Recent Publications by CFE Educators

INTRODUCTION

Icariin has been shown to improve penile hemodynamics in animal models of erectile dysfunction from cavernous nerve injury and castration. The effects of icariin on penile hemodynamics in diabetic animals remain to be determined. Transforming growth factor β1 (TGFβ1) has been implicated in the pathogenesis of diabetes-related erectile dysfunction.

AIM

The aim of this study was to investigate the effects of icariin in the penis of streptozotocin (STZ)-induced diabetic rat.

METHODS

Two-month-old Sprague-Dawley male rats received one-time intraperitoneal (IP) STZ (60 mg/kg) or vehicle injection after a 16-hour fast. Three days later, the STZ-induced diabetic rats were randomly divided into four groups and were treated with daily gavage feedings of a 50:50 mix of normal saline and dimethyl sulfoxide (DMSO) or icariin dissolved in DMSO at doses of 1, 5, and 10 mg/kg for 3 months. A positive control group underwent IP injection of saline followed by daily gavage of saline/DMSO solution. Treatment was stopped 1 week prior to functional assay and euthanasia.

MAIN OUTCOME MEASURE

Penile hemodynamics was assessed by electrical stimulation of the cavernous nerves with real-time intracavernous pressure (ICP) measurement. After euthanasia, penile tissue was studied using immunohistochemistry, Western blot, and enzyme-linked immunosorbent assay (ELISA) to assess the nitric oxide-cyclic guanosine monophosphate (NO-cGMP) and TGFβ1/Smad2 signaling pathway.

RESULTS

Diabetes attenuated ICP response in control animals. Untreated diabetic animals had decreased smooth muscle/collagen ratio and endothelial cell content in the corpora cavernosa; treatment with icariin partially attenuating these effects. Icariin-treated animals also had a significantly greater expression of nicotinamide adenine dinucleotide phosphate-positive nerves and the endothelial cell markers, von Willebrand factor (vWF), and platelet endothelial cell adhesion molecule-1 (PECAM). TGFβ1/Smad2 signaling pathway was down-regulated in the penis from icariin-treated models relative to what was observed in negative control animals.

CONCLUSION

Icariin treatment preserved penile hemodynamics, smooth muscle and endothelial integrity, and neuronal nitric oxide synthase expression in the penis of diabetic rats. Down-regulation of TGFβ1/Smad2 signaling pathway might mediate this effect.

Abstract Study Objective. To assess the effects of the cytochrome P450 (CYP) 3A genotype, CYP3A5, on atorvastatin pharmacokinetics and its interaction with clarithromycin. Design. Prospective, two-phase, randomized-sequence, open-label pharmacokinetic study. Setting. Clinical research center at a teaching hospital. Subjects. Twenty-three healthy volunteers who were screened for genotype: 10 subjects carried the CYP3A5*1 allele (expressors) and 13 subjects did not (nonexpressors). Intervention. In one phase, subjects received a single oral dose of atorvastatin 20 mg. In the other phase, subjects received clarithromycin 500 mg twice/day for 5 days; on day 4 after the morning dose, subjects also received a single oral dose of atorvastatin 20 mg. All subjects participated in both phases of the study, which were separated by at least 14 days. Measurements and Main Results. Pharmacokinetic parameters of both forms of atorvastatin-atorvastatin acid and atorvastatin lactone-were compared between CYP3A5 expressors and nonexpressors, both in the absence and presence of clarithromycin, a strong CYP3A inhibitor. The acid form is pharmacologically active, and the lactone form has been associated with the atorvastatin's muscle-related adverse effects. Atorvastatin acid exposure did not differ significantly between CYP3A5 genotype groups. When subjects had not received clarithromycin pretreatment, the area under the concentration-time curve from time zero extrapolated to infinity (AUC(0-∞)) of atorvastatin lactone was 36% higher in nonexpressors than in expressors (median 47.6 ng•hr/ml [interquartile range (IQR) 37.8-64.3 ng•hr/ml] vs 34.9 ng•hr/ml [IQR 21.6-42.2 ng•hr/ml], p=0.038). After clarithromycin pretreatment, changes in the pharmacokinetic parameters of atorvastatin acid and lactone were not significantly different between the nonexpressors versus the expressors; however, the increase in the AUC(0-∞) of atorvastatin lactone was 37% greater in expressors than in nonexpressors (geometric mean ± SD 3.59 ± 0.57 vs 2.62 ± 0.35, p=0.049). Conclusion. Our data suggest that the CYP3A5 genotype has minimal effects on the pharmacokinetic parameters of atorvastatin and its interaction with clarithromycin; these effects are unlikely to be clinically significant.

