Stress Affects a Gastrin-Releasing Peptide System in the Spinal Cord That Mediates Sexual Function: Implications for Psychogenic Erectile Dysfunction

Background

Many men suffering from stress, including post-traumatic stress disorder (PTSD), report sexual dysfunction, which is traditionally treated via psychological counseling. Recently, we identified a gastrin-releasing peptide (GRP) system in the lumbar spinal cord that is a primary mediator for male reproductive functions.

Methodology/Principal Findings

To ask whether an acute severe stress could alter the male specific GRP system, we used a single-prolonged stress (SPS), a putative rat model for PTSD in the present study. Exposure of SPS to male rats decreases both the local content and axonal distribution of GRP in the lower lumbar spinal cord and results in an attenuation of penile reflexes in vivo. Remarkably, pharmacological stimulation of GRP receptors restores penile reflexes in SPS-exposed males, and induces spontaneous ejaculation in a dose-dependent manner. Furthermore, although the level of plasma testosterone is normal 7 days after SPS exposure, we found a significant decrease in the expression of androgen receptor protein in this spinal center.

Conclusions/Significance

We conclude that the spinal GRP system appears to be a stress-vulnerable center for male reproductive functions, which may provide new insight into a clinical target for the treatment of erectile dysfunction triggered by stress and psychiatric disorders.     

New Insights on Neuronal Alterations in Jimpy Mutant Brain

In spite of abundant data on oligodendrocyte abnormalities in dysmyelinated jimpy brain, little is known about the axonal damage and the expression of neuronal genes. Recent findings indicate that Nogo-A, oligodendrocyte-myelin glycoprotein (OMgp), and myelin-associated glycoprotein (MAG) inhibit axonal growth by binding a common receptor, the Nogo-A receptor (NgR)-p75 complex. In order to evaluate neuronal modifications in the absence of myelin and in the presence of abnormal oligodendrocytes at different developmental stages, the expression of these inhibitory proteins and their receptors was investigated in jimpy mutant brain. Despite the decrease in oligodendrocyte number at P15 and P25 in jimpy, Nogo-A and OMgp mRNA levels are not significantly different compared with control, suggesting an overexpression of neuronal Nogo-A and OMgp in mutant. Double immunolabeling for Nogo-A and neurofilaments shows strong axonal staining of Nogo-A in jimpy and its down-regulation in oligodendrocytes. The current data raise questions about functions of Nogo-A other than neurite growth inhibition in the CNS. No significant changes in NgR mRNA levels were observed in jimpy, where the increase in p75 level can be correlated with the cell death of oligodendrocytes. In the paranodal region, the cell adhesion molecule neurofascin glial isoform NFN155 mRNA level is reduced by 40% whereas neuronal form NFN186 is up-regulated. These results may explain the failure of paranodal region organization, even with normal level of CASPR (paranodin) mRNA detected in jimpy brain.     

基于复杂网络的脑疾病功能网络研究进展

脑功能连接能够反映脑区间的相互联系状况,目前已成为脑功能研究的主要方法。复杂网络方法源于图论分析,可以对功能连接所构网络进行量化分析,提供多种量化指标。本文介绍了当前复杂网络的多种基本概念,及其在几种典型脑部疾病上的应用情况。     

