Differential Effects of Ethanol on Serum GABAergic 3α,5α/3α,5β Neuroactive Steroids in Mice,Rats, Cynomolgus Monkeys,and Humans

Background: Acute ethanol administration increases plasma and brain levels of progesterone and deoxycorticosterone‐derived neuroactive steroids (3α,5α)‐3‐hydroxypregnan‐20‐one (3α,5α‐THP) and (3α,5α)‐3,21‐dihydroxypregnan‐20‐one (3α,5α‐THDOC) in rats. However, little is known about ethanol effects on GABAergic neuroactive steroids in mice, nonhuman primates, or humans. We investigated the effects of ethanol on plasma levels of 3α,5α‐ and 3α,5β‐reduced GABAergic neuroactive steroids derived from progesterone, deoxycorticosterone, dehydroepiandrosterone, and testosterone using gas chromatography‐mass spectrometry. Methods: Serum levels of GABAergic neuroactive steroids and pregnenolone were measured in male rats, C57BL/6J and DBA/2J mice, cynomolgus monkeys, and humans following ethanol administration. Rats and mice were injected with ethanol (0.8 to 2.0 g/kg), cynomolgus monkeys received ethanol (1.5 g/kg) intragastrically, and healthy men consumed a beverage containing 0.8 g/kg ethanol. Steroids were measured after 60 minutes in all species and also after 120 minutes in monkeys and humans. Results: Ethanol administration to rats increased levels of 3α,5α‐THP, 3α,5α‐THDOC, and pregnenolone at the doses of 1.5 g/kg (+228, +134, and +860%, respectively, p < 0.001) and 2.0 g/kg (+399, +174, and +1125%, respectively, p < 0.001), but not at the dose of 0.8 g/kg. Ethanol did not alter levels of the other neuroactive steroids. In contrast, C57BL/6J mice exhibited a 27% decrease in serum 3α,5α‐THP levels (p < 0.01), while DBA/2J mice showed no significant effect of ethanol, although both mouse strains exhibited substantial increases in precursor steroids. Ethanol did not alter any of the neuroactive steroids in cynomolgus monkeys at doses comparable to those studied in rats. Finally, no effect of ethanol (0.8 g/kg) was observed in men. Conclusions: These studies show clear species differences among rats, mice, and cynomolgus monkeys in the effects of ethanol administration on circulating neuroactive steroids. Rats are unique in their pronounced elevation of GABAergic neuroactive steroids, while this effect was not observed in mice or cynomolgus monkeys at comparable ethanol doses.     

Creatine supplementation for patients with COPD receiving pulmonary rehabilitation: A systematic review and meta‐analysis

Background and objective: Creatine improves muscle strength in exercising healthy individuals, and in patients with neuromuscular disease and heart failure. The aim of this study was to assess whether creatine supplementation improves pulmonary rehabilitation (PR) outcomes in patients with COPD. Methods: A systematic review and meta‐analysis was performed of randomized controlled trials published between January 1966 and February 2009 that evaluated the effect of creatine compared with placebo on exercise capacity, muscle strength and health‐related quality of life (HR‐QoL) in patients undergoing PR for COPD. The pooled estimates were expressed as mean differences (MD) or standardized mean differences (SMD). Results: Four randomized controlled trials that included 151 patients were identified. There was no effect of creatine supplementation on exercise capacity (SMD ?0.01, 95% CI: ?0.42 to 0.22, n = 151). Creatine supplementation did not improve lower extremity muscle strength (SMD 0.03, 95% CI: ?0.55 to 0.61, n = 140) or upper limb muscular strength (SMD 0.02, 95% CI: ?0.33 to 0.38, n = 128) compared with placebo. Two studies (n = 48) assessed quality of life using the St. George's Respiratory Disease Questionnaire. There were no differences in HR‐QoL according to domain or total scores. Overall, creatine appeared to be safe and was well tolerated. Quality assessment of the studies showed important limitations. Conclusions: Creatine supplementation does not improve exercise capacity, muscle strength or HR‐QoL in patients with COPD receiving PR. However, important limitations were identified in the quality of the available evidence, suggesting that further research is required in this area.     