The term 'dementia' encompasses a number of neurodegenerative diseases of which Alzheimer's disease (AD) is the most common. Prior to 2003, cholinesterase inhibitors, such as donezepil, were the only class of drugs approved to treat mild-to-moderate AD. In 2003, memantine became the first drug approved by the US FDA to treat moderate-to-severe AD. Currently, both memantine and donepezil are FDA approved for the treatment of moderate-to-severe AD. This article examines the pharmacologic profile of memantine, evidence for memantine's efficacy in moderate-to-severe AD and other dementias, its novel use in other neuropsychiatric disorders and future implications and research directions for memantine.

OBJECTIVE

Obesity is associated with high rates of disability in the general population. The nature of the relationship between obesity and disability in systemic lupus erythematosus (SLE), a condition with a high background rate of disability, is unknown.

METHODS

Data were from 2 interviews, 4 years apart, of a longitudinal cohort of individuals with SLE (n = 716 women). Body mass index (BMI) was calculated from self-reported height and weight; obesity was classified by usual (BMI ≥30) and revised (BMI ≥26.8) definitions. Three measures of functioning were examined: the Short Form 36 (SF-36) Health Survey physical function (PF) subscale, Valued Life Activities (VLA) Disability Questionnaire, and employment. Multivariate analyses controlled for demographics, SLE duration and disease activity, glucocorticoid use, depression, and comorbidities. Prospective analyses also controlled for baseline function.

RESULTS

At a BMI of ≥30, 27.8% of the subjects were obese; at a BMI of ≥26.8, 40.6% of the subjects were obese. Regardless of obesity definition, obese women exhibited poorer baseline function, with decrements ranging from 20-33% depending on the functional measure and obesity definition. With a BMI of ≥26.8, the adjusted SF-36 PF scores were 4.3 points lower for obese women (P 0.0001), VLA difficulty was 0.09 higher (P = 0.01), and odds of employment were 80% of nonobese women (odds ratio 0.8, 95% confidence interval 0.5-1.1). At the 4-year followup, women who were obese at baseline had poorer function and experienced greater functional declines.

CONCLUSION

Obesity was associated with clinically significant negative effects on function, both concurrently and prospectively. This negative impact occurred at a lower BMI than is often considered problematic clinically. Because of the high rate of SLE-related disability, addressing preventable risk factors such as obesity may improve long-term SLE outcomes.

Research on management of Chlamydia trachomatis (CT) among men has largely been neglected. Findings from an audit of 284 CT-infected men from 2004 to 2005 attending a young men's clinic primarily serving Latino men in New York City, NY, USA, are presented. Ninety-nine percent received treatment, with 81% treated within 14 days of a positive test. Three percent reported no partner in the last three months, 17% were referred by a CT-positive partner and 24% were missing partner information. Among the rest, 18% received expedited partner therapy, 4% directly observed therapy, 12% partner referral and 65% did not receive documented partner management. Of the 34% who had a post-treatment visit at least three months after their index visit, only 36% received a test for re-infection. Among primarily Latino men in an urban clinic in New York City, a high proportion of CT cases were treated in a timely manner. However, documentation of partner management was often lacking and few CT cases received tests for re-infection.