Management of Erectile Dysfunction in the Hypogonadal Man: A Case-Based Review

Erectile dysfunction (ED) has emerged as an important marker of cardiovascular and overall health, independent of other known conventional risk factors. ED often precedes coronary artery disease in half of affected subjects, and could indicate the presence of cardiovascular pathology. The pathophysiology and role of androgens in sexual function are described, along with the relevant literature on the effects of aging in erectile and gonadal function. The concept of testosterone supplementation (TST) in men with ED is reviewed. The authors utilize clinical vignettes to discuss the appropriate management of two clinical cases of men at different life stages who have ED in the setting of hypogonadism and propose a treatment algorithm. In patients of all ages, proper identification of the underlying pathophysiology of decreased libido and erectile function is paramount in choosing between the use of TST, phosphodiesterase type 5 inhibitors, or both, in the management of these disorders.Key words: Erectile dysfunction, Testosterone supplementation, Hypogonadism, Phosphodiesterase type 5 inhibitorsErectile dysfunction (ED) has emerged as an important marker of cardiovascular and overall health, independent of other known conventional risk factors. Because ED often precedes coronary artery disease (CAD) in half of affected subjects, it may be considered a harbinger of indolent cardiovascular pathology.^1,2 The modulation of erectile function by testosterone is well known,^3,4 and in men with both hypogonadism and ED a treatment strategy necessitating management of both conditions is required.Phosphodiesterase type 5 inhibitors (PDE5i) and testosterone supplementation therapy (TST) are established treatment strategies for ED and hypogonadism, respectively. Using a PDE5i in combination with TST has the potential for improving efficacy in men with concurrent ED and hypogonadism compared with the use of either agent alone. However, in light of the recent evidence associating testosterone with cardiovascular risk in elderly men,^5,6 TST should be used judiciously in the management of ED in older men.     

如何使万艾可更有效的治疗老年性功能障碍(ED)患者(附143例临床观察)

目的:探讨如何使万艾可更有效治疗老年ED患者.方法:采用回顾性调查研究,分析2004年10月-2007年12月在我院男性健康门诊治老年ED患者143例,按性生活频率分为两组,每月3-4次为实验组共60例,比较两组治疗前平均年龄、并发症及最近10个月的用药量及性生活频率.结果:1.实验组IIEF-5评分由用药前平均6.2分提高到平均20分,对照组由平均5.8分提高到平均18分.2药物起效时间,实验组最短15分钟,最长60分钟,平均30分钟,对照组最短时间20分钟,最长120分钟,平均45分钟(p＞0.05).结论:适当增加性生活频率,可减少每次万艾可的用量,并能增加性生活的满意度,使万艾可的治疗效果达到最佳.     

Acromegaly Presenting as Erectile Dysfunction: Case Reports and Review of the Literature

Erectile dysfunction (ED) is a common yet complex condition. The authors report two cases of acromegaly presenting with ED and hypogonadotropic hypogonadism. Surgical cure of the acromegaly was associated with either an improvement or resolution of hypogonadotropic hypogonadism-associated ED. Active acromegaly should be considered in the differential diagnosis of ED presenting with supporting clinical features, particularly hypogonadotropic hypogonadism.Key words: Erectile dysfunction, Endocrine dysfunction, Endocrinology, Acromegaly, Growth hormoneErectile dysfunction (ED), defined as an inability to obtain or maintain penile erection sufficient for sexual activity, is a common complaint with often complex etiology. Prevalence increases with age, ranging from 1% to 10% of men under age 40, 20% to 40% of men age 60 to 69 years, and 50% to 100% of men in their 70s and 80s.¹ ED can be a symptom of numerous underlying conditions, and guidelines on management of ED outline assessment for reversible hormonal causes such as hypogonadism, thyroid dysfunction, and hyperprolactinemia.^2,3 Although hypogonadism and hyperprolactinemia have been shown to be associated with acromegaly,⁴ the link between acromegaly and ED has not been widely reported.^5,6 We describe two cases of acromegaly with ED as the presenting feature and review the outpatient diagnosis of acromegaly.     

Smoking and Risk of Erectile Dysfunction: Systematic Review of Observational Studies with Meta-Analysis

Background

There are many recent observational studies on smoking and risk of erectile dysfunction (ED) and whether smoking increases the risk of ED is still inconclusive. The objective of this meta-analysis was to synthesize evidence from studies that evaluated the association between smoking and the risk of ED.