Hot flashes: a review of pathophysiology and treatment modalities

Many therapies are being studied for the treatment of hot flashes for individuals with cancer, yet few studies have demonstrated safe and effective clinical benefit for those who suffer from this distressing symptom. The purpose of this paper is to assess the current options for the management of hot flashes, examining key endpoints from recent clinical trials and reviewing future directions. Hot flashes are a common stressful symptom for individuals with cancer, particularly women with a history of breast cancer and men with prostate cancer. Lifestyle modifications are proposed as the first step in the management of less severe hot flashes. Several publications have addressed nonhormonal agents as a treatment option for hot flashes. Newer antidepressant and anticonvulsant agents have been studied and show potential in treating vasomotor symptoms. Although many complementary and alternative therapies, including herbal medications and phytoestrogens, have been studied for the treatment of hot flashes, none are clinically recommended at this time. Additionally, further evidence is needed for supportive exercise such as yoga and relaxation techniques. Acupuncture may warrant further investigation in the reduction and severity of hot flashes in both men and women. Hormonal therapies, including estrogens and progestogens, are the most well-known and efficient agents in alleviating hot flashes; however, the safety of these agents is disputable.     

Measuring quality of life in oncologic breast surgery: a systematic review of patient-reported outcome measures

Multiple randomized trials demonstrate equivalent survival between BCT and mastectomy, but clinical outcomes research must also evaluate patient satisfaction and quality of life. This review analyzes existing patient-reported outcome (PRO) measures in oncologic breast surgery to assess utility and make recommendations for future research. We performed a systematic literature review to identify PRO measures used in oncologic breast surgery patients. After applying inclusion and exclusion criteria, qualifying instruments were assessed for adherence to international guidelines for health outcomes instrument development and validation. Ten measures underwent development and psychometric evaluation in an oncologic breast surgery population. Five of ten measures (EORTC QLQ BR-23, FACT-B, HBIS, BIBCQ, and BREAST-Q) reported an adequate development and validation process. Three of these 5 measures (EORTC QLQ BR-23, FACT-B, HBIS) focused on non-surgical treatment issues. A fourth instrument (BIBCQ) did not address aesthetic concerns after breast reconstruction. The fifth instrument (BREAST-Q) was developed for use in patients undergoing mastectomy ± reconstruction, but did not address breast-conserving therapy. Overall, two key limitations were noted: 1) surgery-specific issues of breast-conserving surgery patients were not well represented and 2) measures were largely developed without the aid of newer psychometric methods that may improve their clinical utility. Reliable and valid PRO measures in breast cancer patients exist, but even the best instruments do not address all important surgery-specific and psychometric issues of oncologic breast surgery patients. Newer psychometric methods would facilitate development of scales for use in individual patient care as well as group level comparisons.     

Chronic kidney disease management in an academic internal medicine clinic

Objective  

We sought to evaluate the current state of chronic kidney disease (CKD) management in our academic internal medicine clinic.     

Potential New Indication for Ivabradine: Treatment of a Patient with Congenital Junctional Ectopic Tachycardia

Ivabradine is a new antiarrhythmic agent with direct inhibition of the pacemaker (If) current. It has been used extensively to decrease sinus rate in the treatment of cardiac failure, and also in a single case of atrial ectopic tachycardia in a child. Here we report the case of a 3‐year‐old girl with congenital junctional ectopic tachycardia (JET), resistant to conventional antiarrhythmic medications, who was successfully treated with ivabradine. We suggest that ivabradine can be an effective treatment for junctional automatic tachycardias and can be considered as a new line of therapy for this incessant form of tachycardia.     

Carotid Revascularization: A Systematic Review of the Evidence

Objective and Background

The aim of this study is to provide an evidence‐based review of the periprocedural safety and long‐term effectiveness of carotid artery stenting (CAS) compared to carotid endarterectomy (CEA), with particular attention paid to the use of embolic protection devices and patients at high risk for CEA.

Methods

Electronic databases (Ovid Medline, Cochrane central register of controlled trials, Pubmed, and Embase) were searched to identify: (1) randomized controlled trials (RCT) comparing outcomes of CEA and CAS, and (2) prospective clinical trials assessing the safety of CAS in patients at high surgical risk. Pooled incidence rates and one‐sided 95% confidence interval for the periprocedural and long‐term composite end‐point of stroke, myocardial infarction, or death among high surgical risk patients were generated and compared to objective performance criteria (OPC) reported by previous trials.

Results

Six RCTs and 14 prospective clinical trials met our search criteria. Selected RCTs showed inconsistency in reported periprocedural and long‐term outcome rates. Pooled incidence rates of the periprocedural and long‐term composite end‐point of stroke, myocardial infarction or death in high surgical risk candidates were 5.59% and 7.92%, respectively. These results were noninferior to selected OPCs (P‐value <0.001).

Conclusions

CAS represents a safe and effective stroke prevention strategy in high surgical risk patients when compared with CEA. The inconsistent results from the RCTs and the improved outcomes in the prospective clinical trials are likely related to variability in operator experience, use of embolic protection devices, and patient selection strategies.