Testosterone replacement in transgenic sickle cell mice controls priapic activity and upregulates PDE5 expression and eNOS activity in the penis.

Sickle cell disease (SCD)-associated priapism is characterized by decreased nitric oxide (NO) signaling and downregulated phosphodiesterase (PDE)5 protein expression and activity in the penis. Priapism is also associated with testosterone deficiency, but molecular mechanisms underlying testosterone effects in the penis in SCD are not known. Given the critical role of androgens in erection physiology and NO synthase (NOS)/PDE5 expression, we hypothesized that testosterone replacement to eugonadal testosterone levels reduces priapism by reversing impaired endothelial (e)NOS activity and molecular abnormalities involving PDE5. Adult male transgenic Berkeley sickle cell (Sickle) and wild-type (WT) mice were implanted with testosterone pellets, which release 1.2 µg testosterone/day for 21 days, or vehicle. After 21 days, animals underwent erectile function assessment followed by collection of blood for serum testosterone measurements, penes for molecular analysis, and seminal vesicles as testosterone-responsive tissue. Serum testosterone levels were measured by radioimmunoassay; protein expressions of PDE5, α-smooth muscle actin, eNOS and nNOS, and phosphorylation of PDE5 at Ser-92, eNOS at Ser-1177, neuronal (n) NOS at Ser-1412, and Akt at Ser-473 were measured by Western blot in penile tissue. Testosterone treatment reversed downregulated serum testosterone levels and increased (p < 0.05) the weight of seminal vesicles in Sickle mice to levels comparable to that of WT mice, indicating restored testosterone levels in Sickle mice. Testosterone treatment reduced (p < 0.05) prolonged detumescence in Sickle mice and normalized downregulated P-PDE5 (Ser-92), PDE5, P-eNOS (Ser-1177), and P-Akt (Ser-473) protein expressions in the Sickle mouse penis. Testosterone treatment did not affect P-nNOS (Ser-1412), eNOS, nNOS, or α-smooth muscle actin protein expressions in the Sickle mouse penis. In conclusion, in the mouse model of human SCD, increasing testosterone to eugonadal levels reduced priapic activity and reversed impaired Akt/eNOS activity and PDE5 protein expression in the penis.

Constitutive NOS uncoupling and NADPH oxidase upregulation in the penis of type 2 diabetic men with erectile dysfunction.

Erectile dysfunction (ED) associated with type 2 diabetes mellitus (T2DM) involves dysfunctional nitric oxide (NO) signaling and increased oxidative stress in the penis. However, the mechanisms of endothelial NO synthase (eNOS) and neuronal NO synthase (nNOS) dysregulation, and the sources of oxidative stress, are not well defined, particularly at the human level. The objective of this study was to define whether uncoupled eNOS and nNOS, and NADPH oxidase upregulation, contribute to the pathogenesis of ED in T2DM men. Penile erectile tissue was obtained from 9 T2DM patients with ED who underwent penile prosthesis surgery for ED, and from six control patients without T2DM or ED who underwent penectomy for penile cancer. The dimer-to-monomer protein expression ratio, an indicator of uncoupling for both eNOS and nNOS, total protein expressions of eNOS and nNOS, as well as protein expressions of NADPH oxidase catalytic subunit gp91phox (an enzymatic source of oxidative stress) and 4-hydroxy-2-nonenal [4-HNE] and nitrotyrosine (markers of oxidative stress) were measured by western blot in this tissue. In the erectile tissue of T2DM men, eNOS and nNOS uncoupling and protein expressions of NADPH oxidase subunit gp91phox, 4-HNE- and nitrotyrosine-modified proteins were significantly (p < 0.05) increased compared to control values. Total eNOS and nNOS protein expressions were not significantly different between the groups. In conclusion, mechanisms of T2DM-associated ED in the human penis may involve uncoupled eNOS and nNOS and NADPH oxidase upregulation. Our description of molecular factors contributing to the pathogenesis of T2DM-associated ED at the human level is relevant to advancing clinically therapeutic approaches to restore erectile function in T2DM patients.

Mechanistic link between erectile dysfunction and systemic endothelial dysfunction in type 2 diabetic rats.

