Updates on Molecular Targets and Epigenetic-Based Therapies for PCOS.

Polycystic ovarian syndrome (PCOS) can cause infertility in females due to hyperandrogenism and neuroendocrine abnormalities. The aim of this study is to decipher the impact of endocrine variables, hyperandogenism, insulin resistance, oxidative stress, and dietary conditions in PCOS conditions, subsequently to depict the role of epigenetic factors relative to phenotypic manifestations in PCOS conditions. We have reviewed several metabolic milieus pertinent to PCOS conditions. Comparative efficacies of various PCOS therapies, and recent clinical recommendations for the effective management of PCOS and role of metabolic/endocrine variables in PCOS conditions were described. Comparative therapeutic effects were vividly delineated according to the variable pathophysiology and internal variables during PCOS syndrome on the female body through the formation of cascade of endocrine pathology, which affects working capacity and fosters redox stress-induced cardiovascular, neural, and liver abnormalities. GLP-1 agonists, insulin sensitizers (metformin), and diet and exercise regimens efficacy were explained in enhancing the fertility outcomes among the overweight or obese females with PCOS. Comprehensive appraisal of DNA methylation as epigenetic changes and the manifestations of methylated genes in PCOS conditions were discussed particularly to screen novel molecular targets for developing efficient diagnostic indicators for predicting PCOS risk or its progression. Due to the reversible nature of epigenetic modifications, it is possible to screen the "druggable" regions to target or to correct abnormalities in the gene expression subsequently to develop chromatin-modifying therapies against PCOS.

The Role of Mitochondria in Piperine Mediated Cardioprotection in Isoproterenol Induced Myocardial Ischemia.

BACKGROUND: Several pharmacological therapeutic interventions are being used as therapeutic agents against myocardial infarction/ischemia (MI) but their usage is constrained by toxicity and nonselective pharmacological actions. Our preliminary report depicted the cardioprotective effect of piperine against isoproterenol (ISO)-induced MI. AIM: Current study determined the protective efficacy of piperine by modulating mitochondrial function in rat models of isoproterenol (ISO)-induced myocardial ischemia. METHODS: The above aim was achieved by analyzing mitochondrial antioxidant status, mitochondrial calcium, mitochondrial enzyme activity, ATP level, and apoptosis. Ultra-structural alterations in heart tissue were determined by TEM analysis. RT-PCR studies and Western blotting were executed to determine apoptotic and proapoptotic gene expression, and apoptotic protein expression, respectively. RESULTS: The results elucidate that piperine pre-treatment prevents ISO induced alterations in the mitochondrial antioxidant status, Krebs cycle as well as mitochondrial respiratory chain enzyme activities (MRCEs). ISO induced ultrastructural changes of heart mitochondria were significantly reduced in the group that received piperine pretreatment followed by ISO injection. Piperine maintains mitochondrial calcium homeostasis and inhibits ISO-induced myocardial apoptosis. A significant increase in the expression levels of proapoptotic genes such as Bax, caspases (caspase 9, caspase 3), and cytochrome-c with a concomitant decrease in Bcl-2 expression (anti-apoptotic gene) was observed in ISO injected group compared to the control group. The group that received the piperine pretreatment followed by ISO administration showed a significant decrease in the expression profile of proapoptotic genes with a concomitant increase in the anti-apoptotic gene expression than the ISO injected group. Apoptotic protein expressions including Bax, cytochrome-c, caspase-3, and cleaved PARP were upregulated & Bcl-2 was downregulated with ISO treatment, whereas piperine pre-treatment prevented these changes in apoptotic protein expressions during ISO-induced myocardial cell damage. CONCLUSION: Current results demonstrate the efficacy of piperine for attenuating ISO-induced myocardial ischemia by enhancing mitochondria function. This study described that piperine could be used as a nutritional intervention against ISO-induced myocardial ischemia.

Efficacy of endovascular Z-configuration stenting for malignant versus nonmalignant caval obstruction.