Methods

We searched PubMed, Embase, Web of Science, and Scopus in January 2013 to identify cohort and case-control studies that evaluated the association between smoking and ED. Study quality of included studies was assessed by the Newcastle-Ottawa scale. Random-effects meta-analyses were used to combine the results of included studies.

Results

Four prospective cohort studies and four case-control studies involving 28, 586 participants were included. Because of significant heterogeneity after including case-control studies in meta-analysis, the consistent results of prospective cohort studies were considered more accurate, Because of significant heterogeneity after including case-control studies in meta-analysis, the consistent results of prospective cohort studies were considered more accurate, Compared with non-smokers, the overall odd ratio of ED in prospective cohort studies was 1.51(95% CI: 1.34 to 1.71) for current smokers, and it was 1.29 (95% CI: 1.07 to 1.47) for former smokers. Evidence of publication bias was not found.

Conclusion

Evidence from epidemiological studies suggests that smoking, especially current smoking, may significantly increase the risk of ED     

Mitochondrial Dysfunction and Redox Homeostasis Impairment as Pathomechanisms of Brain Damage in Ethylmalonic Encephalopathy: Insights from Animal and Human Studies

Cellular and Molecular Neurobiology - Ethylmalonic encephalopathy (EE) is a severe intoxication disorder caused by mutations in the ETHE1 gene that encodes a mitochondrial sulfur dioxygenase...     

Erectile Dysfunction and Cardiovascular Events in Diabetic Men: A Meta-analysis of Observational Studies

Background

Several studies have shown that erectile dysfunction (ED) influences the risk of cardiovascular events (CV events). However, a meta-analysis of the overall risk of CV events associated with ED in patients with diabetes has not been performed.

Methodology/Principal Findings

We searched MEDLINE and the Cochrane Library for pertinent articles (including references) published between 1951 and April 22, 2012. English language reports of original observational cohort studies and cross-sectional studies were included. Pooled effect estimates were obtained by random effects meta-analysis.A total of 3,791 CV events were reported in 3 cohort studies and 9 cross-sectional studies (covering 22,586 subjects). Across the cohort studies, the overall odds ratio (OR) of diabetic men with ED versus those without ED was 1.74 (95% confidence interval [CI]: 1.34–2.27; P<0.001) for CV events and 1.72 (95% CI: 1.5–1.98; P<0.001) for coronary heart disease (CHD). The funnel plot, Begg''s test, and Egger''s test did not show evidence of publication bias (all P>0.05). Moreover, meta-regression analysis found no relationship between the method used to assess ED (questionnaire or interview), mean age, mean hemoglobin A_1c, mean body mass index, or mean duration of diabetes and the risk of CV events or CHD. In the cross-sectional studies, the OR of diabetic men with ED versus those without ED was 3.39 (95% CI: 2.58–4.44; P<0.001) for CV events (N = 9), 3.43 (95% CI: 2.46–4.77; P<0.001) for CHD (N = 7), and 2.63 (95% CI: 1.41–4.91; P = 0.002) for peripheral vascular disease (N = 5).

Conclusion/Significance

ED was associated with an increased risk of CV events in diabetic patients. Prevention and early detection of cardiovascular disease are important in the management of diabetes, especially in view of the rapid increase in its prevalence.     

Role of Caffeine Intake on Erectile Dysfunction in US Men: Results from NHANES 2001-2004

Objectives

Caffeine is consumed by more than 85% of adults and little is known about its role on erectile dysfunction (ED) in population-based studies. We investigated the association of caffeine intake and caffeinated beverages with ED, and whether these associations vary among comorbidities for ED.

Material and Method

Data were analyzed for 3724 men (≥20 years old) who participated in the National Health and Nutrition Examination Survey (NHANES). ED was assessed by a single question during a self-paced, computer-assisted self-interview. We analyzed 24-h dietary recall data to estimate caffeine intake (mg/day). Multivariable logistic regression analyses using appropriate sampling weights were conducted.

