Neurologic, clinical, and immunologic features in a cohort of HTLV-1 carriers with high proviral loads.

A high proviral load (PVL) is recognized as a risk factor for human T cell leukemia virus-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), but there is a lack of prospective studies evaluating whether or not HTLV-1 carriers with high PVL are at risk of developing HAM/TSP or other HTLV-1-related diseases. Here, we compare the incidence of clinical manifestations and the cytokine levels in 30 HTLV-1 carriers with high (> 50,000 copies/106 PBMC) and an equal number of subjects with low proviral load. Participants were followed for 3 to 16 years (median of 11 years). The PVL, IFN-γ, TNF, and IL-10 levels were quantified at entry and at the end of the follow-up. Among the self-reported symptoms in the initial evaluation, only the presence of paresthesia on the hands was more frequent in the group with high PVL (p < 0.04). The production of IFN-γ was higher in the group with high PVL group (median of 1308 versus 686 pg/ml, p < 0.011) when compared with the control group in the first assessment. There was no difference in the occurrence of urinary symptoms or erectile dysfunction, periodontal disease, Sicca syndrome, and neurologic signs between the two groups during the follow-up. The observation that none of the HTLV-1 carriers with high PVL and with exaggerated inflammatory response progressed to HAM/TSP indicates that other factors in addition to the PVL and an exaggerated immune response are involved in the pathogenesis of HAM/TSP.

Pathophysiology and Future Therapeutic Perspectives for Resolving Fibrosis in Peyronie's Disease.

INTRODUCTION: Peyronie's disease (PD) is a debilitating affliction for the male population, causing severe curvatures to the erect penis and erectile dysfunction in about 50% of men. This deviation of the penis significantly impairs sexual intercourse and causes depression and strains in the relationship. As of today, medical treatment options are few and far between, with surgery remaining as the sole reliable treatment. AIM: To give a general overview regarding fibrosis and the specific role of extracellular matrix, macrophages, and myofibroblasts in PD. Additionally, we will provide an overview of past and present research and how this has shaped our vision concerning the pathophysiology of PD. METHODS: We performed a non-systematic literature review using the search terms "fibrosis," "pathophysiology," "myofibroblast," "extracellular matrix," "Peyronie's disease," and "drug discovery." MAIN OUTCOME MEASURE: We assessed current knowledge regarding fibrosis in PD and the possibility to use this knowledge for new treatment options. RESULTS: Interpreting findings from the most recent next-generation sequencing, in vitro and in vivo PD research, we provide novel insights for the pathophysiology of PD. Using this knowledge, we will attempt to provide future directions for PD research and drug discovery, which is urgently needed, because its treatment has essentially been stagnating for about 30 years. CONCLUSION: Historically, PD has not been studied as widely as kidney, lung, or hepatic fibrosis, and our knowledge of its pathophysiology still remains relatively obscure. Nonetheless, recent breakthroughs using stem cells, next-generation sequencing, and phenotypical screening assays bring us several steps closer to filling the gaps in our knowledge. In the near future, clinical trials will prove essential to translate this plethora of preclinical data into usable tools that can improve the lives of many of our patients. Milenkovic U, Ilg MM, Cellek S, et al. Pathophysiology and Future Therapeutic Perspectives for Resolving Fibrosis in Peyronie's Disease. Sex Med Rev 2019;7:679-689.

Inhibition of proNGF and p75NTR Pathway Restores Erectile Function Through Dual Angiogenic and Neurotrophic Effects in the Diabetic Mouse.