OBJECTIVE: The objective of this study was to assess factors associated with symptom resolution after endovascular stenting for superior or inferior vena cava syndrome. METHODS: Eighty-six consecutive vena cava Z-configuration stent placements in 82 patients (53 ± 14 years old) at a single institution were reviewed for patient demographics, comorbidities, and durability of stent patency (also evaluated were persistent or recurrent symptoms, stent occlusion, and need for repeated stenting). Logistic regression was used to identify independent factors associated with stent patency, and Φ coefficients and analysis of variance were used to compare cases subdivided by lesion location (superior vena cava, inferior vena cava) and the presence or absence of malignant disease. RESULTS: Clinical follow-up was available in 77 of 86 (90%) cases. Technical success with clinical failure (persistent symptoms) occurred in 40% of these cases with a median follow-up of 67 (interquartile range, 14-570) days and mortality rate of 63% during this period. Malignant obstructions had a significantly higher clinical failure rate of 54% compared with 15% for nonmalignant obstructions (Φ = 0.34; P = .002). However, only metastatic disease was independently associated with clinical failure when controlling for demographics, other comorbidities, and differential follow-up (adjusted odds ratio, 8.27; 95% confidence interval, 2.79-24.50). CONCLUSIONS: Vena cava Z-stenting effectively resolves symptoms in 85% of nonmalignant obstructions compared with only 46% of malignant obstructions. Patients should be counseled accordingly, and those with malignant obstructions may require closer follow-up to evaluate the need for reintervention and goals of care.

Atrial Fibrillation in Athletes-Features of Development, Current Approaches to the Treatment, and Prevention of Complications.

Atrial fibrillation (AF) is one of the most common types of cardiac arrhythmias. This review article highlights the problem of the development of atrial fibrillation in individuals engaged in physical activity and sports. Predisposing factors, causes, and development mechanisms of atrial fibrillation in athletes from the perspective of the authors are described. Methods of treatment, as well as prevention of thromboembolic complications, are discussed. Directions for further studies of this problem and prevention of complications are proposed.

Predictors of Disease Recurrence after Venoplasty and Stent Placement for May-Thurner Syndrome.

PURPOSE: To identify factors independently associated with disease recurrence after venoplasty and stent placement for May-Thurner syndrome (MTS). MATERIALS AND METHODS: Fifty-nine consecutive patients (age, 47 y ± 15; 93% female) were identified who had undergone endovascular stent placement for MTS. Patient charts were reviewed for demographic data, risk factors for venous thrombosis, comorbidities, and venous inflow or outflow at first follow-up (3 wk to 6 mo after treatment). Logistic regression was used to identify independent predictors of symptom recurrence or repeat intervention, and multivariate analysis of variance and receiver operator characteristic curve analysis were used to assess relationships between degrees of in-stent stenosis and other variables in the 73% of patients with available cross-sectional imaging. Median follow up was 20.7 months (interquartile range, 4.7-49.5 mo). RESULTS: All procedures were technically successful. Disease recurrence, defined as symptom recurrence following initial postprocedural resolution, was observed in 38% of patients. No preprocedural variable was found to be independently predictive of disease recurrence; however, poor venous inflow or outflow were both strongly associated with recurrent disease, with adjusted odds ratios and 95% confidence intervals of 38.02 (3.76-384.20; P = .002) and 7.00 (1.15-42.71; P = .04), respectively. Higher degrees of in-stent stenosis were also associated with symptom recurrence, with an area under the curve of 0.93 (P = .000002) and 39%-41% stenosis being 78%-83% sensitive and 88%-92% specific for symptom recurrence. CONCLUSIONS: These results suggest that cross-sectional imaging can help differentiate patients in whom closer follow-up may be warranted after venoplasty and stent placement for MTS and also guide counseling regarding prognosis.

A curious case of forceps delivery in IR.