Results

We found that men in the 3^rd (85-170 mg/day) and 4^th (171-303 mg/day) quintiles of caffeine intake were less likely to report ED compared to men in the lowest 1^st quintile (0-7 mg/day) [OR: 0.58; 95% CI, 0.37–0.89; and OR: 0.61; 95% CI, 0.38–0.97, respectively], but no evidence for a trend. Similarly, among overweight/obese and hypertensive men, there was an inverse association between higher quintiles of caffeine intake and ED compared to men in the lowest 1^st quintile, P≤0.05 for each quintile. However, only among men without diabetes we found a similar inverse association (P_trend = 0.01).

Conclusion

Caffeine intake reduced the odds of prevalent ED, especially an intake equivalent to approximately 2-3 daily cups of coffee (170-375 mg/day). This reduction was also observed among overweight/obese and hypertensive, but not among diabetic men. Yet, these associations are warranted to be investigated in prospective studies.     

Resequencing 250 Soybean Accessions: New Insights into Genes Associated with Agronomic Traits and Genetic Networks

The limited knowledge of genomic diversity and functional genes associated with the traits of soybean varieties has resulted in slow progress in breeding.In this study,we sequenced the genomes of 250 soybean landraces and cultivars from China,America,and Europe,and investigated their population structure,genetic diversity and architecture,and the selective sweep regions of these accessions.Five novel agronomically important genes were identified,and the effects of functional mutations in respect...     

ADP-Regulation of Mitochondrial Free Radical Production Is Different with Complex I- or Complex II-Linked Substrates: Implications for the Exercise Paradox and Brain Hypermetabolism

In agreement with classic studies, succinate-supplemented rat and pigeon heart and nonsynaptic brain mitochondrial free radical production is stopped by ADP additions causing the stimulation of respiration from State 4 to State 3. Nevertheless, with Complex I-linked substrates, mitochondria produce free radicals in State 3 at rates similar or somewhat higher than during resting respiration. The absence of sharp increases in free radical production during intense respiration is possible due to strong decreases of free radical leak in State 3. The results indicate that Complex I is the main mitochondrial free radical generator in State 3, adding to its already known important generation of active oxygen species in State 4. The observed rate of mitochondrial free radical production with Complex I-linked substrates in the active State 3 can help to explain two paradoxes: (a) the lack of massive muscle oxidative damage and shortening of life span due to exercise, in spite of up to 23-fold increases of oxygen consumption together with the very low levels of antioxidants present in heart, skeletal muscle, and brain; (b) the presence of some degree of oxidative stress during exercise and hyperactivity in spite of the stop of mitochondrial free radical production by ADP with succinate as substrate.     

Structure of the HRV-C 3C-Rupintrivir Complex Provides New Insights for Inhibitor Design

Human rhinoviruses(HRVs) are the predominant infectious agents for the common cold worldwide. The HRV-C species cause severe illnesses in children and are closely related to acute exacerbations of asthma. 3C protease, a highly conserved enzyme, cleaves the viral polyprotein during replication and assists the virus in escaping the host immune system. These key roles make 3C protease an important drug target. A few structures of 3Cs complexed with an irreversible inhibitor rupintrivir have been determined. These structures shed light on the determinants of drug specificity. Here we describe the structures of HRV-C15 3C in free and inhibitor-bound forms. The volume-decreased S1' subsite and half-closed S2 subsite, which were thought to be unique features of enterovirus A 3C proteases, appear in the HRV-C 3C protease.Rupintrivir assumes an ‘‘intermediate' conformation in the complex, which might open up additional avenues for the design of potent antiviral inhibitors. Analysis of the features of the three-dimensional structures and the amino acid sequences of 3C proteases suggest new applications for existing drugs.     