INTRODUCTION: Penile neurovascular dysfunction is a major cause of erectile dysfunction (ED) in diabetic patients, which causes poor response to oral phosphodiesterase-5 inhibitors. Nerve growth factor precursor (proNGF) and its p75 neurotrophin receptor (p75NTR) have been known to be involved in microvascular complications and neurodegeneration. AIM: To examine the role of proNGF and its receptor p75NTR signaling pathway in diabetic ED, and to determine the effectiveness of proNGF neutralizing antibody (proNGF-Ab) in restoring erectile function in streptozotocin (STZ)-induced diabetic mice. METHODS: Diabetes mellitus was induced by intraperitoneal injection of STZ (50 mg/kg) into 8-week-old C57BL/6 male mice for 5 consecutive days. At 8 weeks after the induction of diabetes mellitus, the animals were distributed into 3 groups: controls and STZ-induced diabetic mice receiving 2 intracavernous injections of either saline (days -3 and 0; 20 µL) or proNGF-Ab (days -3 and 0; 20 µg in 20 µL of saline). We also examined the effect of proNGF-Ab or p75NTR small interfering RNA in primary cultured mouse cavernous endothelial cells, pericytes, and major pelvic ganglion. MAIN OUTCOME MEASURES: Erectile function was measured by electrical stimulation of the cavernous nerve at 2 weeks after treatment, and the penis was then harvested for histologic and biochemical studies. RESULTS: The cavernous expression of proNGF and p75NTR was upregulated under diabetic conditions. Intracavernous injection of proNGF-Ab successfully restored erectile function in diabetic mice, which reach 93-96% of control values. ProNGF-Ab significantly restored cavernous endothelial cell, pericyte, and neuronal cell content, and increased endothelial cell-to-cell junction proteins in the diabetic mice. Under the high-glucose condition, proNGF-Ab or p75NTR small interfering RNA promoted tube formation in mouse cavernous endothelial cells and pericytes, decreased apoptosis of endothelial cells and pericytes, and enhanced neurite sprouting from major pelvic ganglion. CLINICAL IMPLICATIONS: The ProNGF/p75NTR pathway will be a new therapeutic target for diabetic ED. STRENGTH & LIMITATIONS: This is the first study demonstrating the efficacy of the inhibition of proNGF/p75NTR pathway in diabetic ED. Further studies are needed to test whether a different dosing of proNGF-Ab would induce more durable erectile function recovery. CONCLUSION: Our findings suggest that inhibition of the proNGF/p75NTR signaling pathway is a promising therapeutic strategy for diabetic ED. Nguyen NM, Song K-M, Choi M-J, et al. Inhibition of proNGF and p75NTR Pathway Restores Erectile Function Through Dual Angiogenic and Neurotrophic Effects in the Diabetic Mouse. J Sex Med 2019;16:351-364.

Elucidating Mechanisms of Long-Term Gasoline Vehicle Exhaust Exposure-Induced Erectile Dysfunction in a Rat Model.

INTRODUCTION: Exposure to air pollution poses a risk for morbidity in multiple diseases. However, the role of ambient air pollutant emissions in public sexual health is just beginning to be understood and remains controversial. AIM: We have determined to elucidate the specific role of gasoline vehicle exhaust (VE), a crucial source and toxicant of air pollution, in the penile erectile function via a rat model. METHODS: 40 male Sprague Dawley rats, 12 weeks of age, were used in this experiment. Except for the control group (10 rats), rats were equally exposed to VE for total 2 hours, 4 hours, and 6 hours daily for 3 months consecutively. During each VE exposure periods, particulate matter (PM) mass concentrations of PM1, PM2.5, and PM10 were 1.43 ± 0.036, 1.45 ± 0.033, and 1.47 ± 0.037 mg/m3, respectively. MAIN OUTCOME MEASURE: Erectile function, pulmonary function, serum inflammatory factors, and histologic examinations of the lung and penile tissues were evaluated. RESULTS: Our study indicates that in vivo, 4-hour, and 6-hour daily exposure to VE causes significant reduction of erectile function, as judged by intracavernous pressure measurement. Meanwhile, we have observed that the 4-hour and 6-hour VE exposure rats exhibited remarkable increased levels of serum inflammatory factors, decreased total lung capacity and chord compliance, thickened alveoli septum, destroyed alveoli, pulmonary fibrosis, as well as down-regulation of the messenger RNA and protein expression of endothelial and neuronal nitric oxide synthase in the penile tissue when compared with normal control rats. CLINICAL IMPLICATIONS: We speculated that the underlying mechanisms of VE inducing erectile dysfunction could be attributed to systemic inflammation, pulmonary dysfunction, and the reduction of nitric oxide synthase activity in the corpus cavernosum. STRENGTH & LIMITATIONS: For the first time, our study revealed the deleterious effect of VE on penile erection in vivo. However, the VE exposure model might not entirely mimic the natural condition of ambient air pollution. CONCLUSION: Our results raise concerns about the potential role played by long-term exposure to gasoline VE in the development of erectile dysfunction. Zhao S, Wang J, Xie Q, et al. Elucidating Mechanisms of Long-Term Gasoline Vehicle Exhaust Exposure-Induced Erectile Dysfunction in a Rat Model. J Sex Med 2019;16:155-167.

The role of neutrophil-to-lymphocyte ratio in men with erectile dysfunction-preliminary findings of a real-life cross-sectional study.

