Results: We examined mouse Wnt8a^–/– and Wnt3a^–/– single and double mutants to explore whether mammalian Wnt8a contributes to body axis extension and to determine whether a posterior growth function for Wnt8a is conserved throughout the vertebrate lineage. We find that caudal Wnt8a is expressed only during early somite stages and is required for normal development of the anterior trunk in the absence of Wnt3a. During this time, we show that Wnt8a and Wnt3a cooperate to maintain Fgf8 expression and prevent premature Sox2 up‐regulation in the axial stem cell niche, critical for posterior growth. Similar to Fgf8, Wnt8a requires retinoic acid (RA) signaling to restrict its caudal expression boundary and possesses an upstream RA response element that binds RA receptors. Conclusions: These findings provide new insight into interaction of caudal Wnt‐FGF‐RA signals required for body axis extension. Developmental Dynamics 244:797–807, 2015. © 2015 Wiley Periodicals, Inc.     

Absence of late gadolinium enhancement on cardiac magnetic resonance imaging in ventricular fibrillation and nonischemic cardiomyopathy

Introduction

Cardiac magnetic resonance (CMR)‐identified late gadolinium enhancement (LGE), representing regional fibrosis, is often used to predict ventricular arrhythmia risk in nonischemic cardiomyopathy (NICM). However, LGE is more closely correlated with sustained monomorphic ventricular tachycardia (SMVT) than ventricular fibrillation (VF). We characterized CMR findings of ventricular LGE in VF survivors.

Methods

We examined consecutively resuscitated VF survivors undergoing contrast‐enhanced 1.5T CMR between 9/2007 and 7/2016. We excluded coronary artery disease, hypertrophic cardiomyopathy, amyloid, sarcoid, arrhythmogenic right ventricular cardiomyopathy, and channelopathy. Preexisting implantable cardioverter‐defibrillator (ICD) was a CMR contraindication. VF patients were divided into three groups: (1) NICM, (2) left ventricular (LV) dilatation with normal LV ejection fraction (LVEF), and (3) normal LV size and LVEF. Two groups of NICM patients with and without SMVT were examined for comparison.

Results

We analyzed 87 VF patients, and found that LGE was seen in 8/22 (36%) with NICM (LVEF 38 ± 11%, LV end‐diastolic volume index [LVEDVI] 134 ± 68 mL/BSA), 11/40 (28%) with LV dilatation and normal LVEF (LVEDVI 103 ± 17 mL/BSA), 4/25 (16%) with normal LV size and LVEF. Incidence of LGE in NICM patients without prior ventricular tachycardia/VF (LVEF 36 ± 12%, LVEDVI 141 ± 46 mL/body surface area [BSA]) was 117/277 and was not lower than those with VF and NICM (42% vs 36%; P = 0.59). By contrast, 22/37 NICM patients with SMVT (LVEF 42 ± 11%, LVEDVI 123 ± 48 mL/BSA) were LGE‐positive (59% NICM‐SMVT vs 36% NICM‐VF; P = 0.04).

Conclusion

Most VF survivors with a diagnosis of NICM did not have LGE on CMR and would not have met primary prevention ICD criteria based on LVEF. Absence of LGE may not portend a benign prognosis in NICM. Novel strategies for determining SCD risk in this cohort are required.

     

Ag2O nanoparticle-catalyzed substrate-controlled regioselectivities: direct access to 3-ylidenephthalides and isocoumarins

Herein, we disclose the first example of an efficient, silver oxide nanoparticle-catalyzed, direct regioselective synthesis of 3-ylidenephthalides 11–16 and isocoumarins 17–20via sonogashira type coupling followed by substrate-controlled 5-exo-dig or 6-endo-dig cyclization reaction, respectively. This one pot coupling involves reaction of substituted 2-halobenzoic acid with meta/para-substituted and ortho-substituted terminal alkynes, which proceeded in a regioselective manner resulting in the formation of 3-ylidenephthalides or isocoumarins, respectively, in excellent yields (up to 95%) with complete Z-selectivity. This protocol features relatively broad substrate scope, mild conditions, operational simplicity, and is favourable with aromatic/alicyclic terminal alkynes. The competition experiments and gram-scale synthesis further highlight the importance and versatility of the methodology. The proposed mechanistic pathways illustrate that the regioselectivity is substantially being controlled by the substituent(s) present on the acetylenic phenyl ring.

We report the first example of an efficient, Ag₂O nanoparticle-catalyzed, direct regioselective synthesis of 3-ylidenephthalides and isocoumarins via Sonogashira type coupling followed by substrate-controlled 5-exo-dig or 6-endo-dig cyclization reaction, respectively.     

An elaborative NMR based plasma metabolomics study revealed metabolic derangements in patients with mild cognitive impairment: a study on north Indian population

Metabolic Brain Disease - Mild cognitive impairment (MCI) is transition phase between cognitive decline and dementia. The current study aims to investigate altered metabolic pattern in plasma of...     

Frequent occurrence of hypogonadotropic hypogonadism in type 2 diabetes

Type 2 diabetes is associated with lower total testosterone (T) levels in cross-sectional studies. However, it is not known whether the defect is primary or secondary. We investigated the prevalence of hypogonadism in type 2 diabetes by measuring serum total T, free T (FT), SHBG, LH, FSH, and prolactin (PRL) in 103 type 2 diabetes patients. FT was measured by equilibrium dialysis. FT was also calculated by using T and SHBG (cFT). Hypogonadism was defined as low FT or cFT. The mean age was 54.7 +/- 1.1 yr, mean body mass index (BMI) was 33.4 +/- 0.8 kg/m(2), and mean HbA1c was 8.4 +/- 0.2%. The mean T was 12.19 +/- 0.50 nmol/liter (351.7 +/- 14.4 ng/dl), SHBG was 27.89 +/- 1.65 nmol/liter, and FT was 0.250 +/- 0.014 nmol/liter. Thirty-three percent of patients were hypogonadal. LH and FSH levels were significantly lower in the hypogonadal group compared with patients with normal FT levels (3.15 +/- 0.26 vs. 3.91 +/- 0.24 mIU/ml for LH and 4.25 +/- 0.45 vs. 5.53 +/- 0.40 mIU/ml for FSH; P < 0.05). There was a significant inverse correlation of BMI with FT (r = -0.382; P < 0.01) and T (r = -0.327; P < 0.01). SHBG correlated inversely with BMI (r = -0.267; P < 0.05) but positively with age (r = 0.538; P < 0.001) and T (r = 0.574; P < 0.001). FT correlated strongly with cFT (r = 0.919; P < 0.001) but not with SHBG. LH levels correlated positively with FT (r = 0.287; P < 0.05). We conclude that hypogonadotropic hypogonadism occurs commonly in type 2 diabetes.