Underperformance of African Protected Area Networks and the Case for New Conservation Models: Insights from Zambia

Many African protected areas (PAs) are not functioning effectively. We reviewed the performance of Zambia’s PA network and provide insights into how their effectiveness might be improved. Zambia’s PAs are under-performing in ecological, economic and social terms. Reasons include: a) rapidly expanding human populations, poverty and open-access systems in Game Management Areas (GMAs) resulting in widespread bushmeat poaching and habitat encroachment; b) underfunding of the Zambia Wildlife Authority (ZAWA) resulting in inadequate law enforcement; c) reliance of ZAWA on extracting revenues from GMAs to cover operational costs which has prevented proper devolution of user-rights over wildlife to communities; d) on-going marginalization of communities from legal benefits from wildlife; e) under-development of the photo-tourism industry with the effect that earnings are limited to a fraction of the PA network; f) unfavourable terms and corruption which discourage good practice and adequate investment by hunting operators in GMAs; g) blurred responsibilities regarding anti-poaching in GMAs resulting in under-investment by all stakeholders. The combined effect of these challenges has been a major reduction in wildlife densities in most PAs and the loss of habitat in GMAs. Wildlife fares better in areas with investment from the private and/or NGO sector and where human settlement is absent. There is a need for: elevated government funding for ZAWA; greater international donor investment in protected area management; a shift in the role of ZAWA such that they focus primarily on national parks while facilitating the development of wildlife-based land uses by other stakeholders elsewhere; and new models for the functioning of GMAs based on joint-ventures between communities and the private and/or NGO sector. Such joint-ventures should provide defined communities with ownership of land, user-rights over wildlife and aim to attract long-term private/donor investment. These recommendations are relevant for many of the under-funded PAs occurring in other African countries.     

Erectile Dysfunction and Risk of End Stage Renal Disease Requiring Dialysis: A Nationwide Population-Based Study

Background

Previous studies have suggested that erectile dysfunction (ED) is an independent risk factor for macrovascular disease. Very few studies have evaluated the relationship between ED and risk of end stage renal disease (ESRD) requiring dialysis.

Methods

A random sample of 1,000,000 individuals from Taiwan''s National Health Insurance database was collected. We selected the control group by matching the subjects and controls by age, diabetes, hypertension, coronary heart disease, hyperlipidemia, area of residence, monthly income and index date. We identified 3985 patients with newly-diagnosed ED between 2000 and 2008 and compared them with a matched cohort of 23910 patients without ED. All patients were tracked from the index date to identify which patients subsequently developed a need for dialysis.

Results

The incidence rates of dialysis in the ED cohort and comparison groups were 10.85 and 9.06 per 10000 person-years, respectively. Stratified by age, the incidence rate ratio for dialysis was greater in ED patients aged <50 years (3.16, 95% CI: 1.62–6.19, p = 0.0008) but not in aged 50–64 (0.94, 95% CI: 0.52–1.69, p = 0.8397) and those aged ≧65 (0.69, 95% CI: 0.32–1.52, p = 0.3594). After adjustment for patient characteristics and medial comorbidities, the adjusted HR for dialysis remained greater in ED patients aged <50 years (adjusted HR: 2.08, 95% CI: 1.05–4.11, p<0.05). The log-rank test revealed that ED patients <50-years-old had significantly higher cumulative incidence rates of dialysis than those without (p = 0.0004).

Conclusion

Patients with ED, especially younger patients, are at an increased risk for ESRD requiring dialysis later in life.     

Function and Dysfunction of CNG Channels: Insights from Channelopathies and Mouse Models

Channels directly gated by cyclic nucleotides (CNG channels) are important cellular switches that mediate influx of Na⁺ and Ca²⁺ in response to increases in the intracellular concentration of cAMP and cGMP. In photoreceptors and olfactory receptor neurons, these channels serve as final targets for cGMP and cAMP signaling pathways that are initiated by the absorption of photons and the binding of odorants, respectively. CNG channels have been also found in other types of neurons and in non-excitable cells. However, in most of these cells, the physiological role of CNG channels has yet to be determined. CNG channels have a complex heteromeric structure. The properties of individual subunits that assemble in specific stoichiometries to the native channels have been extensively investigated in heterologous expression systems. Recently, mutations in human CNG channel genes leading to inherited diseases (so-called channelopathies) have been functionally characterized. Moreover, mouse knockout models were generated to define the role of CNG channel proteins in vivo. In this review, we will summarize recent insights into the physiological and pathophysiological role of CNG channel proteins that have emerged from genetic studies in mice and humans.     