The aim of this study was to investigate the role of systemic inflammation by means of the neutrophil-to-lymphocyte ratio (NLR) in men with erectile dysfunction (ED). Complete demographic, clinical, and laboratory data from 279 consecutive men with newly diagnosed ED were analyzed. Health-significant comorbidities were scored with the Charlson Comorbidity Index (CCI). A complete blood count was requested for every man, and the NLR was calculated for every individual. Patients were invited to complete the IIEF questionnaire. Logistic regression models tested the odds (OR, 95% CI) of severe ED (defined as IIEF-EF <11, according to Cappelleri's criteria) after adjusting for age, BMI, comorbidities (CCI >0), metabolic syndrome, NLR, cigarette smoking, and color duplex Doppler ultrasound parameters. Likewise, LNR values were also dichotomized according to the most informative cutoff predicting severe ED using the minimum p value approach. Median [IQR] age of included men was 51 [40-64] years. Of all, 87 (31%) men had severe ED. Men with severe ED were older (median [IQR] age: 61 [47-67] vs. 49 [39-58] years) and had a higher rate of CCI>0 [46/87 (53%) vs. 44/192 (23%) patients]. Thereof, NLR was dichotomized according to the most informative cutoff (NLR>3); patients with severe ED more frequently had NLR>3 as compared to all other ED patients [namely, 18/87 (21%) vs. 13/192 (7%)]. At multivariable logistic regression analysis, NLR>3.0 emerged as an independent predictor (OR [CI] 2.43 [1.06; 5.63]) of severe ED, after accounting for other clinical variables. A NLR>3 increased the risk of having severe ED in our cohort, boosting the already existing evidence linking systemic inflammation to ED. Moreover, this easily obtainable index can be clinically useful in better risk-stratifying patients with ED.

Relationship between erectile dysfunction and the neutrophil to lymphocyte and platelet to lymphocyte ratios.

The most important cause of erectile dysfunction (ED) among aging men is organic disease due to vascular disturbance that is often caused by atherosclerosis. Recently, studies have shown that atherosclerosis can manifest as an active inflammatory process rather than as passive vascular injury caused by lipid infiltration. Our study aimed to examine the association of ED with the neutrophil/lymphocyte ratio (NLR) and the platelet/lymphocyte ratio (PLR), both of which are markers of inflammation. Between December 2014 and May 2015, 101 male patients aged 40-70 years who were seen at our institute due to ED were included in this study. Thirty-one sexually active men with similar clinical and demographic characteristics without ED were included in our study as a control group. The control and patient groups were compared with respect to their NLR and PLR values as well as other hormonal, biochemical, hematological parameters. The median ages of the patient and control groups were 49 (40-69) and 48 (43-65) years old, respectively. Comorbidities such as hypertension, diabetes, chronic obstructive pulmonary disease (COPD), and coronary artery disease were not significantly different between the groups (p > 0.05). The neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios were significantly higher in the patient group than in the control group (p < 0.05). Furthermore, the detected CRP levels were also significantly higher in the patient group than in the control group (p < 0.001). In the correlation analysis, the NLR, PLR, and CRP levels were negatively correlated with the IIEF-5 scores. A multivariate analysis was performed to determine the independent predictors of ED. PLR was identified as an independent predictor for ED. The neutrophil-to-lymphocyte and especially platelet-to-lymphocyte ratios are correlated with a diagnosis of ED, and these ratios could serve as practical parameters that will not elicit additional costs.

Toll-like receptor 4 (TLR4) impairs nitric oxide contributing to Angiotensin II-induced cavernosal dysfunction.

