Subchronic administration of nandrolone decanoate in acetylcholinesterase activity in Wistar rats

Health sciences have recently discovered the medical uses of nandrolone decanoate (ND), an androgenic anabolic steroid (AAS), and reported its use in human and animal patients. Clinical evidences suggest that the AAS excess may affect the cholinergic system, which is responsible for several vital functions like learning, memory, and the organization of the movements. Thus, our aim is to research the subchronic effect of ND when administered in varying doses on the acetylcholinesterase (AChE) activity in these brain structures: cerebellum (CE), hippocampus, striatum (ST), and cortex of adult rats. We used 36 male Wistar rats, which were divided into six groups (n?=?6). The groups were divided into: G1—control (physiologic solution), G2—diluents control (only an oleaginous vehicle of vegetal origin—olive oil), G3—0.42?mg?kg^?1 of ND, G4—1.8?mg?kg^?1 of ND, G5—4.6?mg?kg^?1 of ND, and G6—10.0?mg?kg^?1 of ND. We applied the doses once every week during a 3-week period. The values obtained demonstrated a significant increase in the AChE activity (referring to ST and CE for the 4.6 and 10.0?mg?kg^?1 doses of ND). The ND causes increase in AChE activity, which could impair neurotransmission and cholinergic modulation.     

An Investigation of the Mineral in Ductile and Brittle Cortical Mouse Bone

Bone is a strong and tough material composed of apatite mineral, organic matter, and water. Changes in composition and organization of these building blocks affect bone's mechanical integrity. Skeletal disorders often affect bone's mineral phase, either by variations in the collagen or directly altering mineralization. The aim of the current study was to explore the differences in the mineral of brittle and ductile cortical bone at the mineral (nm) and tissue (µm) levels using two mouse phenotypes. Osteogenesis imperfecta model, oim^‐/‐, mice have a defect in the collagen, which leads to brittle bone; PHOSPHO1 mutants, Phospho1^‐/‐, have ductile bone resulting from altered mineralization. Oim^‐/‐ and Phospho1^‐/‐ were compared with their respective wild‐type controls. Femora were defatted and ground to powder to measure average mineral crystal size using X‐ray diffraction (XRD) and to monitor the bulk mineral to matrix ratio via thermogravimetric analysis (TGA). XRD scans were run after TGA for phase identification to assess the fractions of hydroxyapatite and β‐tricalcium phosphate. Tibiae were embedded to measure elastic properties with nanoindentation and the extent of mineralization with backscattered electron microscopy (BSE SEM). Results revealed that although both pathology models had extremely different whole‐bone mechanics, they both had smaller apatite crystals, lower bulk mineral to matrix ratio, and showed more thermal conversion to β‐tricalcium phosphate than their wild types, indicating deviations from stoichiometric hydroxyapatite in the original mineral. In contrast, the degree of mineralization of bone matrix was different for each strain: brittle oim^‐/‐ were hypermineralized, whereas ductile Phospho1^‐/‐ were hypomineralized. Despite differences in the mineralization, nanoscale alterations in the mineral were associated with reduced tissue elastic moduli in both pathologies. Results indicated that alterations from normal crystal size, composition, and structure are correlated with reduced mechanical integrity of bone. © 2014 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research.     

High plasma HDL-C attenuates stress hyperglycemia during acute phase of myocardial infarction

ObjectiveDuring myocardial infarction (MI), a transient decrease of both insulin sensitivity and secretion triggers stress hyperglycemia, which is followed by a substantial increase in mortality. Recent findings in cellular models indicate that HDL may act on glucose homeostasis by improving insulin sensitivity and secretion. In this study, we explored this potential effect in patients during the acute phase of MI.MethodsPlasma glucose, insulin and C-peptide were measured at admission in the first 24 h and on the fifth day after MI with ST-segment elevation in 183 consecutive non-diabetic patients. Patients were divided into HDL-C quartiles for the analyses (Q1: <31, Q2: 31–38, Q3: 38–47 and Q4: >47 mg/dL). The Homeostasis Model Assessment version 2 was used to assess insulin sensitivity (HOMA2S) and beta-cell function (HOMA2B).ResultsOn admission, no difference was found between the quartiles in glucose (p = 0.6), insulin (p = 0.6) or C-peptide (p = 0.5) levels, HOMA2S (p = 0.9) or HOMA2B (p = 1.0). On the fifth day there was a reduction in glucose levels whose intensity was directly proportional to the HDL-C quartile (p < 0.001). At the same time, there was a reduction in plasma insulin (p < 0.001) and C-peptides (p < 0.001) whose magnitude was inversely proportional to the HDL-C quartile. Consistently, the increase of HOMA2S (p < 0.001) and HOMA2B (p = 0.01) were also positively associated with HDL-C levels. Furthermore, plasma HDL-C levels were inversely and independently associated with blood glucose change during the acute phase.ConclusionThis study demonstrates the association between low plasma HDL-C levels and increased duration of stress hyperglycemia during MI and suggests in humans the interaction between HDL and insulin secretion and sensitivity.     