Self-expanding nitinol stents are routinely used to treat left common iliac vein compression in patients with May-Thurner syndrome. On occasion these stents do not provide adequate radial force to achieve a sufficient iliac lumen. If symptoms persist and persistent iliac vein compression is noted then balloon-expandable stents may be used to provide buttressing support at the compression site. We present a case where the buttressing balloon-expandable stent is crushed and subsequently removed percutaneously prior to placement of a high radial force self-expanding stent at the compressive site.

Single-Center Retrospective Review of Radiofrequency Wire Recanalization of Refractory Central Venous Occlusions.

PURPOSE: To retrospectively review the effectiveness and safety of radiofrequency (RF) wire recanalization of refractory central venous occlusions (CVOs) and compare recurrent and nonrecurrent CVOs in terms of patient and occlusion characteristics. MATERIALS AND METHODS: Twenty CVOs were treated in 18 patients (age 40 y ± 13; 9 women) with 11 superior vena cava (SVC) or brachiocephalic vein occlusions (ie, supradiaphragmatic) and 9 inferior vena cava or iliac vein occlusions (ie, infradiaphragmatic). Indications included pain, edema, ulceration, and/or dialysis arteriovenous fistula dysfunction peripheral to the CVO(s). All patients had multiple venous thrombotic risk factors, including mechanical venous compression, endothelial injury, and/or coagulopathies. CVO traversal was first attempted with standard and advanced techniques before RF wire recanalization and followed up with computed tomographic venography and clinic visits approximately 1, 3, 6, and 12 months after treatment. RESULTS: Sixteen CVOs (80%) were successfully transversed and associated with symptom relief. One major complication occurred involving SVC perforation into the pericardial space. Primary CVO patency rate was 56% at a median follow-up of 14.1 months (interquartile range [IQR], 9.2-20.0 mo). Recurrent CVOs tended to be infradiaphragmatic (71% vs 12% for supradiaphragmatic; P = .02), longer (12.9 cm ± 10.0 vs 2.3 cm ± 1.3; P < .01), and associated with implanted venous stents, filters, or cardiac pacer/defibrillator leads (86% vs 22%; P = .01). Median time to restenosis/occlusion was 1.5 months (IQR, 1.1-6.1 mo). CONCLUSIONS: RF wire recanalization is a relatively effective and safe option for refractory CVOs. Patients with longer, infradiaphragmatic CVOs associated with indwelling devices may require closer follow-up for CVO recurrence.

Characterization of axial and proximal histidine mutations of the decaheme cytochrome MtrA from Shewanella sp. strain ANA-3 and implications for the electron transport system.

Extracellular respiration of solid-phase electron acceptors in some microorganisms requires a complex chain of multiheme c-type cytochromes that span the inner and outer membranes. In Shewanella species, MtrA, an ~35-kDa periplasmic decaheme c-type cytochrome, is an essential component for extracellular respiration of iron(III). The exact mechanism of electron transport has not yet been resolved, but the arrangement of the polypeptide chain may have a strong influence on the capability of the MtrA cytochrome to transport electrons. The iron hemes of MtrA are bound to its polypeptide chain via proximal (CXXCH) and distal histidine residues. In this study, we show the effects of mutating histidine residues of MtrA to arginine on protein expression and extracellular respiration using Shewanella sp. strain ANA-3 as a model organism. Individual mutations to six out of nine proximal histidines in CXXCH of MtrA led to decreased protein expression. However, distal histidine mutations resulted in various degrees of protein expression. In addition, the effects of histidine mutations on extracellular respiration were tested using ferrihydrite and current production in microbial fuel cells. These results show that proximal histidine mutants were unable to reduce ferrihydrite. Mutations to the distal histidine residues resulted in various degrees of ferrihydrite reduction. These findings indicate that mutations to the proximal histidine residues affect MtrA expression, leading to loss of extracellular respiration ability. In contrast, mutations to the distal histidine residues are less detrimental to protein expression, and extracellular respiration can proceed.