AIM: Angiotensin II (AngII), a corpus cavernosum (CC) constrictor peptide, modulates Toll like receptor (TLR) expression, a key element of the innate immune system, contributing to impaired vascular function in pathological conditions. However, it is unknown whether TLR4 is involved in AngII-induced erectile dysfunction. In this study, we investigated whether TLR4 plays a role in cavernosal dysfunction caused by AngII upregulation. MATERIAL AND METHODS: Cavernosal smooth muscle cells (CSMC) from C57/BL6 mice were treated with AngII (0.1µM) or bacterial LPS (50ng/ml) for 12-24h and TLR4 expression was assessed. Mice were infused with AngII (90ng/min, 28days) and treated with anti-TLR4 antibody (0.1mg/daily, i.p.) for the last 14days of the treatment. CC tissue was used for functional studies and for Western blotting. Nitric Oxide Synthase (NOS) activity was measured by conversion of [3H]-l-arginine to [3H]-l-citrulline, systemic TNF-α levels by ELISA, and reactive oxygen species (ROS) by immunofluorescence. KEY FINDINGS: We report upregulation of TLR4 in CSMC following AngII or LPS stimulation. In AngII-infused mice, chronic treatment with anti-TLR4 antibody (28±2.1%) attenuates adrenergic CC contraction, which also ameliorates nitrergic (68.90±0.21 vs. 51.07±0.63, 8Hz, AngII-infused mice treated vs. non-treated). Decreased endothelial NOS expression, reduced NOS activity, and augmented levels of TNF-α, and ROS were found following AngII-infusion. These alterations were prevented, or at least decreased by anti-TLR4 antibody treatment. SIGNIFICANCE: Inhibition of TLR4 ameliorates AngII-impaired cavernosal relaxation, decreases TNF-α levels, and restores NO bioavailability, demonstrating that TLR4 partly mediates AngII-induced cavernosal dysfunction.

There is a link between erectile dysfunction and heart failure: it could be inflammation.

The rates of erectile dysfunction (ED) in heart failure (HF) are extremely high. Limited capacity of patients with HF to exercise and coronary artery disease are considered to be the main causative mechanisms. Both HF and ED are associated with increased levels of proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and interleukin-8 (IL- 8). The increased levels of proinflammatory cytokines in ED suggest that inflammatory markers act as important active agents in ED development. The innate immune system also reacts to danger signals released by damaged cells. Damage-associated molecular patterns (DAMPs) are molecules released as a result of tissue injury acting on immune activation during non-infectious inflammation. DAMPs may also reach the circulation and mediate pathophysiological processes that occur in distant organs to the injured site. Cardiomyocytes possess abundant mitochondria and during tissue damage, it is likely that the heart releases high amounts of mitochondrial DNA (mtDNA), which acts as a potent ligand for Toll-like receptor 9 (TLR9). Accordingly, in the present manuscript we review the literature pertaining the relationship between HF and ED and the subjacent inflammatory process associated to both diseases. In addition, we propose the hypothesis that TLR9 activation by DAMPs released in HF leads to inflammation, vascular dysfunction and functional changes in cavernosal tissue, providing an additional mechanism that connects HF to ED. Since TNF-α usually is a product of TLRs activation and seems to be a common link between HF and ED, our hypothesis provide two possible targets to treat the ED associated to HF and may have important preventative and therapeutic implications.

Immunization associated with erectile dysfunction based on cross-sectional and genetic analyses.

Erectile dysfunction (ED) is a global disease affecting a large number of people. Some studies have found a relationship between low-grade inflammation and ED. We hypothesized that the immune system might play a key role in the outcome of ED. Five immune agents (C3, C4, IgA, IgM, and IgG) were collected based on the Fangchenggang Area Male Health and Examination Survey (FAMHES), using methods of a traditional cross-sectional analysis. Our results repeated the significant association between ED and metabolic syndrome, obesity, and so forth. However, there seemed to be no positive relation between the tested indexes and ED risk in the baseline analysis (C3: P = 0.737; C4: P = 0.274; IgA: P = 0.943; IgG: P = 0.069; IgM: P = 0.985). Then, after adjusting for age and multivariate covariates, a potentially significant association between ED and IgG was discovered (P = 0.025 and P = 0.034, respectively). Meanwhile, in order to describe the development of ED on a gene level, SNP-set kernel-machine association test (SKAT) was applied with the known humoral immune genes involved. The outcomes suggested that PTAFR (binary P value: 0.0096; continuous P value: 0.00869), IL27 (0.0029; 0.1954), CD37 (0.0248; 0.5196), CD40 (0.7146; 0.0413), IL7R (0.1223; 0.0222), PSMB9 (0.1237; 0.0212), and CXCR3 (0.0849; 0.0478) might be key genes in ED, especially IL27, when we restricted the family-wise error rate (FWER) to 0.5. Our study shows that IgG and seven genes (PTAFR, CD37, CD40, IL7R, PSMB9, CXCR3, and especially IL27) might be key factors in the pathogenesis of ED, which could pave the way for future gene and immune therapies.

Management of benign prostatic hyperplasia: role of phosphodiesterase-5 inhibitors.