Men with type 2 diabetes mellitus (T2DM) and erectile dysfunction (ED) have greater risk of cardiovascular events than T2DM men without ED, suggesting ED as a predictor of cardiovascular events in diabetic men. However, molecular mechanisms underlying endothelial dysfunction in the diabetic penis explaining these clinical observations are not known. We evaluated whether the temporal relationship between ED and endothelial dysfunction in the systemic vasculature in T2DM involves earlier redox imbalance and endothelial nitric oxidase synthase (eNOS) dysfunction in the penis than in the systemic vasculature, such as the carotid artery. Rats were rendered T2DM by high-fat diet for 2 weeks, followed by an injection with low-dose streptozotocin. After 3 weeks, erectile function (intracavernosal pressure) was measured and penes and carotid arteries were collected for molecular analyses of eNOS uncoupling, protein S-glutathionylation, oxidative stress (4-hydroxy-2-nonenal, 4-HNE), protein expression of NADPH oxidase subunit gp91(phox) , endothelium-dependent vasodilation in the carotid artery, and non-adrenergic, non-cholinergic (NANC)-mediated cavernosal relaxation. Erectile response to electrical stimulation of the cavernous nerve and NANC-mediated cavernosal relaxation was decreased (p < 0.05), while relaxation of the carotid artery to acetylcholine was not impaired in T2DM rats. eNOS monomerization, protein expressions of 4-HNE and gp91(phox) , and protein S-glutathionylation, were increased (p < 0.05) in the penis, but not in the carotid artery, of T2DM compared to non-diabetic rats. In conclusion, redox imbalance, increased oxidative stress by NADPH oxidase, and eNOS uncoupling, occur early in T2DM in the penis, but not in the carotid artery. These molecular changes contribute to T2DM ED, while vascular function in the systemic vasculature remains preserved.

Pharmacotherapeutic management of erectile dysfunction.

Erectile dysfunction is a common condition in aging men and significantly affects their quality of life and interpersonal relationships. Its prevalence and incidence are associated with aging, lifestyle factors and cardiovascular comorbidities. Preoccupation with male virility has been present for centuries, and a wide variety of herbs and potions have been used to treat any sexual deficiencies. Recent major advances in understanding of erectile physiology and pathophysiology led to development of currently available systemic and local pharmacotherapies. They are designed to work either centrally or peripherally and to either suppress anti-erectile mechanisms, enhance the pro-erectile ones or influence both. Since all the current formulations have variable safety and efficacy profiles, the search for highly specific, simple, convenient and clinically effective impotence treatments or prophylactics continues.

Rural vs. urban disparities in association with lower urinary tract symptoms and benign prostatic hyperplasia in ageing men, NHANES 2001-2008.

OBJECTIVE: The objective of this study was to investigate rural/urban and socio-demographic disparities in lower urinary tract symptoms and benign prostatic hyperplasia (LUTS/BPH) in a nationally representative population of men. METHODS: Data on men age ≥40 years (N = 4,492) in the 2001-2008 National Health and Nutrition Examination Surveys were analysed. Self-report of physician-diagnosed enlarged prostate and/or BPH medication use defined recognised LUTS/BPH. Urinary symptoms without BPH diagnosis/medications defined unrecognised LUTS/BPH. Rural-Urban Commuting Area Codes assessed urbanisation. Unadjusted and multivariable associations (odds ratios (OR)) between LUTS/BPH and covariates were calculated using logistic regression. RESULTS: Recognised and unrecognised LUTS/BPH weighted-prevalence estimates were 16.5% and 9.6%. There were no significant associations between LUTS/BPH and rural/urban status. Significant predisposing factors for increased adjusted odds of recognised and unrecognised LUTS/BPH included age, hypertension (OR=1.4;1.4), analgesic use (OR=1.4;1.4) and PSA level >4 ng/mL (OR=2.3;1.9) when adjusted for rural/urban status, race, education, income, alcohol, health insurance, health care and proton pump inhibitor (PPI) use (all p ≤ 0.1). Restricting to urban men only (N = 3,371), healthcare use (≥4visits/year) and PPI's increased adjusted odds of recognised LUTS/BPH (OR=2.0;1.6); no health insurance and

Inflatable penile prosthesis technique and outcomes after radial forearm free flap neophalloplasty.