Murine double minute 2 regulates Hu antigen R stability in human liver and colon cancer through NEDDylation

Hu antigen R (HuR) is a central RNA-binding protein regulating cell dedifferentiation, proliferation, and survival, which are well-established hallmarks of cancer. HuR is frequently overexpressed in tumors correlating with tumor malignancy, which is in line with a role for HuR in tumorigenesis. However, the precise mechanism leading to changes in HuR expression remains unclear. In the liver, HuR plays a crucial role in hepatocyte proliferation, differentiation, and transformation. Here, we unraveled a novel mean of regulation of HuR expression in hepatocellular carcinoma (HCC) and colon cancer. HuR levels correlate with the abundance of the oncogene, murine double minute 2 (Mdm2), in human HCC and colon cancer metastases. HuR is stabilized by Mdm2-mediated NEDDylation in at least three lysine residues, ensuring its nuclear localization and protection from degradation. Conclusion: This novel Mdm2/NEDD8/HuR regulatory framework is essential for the malignant transformation of tumor cells, which, in turn, unveils a novel signaling paradigm that is pharmacologically amenable for cancer therapy.     

Inhibition of natural killer cells protects the liver against acute injury in the absence of glycine N-methyltransferase

Glycine N-methyltransferase (GNMT) catabolizes S-adenosylmethionine (SAMe), the main methyl donor of the body. Patients with cirrhosis show attenuated GNMT expression, which is absent in hepatocellular carcinoma (HCC) samples. GNMT(-/-) mice develop spontaneous steatosis that progresses to steatohepatitis, cirrhosis, and HCC. The liver is highly enriched with innate immune cells and plays a key role in the body's host defense and in the regulation of inflammation. Chronic inflammation is the major hallmark of nonalcoholic steatohepatitis (NASH) progression. The aim of our study was to uncover the molecular mechanisms leading to liver chronic inflammation in the absence of GNMT, focusing on the implication of natural killer (NK) / natural killer T (NKT) cells. We found increased expression of T helper (Th)1- over Th2-related cytokines, tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-R2/DR5, and several ligands of NK cells in GNMT(-/-) livers. Interestingly, NK cells from GNMT(-/-) mice were spontaneously activated, expressed more TRAIL, and had strong cytotoxic activity, suggesting their contribution to the proinflammatory environment in the liver. Accordingly, NK cells mediated hypersensitivity to concanavalin A (ConA)-mediated hepatitis in GNMT(-/-) mice. Moreover, GNMT(-/-) mice were hypersensitive to endotoxin-mediated liver injury. NK cell depletion and adoptive transfer of TRAIL(-/-) liver-NK cells protected the liver against lipopolysaccharide (LPS) liver damage. CONCLUSION: Our data allow us to conclude that TRAIL-producing NK cells actively contribute to promote a proinflammatory environment at early stages of fatty liver disease, suggesting that this cell compartment may contribute to the progression of NASH.     

Improved outcomes and complications of atrial fibrillation catheter ablation over time: learning curve, techniques, and methodology

Introduction and objectives

The outcomes of atrial fibrillation ablation procedures vary widely between different centers. Our objective was to analyze the results and complications of this procedure in our center and identify factors predicting the efficacy and safety of atrial fibrillation ablation.

Methods

In total, 726 atrial fibrillation ablation procedures were performed in our center between 2002 and 2009. Beginning in January 2008, a protocol for anticoagulation and conscious sedation was systematically applied. Outcomes and complications could therefore be compared in 2 well-differentiated groups: group A included 419 procedures performed prior to 2008 and group B included 307 procedures completed after 2008 using the new protocol.

Results

During an average follow-up of 8.7 months, 60.9% of patients were arrhythmia-free after one or repeat procedures. After only 1 procedure, the success rate was 41% and significantly higher in group B (51.6% vs 35.2% in group A; P=.001). There were 31 major complications (4.2%), 26 in group A (6.2%) and 5 in group B (1.6%) (P=.002). The implementation of the new protocol was an independent predictor of the absence of complications (odds ratio=0.406; 95% confidence interval, 0.214-0.769; P<.006).

Conclusions

Systematic application of an anticoagulation and conscious sedation protocol is associated with improved results and fewer complications of atrial fibrillation ablation. Factors not evaluated in the present study, such as operator experience and ongoing improvements in atrial fibrillation ablation technology, could have influenced these findings.Full English text available from:www.revespcardiol.org