PURPOSE OF REVIEW

: Altered mental status is a common reason for neurologic consultation. Although it is often due to a systemic infection or metabolic derangement, a host of other etiologies can lead to irreversible brain injury if they are not promptly identified and treated. A systematic approach to the patient is important, with an understanding of when to initiate a more advanced and potentially more resource-intense diagnostic workup.

RECENT FINDINGS

: The last decade has seen advances in both the diagnosis and treatment of altered mental status. A significant step forward in the diagnosis of patients with otherwise unexplained encephalitis has been the identification of numerous antibodies associated with paraneoplastic and nonparaneoplastic autoimmune encephalitis. The use of continuous electroencephalography has shown that a significant proportion of otherwise unexplained altered mental status may be caused by nonconvulsive seizures. Several studies have demonstrated that proactive, multicomponent interventions may be effective in preventing hospital-acquired delirium. The recent introduction of dexmedetomidine may lead to decreased rates of delirium in the intensive care unit if the results of clinical trials are borne out in practice.

SUMMARY

: This article discusses causes of altered mental status, an initial approach to evaluating the patient, and elements of the advanced diagnostic workup. The article concludes with a general discussion of prevention and treatment.

Contrast agents for magnetic resonance imaging are frequently employed as experimental and clinical probes. Drawbacks include low signal sensitivity, fast clearance, and nonspecificity that limit efficacy in experimental imaging. In order to create a bioresponsive MR contrast agent, a series of four Gd(III) complexes targeted to the HaloTag reporter were designed and synthesized. HaloTag is unique among reporter proteins for its specificity, versatility, and the covalent interaction between substrate and protein. In similar systems, these properties produce prolonged in vivo lifetimes and extended imaging opportunities for contrast agents, longer rotational correlation times, and increases in relaxivity (r(1)) upon binding to the HaloTag protein. In this work we report a new MR contrast probe, 2CHTGd, which forms a covalent bond with its target protein and results in a dramatic increase in sensitivity. A 6-fold increase in r(1), from 3.8 to 22 mM(-1) s(-1), is observed upon 2CHTGd binding to the target protein. This probe was designed for use with the HaloTag protein system which allows for a variety of substrates (specific for MRI, florescence, or protein purification applications) to be used with the same reporter.

ABSTRACT: BACKGROUND: Secondhand tobacco smoke (SHS) is associated with increased risk of respiratory illness, cancer, and cardiovascular disease. Prior to smoking bans on airlines in the late 1980s, flight attendants were exposed to a significant amount of SHS. In the present study, we examine associations between flight attendant SHS exposure and development of respiratory illnesses and cardiovascular disease. METHODS: Between December 2006 and October 2010, three hundred sixty-two flight attendants completed an online questionnaire with information regarding experience as a flight attendant, medical history, smoking history, and SHS exposure. Rates of illnesses in flight attendants were compared with an age and smoking history matched population sample from NHANES 2005-2006. Logistic regression analysis was used to examine the association of reported medical conditions and pre-ban years of exposure. RESULTS: Compared with the sample from NHANES 2005-2006, flight attendants had increased prevalence of chronic bronchitis (11.7% vs. 7.2%, p 0.05), emphysema/COPD (3.2% vs. 0.9%, p 0.03), and sinus problems (31.5% vs. 20.9%, p 0.002), despite a lower prevalence of medical illnesses including high blood pressure, diabetes, high cholesterol, heart failure, cancer, and thyroid disease. Amongst flight attendants who reported never smoking over their lifetimes, there was not a significant association between years of service as a flight attendant in the pre-smoking ban era and illnesses. However, in this same group, there was a significantly increased risk of daily symptoms (vs. no symptoms) of nasal congestion, throat, or eye irritation per 10-year increase of years of service as a flight attendant prior to the smoking ban (OR 2.14, 95% CI 1.41 - 3.24). CONCLUSIONS: Flight attendants experience increased rates of respiratory illnesses compared to a population sample. The frequency of symptoms of nasal congestion, throat or eye irritation is associated with occupational SHS exposure in the pre-smoking ban era.