Several studies have highlighted a strong association between benign prostatic hyperplasia/lower urinary tract symptoms (BPH/LUTS) and erectile dysfunction (ED), particularly in elderly men. Many epidemiological trials, such as in vitro and in vivo studies, have reported the emerging role of metabolic syndrome, including abdominal obesity, impaired glucose metabolism, hypertriglyceridemia, low high-density lipoprotein cholesterol, and hypertension, in the development and progression of urinary and sexual symptoms. Moreover, many authors have focused their studies on the identification of all the shared pathogenetic mechanisms of LUTS/BPH and ED, including alteration of cyclic guanosine monophosphate and RhoA-ROCK pathways or vascular and neurogenic dysfunction. All these are potential targets for proposed phosphodiesterase type 5 inhibitors (PDE5-Is). Therefore, several trials have recently been designed to evaluate the role of PDE5-Is alone or in combination with conventional treatment for BPH, such as α-adrenergic blockers, in men affected by LUTS/BPH, with or without ED. Different PDE5-Is are in clinical use worldwide and currently six of them are licensed for the oral treatment of ED. All these compounds differ in pharmacokinetic factors, with influence on drug action, and subsequently in the overall safety and efficacy profile.

Immunologic response and proviral load in human T-lymphotropic virus type 1 infected individuals with erectile dysfunction.

OBJECTIVE: To evaluate the immune response and proviral load in individuals with human T-lymphotropic virus type 1 (HTLV-1) and erectile dysfunction (ED) compared with those in the controls. MATERIALS AND METHODS: We performed a cross-sectional study of 102 men aged 18-70 years with positive serology for HTLV-1, who were interviewed from 2004 to 2010. The study sample was divided into 2 groups: group 1, 42 HTLV-1-infected men with ED, as determined by the International Index of Erectile Function-5 score; and group 2, 60 HTLV-1-infected men without ED. The cytokines interferon-γ and tumor necrosis factor-α, and the proviral load were analyzed between the 2 groups. RESULTS: Compared with those without ED, the men with ED had greater levels of tumor necrosis factor-α (545.37 ± 877.06 vs 509.39 ± 724.70 pg/mL) and interferon-γ (1154.35 ± 1282.98 vs 1122.78 ± 1573.16 pg/mL), but this difference was not significant (P = .69 and P = .57, respectively). The proviral load was 135,695 ± 190,113 copies/10(5) cells in the ED group and 47,607 ± 83,129 copies/10(5) cells in the non-ED patients, with a statistically significant difference (P = .02). When ED was stratified as mild, moderate, and severe, no difference was found in the proviral load among the ED groups (P = .09); however, the levels were greater in the severe forms. CONCLUSION: The association of a greater proviral load in men with ED with HTLV-1 gives support to the idea that ED is part of the autonomic syndrome related to viral infection and should be investigated for early identification of the syndrome.

Oxytocin immunoreactivity in the corpus cavernosum of patients with erectile dysfunction.

OBJECTIVES: Oxytocin is released by the posterior pituitary gland during male orgasm. Additionally, the presence of an oxytocin receptor gene and protein expression in human corpus cavernosum is demonstrated, and it has contractile activity on the smooth muscle of the animal and human corpus cavernosum in vitro. The aim of this study was to investigate the immunoreactivity of oxytocin in corpus cavernosum of patients with organic erectile dysfunction and to compare it with healthy controls. METHODS: Cavernous biopsies were obtained from 31 patients with erectile dysfunction and 11 patients without erectile dysfunction. Oxytocin immunohistochemistry was performed using the streptavidin-biotin immunoperoxidase staining on all cases. Intensity and proportion of stained cells were added for the immunoreactivity score. RESULTS: The mean ages of patients with erectile dysfunction and controls were 41.47 ± 2.08 and 36.50 ± 3.35 years, respectively (p > 0.05). Oxytocin expression was detected in smooth muscle as well as in endothelial cells in both groups. The mean oxytocin immunoreactivity score values of patients with erectile dysfunction and controls were also 2.16 ± 0.12 and 2.30 ± 0.21, respectively (p > 0.05). There was no significant difference in immunoreactivity scores both in arterial and cavernosal failure and also in smoker and nonsmoker groups (p > 0.05). Immunoreactivity scores were not statistically significantly different between patients with concomitant medical disorders and patients with no other medical disorder (p > 0.05). CONCLUSION: We detected oxytocin immunoreactivity in male corpus cavernosum, but staining was not different between patients with erectile dysfunction and controls. However, further studies are necessary to reach a final conclusion regarding the effects of oxytocin on corpus cavernosum.

Imbalanced low-grade inflammation and endothelial activation in patients with type 2 diabetes mellitus and erectile dysfunction.