The aim of this study was to describe the technical aspects and short-term outcomes of inflatable penile prosthesis (IPP) implantation after neophallus reconstruction at a single institution. Nine men with previously constructed radial forearm neophalli underwent IPP implantation. The etiologies of their penile anomaly were bladder exstrophy complex in five, disorder of sexual differentiation in two and genital obliteration secondary to ballistic trauma in two. Median follow-up was 9.6 months (range 1.5-139.7). The records for these patients were retrospectively reviewed and outcomes recorded. Mean age was 23.6 (range 18-31) years, and mean time interval from neophalloplasty to IPP implantation was 22.1 months (range 3-48). In all cases, 3-piece IPPs were employed, with eight of patients having one cylinder implanted in the native corporal body and extending into the neophallus. Mean surgical time was 222 min (range 142-409). Median length of implanted device was 22 cm. No intraoperative complications were observed. At the most recent follow-up, six patients (66.7%) had functional devices, with acceptable surgical outcomes. Three patients (33.3%) sustained device infections, and three (33.3%) sustained cylinder erosion. In three patients in whom neo-tunica albuginea were fashioned by ensheathing the cylinder with allograft human dermal tissue matrix, no erosions occurred. One patient underwent two revisions, the first for the associated erosion and infection and the second for genital pain, and was left with a semi-rigid prosthesis. IPP implantation affords the best opportunity for functionality for patients with a radial forearm free flap neophallus. Caution must be taken to ensure viability of the neophallus intraoperatively, and protocols to minimize the risk of infection should be followed. Fashioning neo-tunica albuginea using graft material may reduce risk of erosion.

Influence of Trifloxystrobin on Primary Inoculum and Progression of Scab Epidemics on Stone Fruit.

The ability of the QoI fungicide trifloxystrobin to reduce production of conidia by Fusicladium carpophilum on twig lesions was quantitatively assessed over a 3-year period from 2005 through 2007. Four annual treatment programs, consisting of two consecutive trifloxystrobin applications at pink + bloom, bloom + petal fall, and petal fall + shuck-split, plus a single application timing at petal fall, were examined in a 'Redgold' nectarine orchard harboring high levels of overwintering scab lesions. Sporulation potential, the ability of twig lesions to produce conidia under optimum environmental conditions, was subsequently assessed five to six times during each spring and early summer. In each year of the study, all four treatments significantly reduced the area under the sporulation curve or peak sporulation. The petal fall + shuck-split program provided the greatest antisporulant activity, reducing conidia production at peak sporulation by 82 to 92%. Furthermore, examination of results over the 3-year period showed that the programs significantly slowed the annual rate of increase in peak sporulation; however, none of the programs completely halted or caused a decline in the annual rate. Although no fungicide was applied after the treatment programs, results from fruit disease assessments showed that these programs, applied as much as 3 months earlier, significantly reduced disease incidence and, in particular, disease severity. A comparison of four QoI fungicides in 2008 indicated that trifloxystrobin and azoxystrobin provided the most control of fruit scab, while pyraclostrobin + boscalid and fluoxastrobin yielded minimal or no benefit. Results of this study demonstrate that certain QoI fungicides, in particular trifloxystrobin and azoxystrobin, can probably improve the efficacy of current protectant programs used for peach scab control by providing season-long control of F. carpophilum sporulation on twig lesions. Such program enhancement may be critical when orchards have high inoculum levels and/or environmental conditions are very favorable to disease development.

Modern utilization of penile prosthesis surgery: a national claim registry analysis.