维药罗补甫克比日丸对DM性勃起功能障碍大鼠性激素水平的影响

目的:揭示维药罗补甫克比日丸对糖尿病(DM)性勃起功能障碍(ED)大鼠性激素水平的影响。方法:取50只SD雄性大鼠,从中随机取7只设为正常对照(A)组,余43只行腹腔注射链尿佐菌素(STZ)制造DM动物模型,未成模者为STZ组,成模者用阿朴吗啡(APO)筛选DM性ED模型,并将其随机分为DM性ED对照组、药罗补甫克比日丸(C)组、胰岛素(D)组、联用(E)组,未成ED模者为DM(F)组,共7组。药物干预6周后,检测外周血中性激素水平。结果:正常对照(A)组、DM性ED胰岛素(D)组、DM性ED联用(E)组、STZ(G)组睾酮(T)水平显著高于DM性ED对照(B)组、DM性ED伊木萨克(C)组、DM(F)组,有显著性差异(P0.01);正常对照(A)组、STZ(G)组促黄体生成激素(LH)水平显著低于DM性ED伊木萨克(C)组、DM性ED联用(E)组,有显著性差异(P0.05、P0.01);DM性ED对照(B)组、DM性ED补甫克比日丸(C)组促卵泡刺激素(FSH)水平显著低于DM性ED胰岛素(D)组、DM性ED联用(E)组,有显著性差异(P0.01、P0.05)。结论:维药罗补甫克比日丸可显著改善DM性ED大鼠睾酮水平,且与胰岛素联用优于单用,维药罗补甫克比日丸治疗DM性ED的作用机制可能与T、LH、FSH含量变化有关。     

Stem Cell Therapy for Erectile Dysfunction of Cavernous Nerve Injury Rats: A Systematic Review and Meta-Analysis

Introduction

Stem cell treatment is a novel therapeutic strategy for erectile dysfunction (ED) patients with bilateral cavernous nerve injury (CNI). The relative animal studies provide important clues to design pre-clinical studies and clinical studies further in the future.

Purpose

This study aims to evaluate the effects and influential factors of stem cell transplantation on ED rats with CNI.

Materials and Methods

We searched PubMed and EBSCO databases published before April 30, 2014 for pre-clinical studies to evaluate the efficacy of stem cell transplantation in the treatment of ED rats with CNI. A systematic review and a planned subgroup analysis were performed to identify whether or not some certain influential factors could bring significant effects on stem cell treatment.

Results

12 studies with 319 rats were enrolled in this meta-analysis. Pooled analysis results confirmed the efficacy of stem cell transplantation. Subgroup analysis results showed that treatment effects were not related to CNI models, follow-up time, stem cell species, stem cell sources, markers and delivery approaches in the transplantation. Uncultured stem cells were poorly effective compared with cultured stem cells. Periprostatic implantation (PPI) with acellular scaffolds could promote cavernous nerve regeneration, but was less effective for smooth muscle cell recovery. Stem cells modified by NGF or BDNF combined with udenafil/bFGF seemed to be more effective than those modified by BDNF alone.

Conclusion

This meta-analysis shows that stem cell therapy can be performed to recover erectile function. Future studies should focus on nerve restoration and vascular cell recovery. The synergistic actions of multiple growth factors following stem cell transplantation should also be considered as beneficial strategies to obtain preferable effects.