INTRODUCTION: Erectile dysfunction (ED) is highly prevalent among type 2 diabetes mellitus patients (T2DM). Although a link among systemic inflammation, endothelial dysfunction, and ED is described in clinical situations mainly related with coronary heart disease (CHD) risk, evidences of this link in T2DM patients are rather limited. AIMS: To evaluate the association between endothelial dysfunction and balance of pro-/anti-inflammatory mediators with ED presence and severity in T2DM. METHODS: We conducted a cross-sectional study of 190 T2DM patients without symptomatic CHD, 150 out of them with ED and 40 without ED. Serum levels of E-selectin, intercellular adhesion molecule-1, tumor necrosis factor-α (TNF-α), and interleukin (IL)-10 were measured using specific enzyme-linked immunosorbent assays (ELISAs). ED presence and severity were tested by the five-item version of the International Index of Erectile Function questionnaire. MAIN OUTCOME MEASURES: Differences in circulating levels of endothelial dysfunction (ICAM-1, E-selectin) and inflammatory/anti-inflammatory (TNF-α, IL-10, TNF-α : IL-10 ratio) markers between T2DM patients with and without ED, and assessment of biomarkers ED predictive value while adjusting for other known ED risk factors. RESULTS: Patients with ED were older and had longer duration of diabetes than patients without ED. E-selectin serum levels were significantly increased, while IL-10 were lower in patients with ED; because TNF-α levels tend to be higher, TNF-α : IL-10 ratio was more elevated in ED patients. No significant differences of ICAM-1 levels were observed between study groups. Endothelial activation markers and TNF-α, as well as diabetes duration, were negatively correlated with erectile function. On multivariate analysis including age, duration of diabetes, insulin treatment, hypertension, insulin resistance, fair-to-poor glycemic control, and metabolic syndrome, increments in E-selectin levels and TNF-α : IL-10 ratio predicted independently ED presence, while IL-10 increases were associated with lower risk of ED in T2DM patients. CONCLUSIONS: ED in T2DM patients without symptomatic CHD is associated with systemic endothelial dysfunction and a predominant, imbalanced low-grade inflammatory response.

Inhibition of interleukin-6 attenuates erectile dysfunction in a rat model of nerve-sparing radical prostatectomy.

INTRODUCTION: The precise mechanisms underlying erectile dysfunction (ED) occurring after cavernous nerve (CN)-sparing surgery remain to be determined. Aim. To evaluate the expression of interleukin-6 (IL-6) and IL-6 receptor (IL-6R) after CN injury, and the effect of inhibiting IL-6 bioactivity on nerve injury-related ED. METHODS: Male Sprague-Dawley rats were divided into three groups: sham operation; bilateral CN dissection without crushing or cutting; and bilateral CN resection. In the interventional experiment, male rats underwent bilateral CN dissection, and anti-rat IL-6 antibody in phosphate-buffered saline (PBS) or vehicle alone was injected intraperitoneally immediately and 24 hours after CN dissection. MAIN OUTCOME MEASURES: One, 3, 7, 28, and 56 days after surgery, the expression of IL-6 and IL-6R in the major pelvic ganglion (MPG) was examined by real-time polymerase chain reaction. In the interventional experiment, erectile function was assessed by determining intracavernous pressure divided by arterial pressure (ICP/AP) during electrical pelvic nerve stimulation at 4 weeks after surgery in the anti-IL-6-injected rats and PBS-injected rats. The degree of nerve injury was also evaluated by retrograde dye tracing with Fluorogold. RESULTS: The expression levels of IL-6 and IL-6R were increased in the early period of CN injury, as compared with the sham group. IL-6 expression on day 1 was particularly enhanced. Four weeks after CN dissection, the anti-IL-6 group had greater ICP/AP and more FG-positive cells than the PBS group. CONCLUSIONS: Expression levels of IL-6 in the MPG were increased in the acute phase following CN injury. Inhibition of IL-6 bioactivity attenuated ED following CN dissection. Thus, the suppression of excess inflammatory responses in the acute phase may lead to improvements in ED occurring after nerve-sparing radical prostatectomy.

[Application of physiobalneotherapeutic factors in the combined rehabilitative treatment of patients with chronic bacterial prostatitis complicated by erectile dysfunction].

Patients with chronic bacterial prostatitis complicated by erectile dysfunction received combined rehabilitative treatment based on the use of various combinations of physiobalneotherapeutic factors, such as ultrasound, local negative pressure, white and yellow turpentine or sodium chloride baths, supplemented by basal medicamentous therapy in the form of rectal suppositories. Efficiency of therapy involving sodium chloride, white and yellow turpentine baths was estimated at 85, 60, and 75% respectively.

Potential of adipose-derived stem cells for treatment of erectile dysfunction.

INTRODUCTION: Adipose-derived stem cells (ADSCs) are a somatic stem cell population contained in fat tissue that possess the ability for self-renewal, differentiation into one or more phenotypes, and functional regeneration of damaged tissue, which may benefit the recovery of erectile function by using a stem cell-based therapy. AIM: To review available evidence concerning ADSCs availability, differentiation into functional cells, and the potential of these cells for the treatment of erectile dysfunction (ED). METHODS: We examined the current data (from 1964 to 2008) associated with the definition, characterization, differentiation, and application of ADSCs, as well as other kinds of stem cells for the cell-based therapies of ED. MAIN OUTCOME MEASURES: There is strong evidence supporting the concept that ADSCs may be a potential stem cell therapy source in treating ED. RESULTS: The ADSCs are paravascularly localized in the adipose tissue. Under specific induction medium conditions, these cells differentiated into neuron-like cells, smooth muscle cells, and endothelium in vitro. The insulin-like growth factor/insulin-like growth factor receptor (IGF/IGFR) pathway participates in neuronal differentiation while the fibroblast growth factor 2 (FGF2) pathway is involved in endothelium differentiation. In a preliminary in vivo experiment, the ADSCs functionally recovered the damaged erectile function. However, the underlying mechanism needs to be further examined. CONCLUSION: The ADSCs are a potential source for stem cell-based therapies, which imply the possibility of an effective clinical therapy for ED in the near future.

Fibroblast growth factor 2 promotes endothelial differentiation of adipose tissue-derived stem cells.

INTRODUCTION: Adipose tissue-derived stem cells (ADSC) could potentially restore endothelial function in vasculogenic erectile dysfunction (ED). The mechanism for ADSC endothelial differentiation remained unidentified. AIM: To test whether ADSC could differentiate into endothelial cells in the penis and to identify the underlying mechanism of ADSC endothelial differentiation. METHODS: For in vivo endothelial differentiation, ADSC were labeled with bromodeoxyuridine (BrdU), injected into rat corpora cavernosa, and localized by immunofluorescence and phase-contrast microscopy. For in vitro endothelial differentiation, ADSC were grown in endothelial growth medium 2 (EGM2), stained for endothelial markers CD31, von Willebrand Factor (vWF), and endothelial nitric oxide synthase (eNOS), and assessed for the ability to form tube-like structures in Matrigel and to endocytose acetylated low-density lipoprotein (Ac-LDL). To identify factors that promote ADSC endothelial differentiation, ADSC were grown in various media, each of which contained a specific combination of supplemental factors and assessed for LDL-uptake. PD173074, a selective inhibitor of fibroblast growth factor 2 (FGF2) receptor, was used to confirm the importance of FGF2 signaling for ADSC endothelial differentiation. MAIN OUTCOME MEASURES: In vivo endothelial differentiation was assessed by immunofluorescence microscopy. In vitro endothelial differentiation was assessed by immunofluorescence, Matrigel tube formation, and Ac-LDL uptake. RESULTS: Injected ADSC were localized to the sinusoid endothelium, some of which stained positive for both BrdU and endothelial antigen rat endothelial cell antigen. ADSC proliferated at a faster rate in EGM2 than in standard DMEM, expressed endothelial markers CD31, vWF, and eNOS, formed tube-like structures in Matrigel, and endocytosed Ac-LDL. These properties were greatly diminished when ADSC were grown in the absence of FGF2 but were unaffected when grown in the absence of vascular endothelial growth factor, insulin-like growth factor, or epidermal growth factor. Furthermore, ADSC displayed similar endothelial properties when grown in FGF2-supplemented basic medium as in EGM2. Finally, blockade of FGF2 signaling with PD173074 abrogated ADSC endothelial differentiation. CONCLUSIONS: ADSC could differentiate into endothelial cells in the penis. FGF2 signaling mediates ADSC endothelial differentiation.

Circulating CD34+ KDR+ endothelial progenitor cells correlate with erectile function and endothelial function in overweight men.

INTRODUCTION: Bone marrow-derived endothelial progenitor cells (EPCs) circulate in the peripheral blood and are involved in endothelial homeostasis and repair. AIM: The aim of this study was to assess the circulating levels of different EPC phenotypes in overweight men with or without erectile dysfunction (ED). As endothelial dysfunction is considered a necessary link with ED, endothelium-dependent vasodilation and its relation with EPCs were also investigated. METHODS: We studied 30, otherwise healthy, overweight subjects with symptomatic ED for at least 6 months, and 30 age- and weight-matched subjects without ED. Erectile function was assessed by completing the International Index of Erectile Function (IIEF-5), which consists of items 5, 15, 4, 2, and 7 from the full-scale IIEF-15. MAIN OUTCOME MEASURES: Seven subpopulations of EPCs were determined by flow cytometry on the basis of the surface expression of CD34, CD133, and KDR antigens: CD34(+), CD133(+), KDR(+), CD34(+)CD133(+), CD34(+)KDR(+), CD133(+)KDR(+), and CD34(+)CD133(+)KDR(+). Endothelium-dependent flow-mediated dilation (FMD) was evaluated in the right brachial artery with a high-resolution ultrasound machine following reactive hyperemia. RESULTS: CD34(+)KDR(+) cell count was significantly lower in men with ED as compared with men without ED (63.1 +/- 4 vs. 92.4 +/- 6 cells/10(6) events, mean +/- standard error, P < 0.01). There was a significant direct correlation between circulating CD34(+)KDR(+) cells and the IIEF score (r = 0.44; P = 0.01): men with the severe form of ED presented the lowest level of circulating EPC CD34(+)KDR(+) cells. No significant correlation was found between the circulating levels of the other EPC phenotypes and the IIEF score. There was a significant correlation between CD34(+)KDR(+) cell count and FMD (r = 0.45; P = 0.01), but not between FMD and the other phenotypes. CONCLUSIONS: Circulating levels of CD34(+)KDR(+) EPC are reduced in overweight subjects with ED and correlate with the severity of ED. Other EPC phenotypes are not related to ED, suggesting that the CD34(+)KDR(+) phenotype of EPCs may be preferred in future studies.

TNF-alpha knockout mice have increased corpora cavernosa relaxation.

INTRODUCTION: Erectile dysfunction is considered an early clinical manifestation of vascular disease and an independent risk factor for cardiovascular events associated with endothelial dysfunction and increased levels of pro-inflammatory cytokines. Tumor necrosis factor-alpha (TNF-alpha), a pro-inflammatory cytokine, suppresses endothelial nitric oxide synthase (eNOS) expression. AIM: Considering that nitric oxide (NO) is of critical importance in penile erection, we hypothesized that blockade of TNF-alpha actions would increase cavernosal smooth muscle relaxation. METHODS: In vitro organ bath studies were used to measure cavernosal reactivity in wild type and TNF-alpha knockout (TNF-alpha KO) mice and NOS expression was evaluated by western blot. In addition, spontaneous erections (in vivo) were evaluated by videomonitoring the animals (30 minutes). Collagen and elastin expression were evaluated by Masson trichrome and Verhoff-van Gieson stain reaction, respectively. MAIN OUTCOME MEASURES: Corpora cavernosa from TNF-alpha KO mice exhibited increased NO-dependent relaxation, which was associated with increased eNOS and neuronal NOS (nNOS) cavernosal expression. RESULTS: Cavernosal strips from TNF-alpha KO mice displayed increased endothelium-dependent (97.4 +/- 5.3 vs. CONTROL: 76.3 +/- 6.3, %) and nonadrenergic-noncholinergic (93.3 +/- 3.0 vs. CONTROL: 67.5 +/- 16.0; 16 Hz) relaxation compared to control animals. These responses were associated with increased protein expression of eNOS and nNOS (P < 0.05). Sympathetic-mediated (0.69 +/- 0.16 vs. CONTROL: 1.22 +/- 0.22; 16 Hz) as well as phenylephrine-induced contractile responses (1.6 +/- 0.1 vs. CONTROL: 2.5 +/- 0.1, mN) were attenuated in cavernosal strips from TNF-alpha KO mice. Additionally, corpora cavernosa from TNF-alpha KO mice displayed increased collagen and elastin expression. In vivo experiments demonstrated that TNF-alpha KO mice display increased number of spontaneous erections. CONCLUSION: Corpora cavernosa from TNF-alpha KO mice display alterations that favor penile tumescence, indicating that TNF-alpha plays a detrimental role in erectile function. A key role for TNF-alpha in mediating endothelial dysfunction in ED is markedly relevant since we now have access to anti-TNF-alpha therapies.