The objective of this study was to evaluate the modern utilization of penile prosthesis surgery based on data derived from national claim databases and contrast to an analysis of patients similarly treated at an academic center during a contemporaneous period. A retrospective claim analysis utilizing a national database (MarketScan, Thomson Reuters) was performed for Commercial insurer and Medicare databases between January 2000 and March 2011. A retrospective analysis of contemporaneous penile prosthesis implantation at the Johns Hopkins Hospital (JHH) was done. Population demographics, comorbidities, previous (ED) therapies and time from ED diagnosis to surgery were assessed. Median ages for patients undergoing penile prosthesis implantation were 58, 70 and 63 years for the Commercial, Medicare and JHH cohorts, respectively. For the claim databases (Commercial, Medicare, respectively), hypertension (72%, 78%), dyslipidemia (71%, 56%) and diabetes mellitus (45%, 40%) were predominant comorbidities, whereas for the JHH database prostate cancer (51%) and its management by prostatectomy (45%) or radiation (12%) were predominant. Previous use of PDE5 inhibitors was similar across databases (60, 58 and 69% for Commercial, Medicare and JHH cohorts, respectively), although previous use of non-oral ED therapies was greater in the JHH database. Median time to surgery from initial ED diagnosis was 2, 2 and 4 years for the Commercial, Medicare and JHH patients, respectively. Demographic variables and ED risk factors associated with penile prosthesis surgery at a national population-based level over a contemporary period were defined. Some differences in utilization trends of penile prosthesis surgery exist at a single institutional level.

Penile straightening maneuvers employed during penile prosthesis surgery: technical options and outcomes.

Straightening maneuvers (SM), including manual penile modeling, tunical relaxing incisions and corporal reconstruction using grafting techniques, are occasionally required during inflatable penile prosthesis (IPP) implantation to ensure functional penile straightness. The aim of this study was to compare the outcomes of men undergoing SM employed during IPP implantation compared with those wherein these maneuvers were not required. A retrospective review of 391 patients undergoing IPP implantation at the Johns Hopkins Hospital from January 2000 to December 2011 was performed. Patients in whom some SM was employed (SM, n=93, 23.9% of the overall cohort) were compared with those for whom SM was not required (IPP group, n=298). Seven patients were excluded from final analysis (6 patients with IPPs inserted in neophalli (SM group), and 1 patient with incomplete data (IPP group). Patients in whom a SM was used were younger (55.4 vs 62.3 years), more likely to have Peyronie's disease, and less likely to have prostate cancer, radical prostatectomy or to have previously used erectile aids (all P<0.05). Mean operating room time in the SM group was longer (173.8 vs 152.9 min, P=0.003). Within the SM group, modeling was performed in 40 (43%), tunical relaxing incisions in 37 (39.8%) and tunical reconstruction in 16 (17.2%) (most commonly using allograft dermis or pericardium, or synthetic gore-tex grafts). There were no significant differences in terms of device infection (P=0.15), mechanical failure (P=0.23) or erosion (P=0.96). Although limited in size, this cohort study suggests that IPP implantation in men with penile deformity requiring complex reconstruction to achieve straightening may be done proficiently and without increased adverse outcome risk.

The assessment of vascular risk in men with erectile dysfunction: the role of the cardiologist and general physician.

Erectile dysfunction (ED) and cardiovascular disease (CVD) share risk factors and frequently coexist, with endothelial dysfunction believed to be the pathophysiologic link. ED is common, affecting more than 70% of men with known CVD. In addition, clinical studies have demonstrated that ED in men with no known CVD often precedes a CVD event by 2-5 years. ED severity has been correlated with increasing plaque burden in patients with coronary artery disease. ED is an independent marker of increased CVD risk including all-cause and especially CVD mortality, particularly in men aged 30-60 years. Thus, ED identifies a window of opportunity for CVD risk mitigation. We recommend that a thorough history, physical exam (including visceral adiposity), assessment of ED severity and duration and evaluation including fasting plasma glucose, lipids, resting electrocardiogram, family history, lifestyle factors, serum creatinine (estimated glomerular filtration rate) and albumin:creatinine ratio, and determination of the presence or absence of the metabolic syndrome be performed to characterise cardiovascular risk in all men with ED. Assessment of testosterone levels should also be considered and biomarkers may help to further quantify risk, even though their roles in development of CVD have not been firmly established. Finally, we recommend that a question about ED be included in assessment of CVD risk in all men and be added to CVD risk assessment guidelines.

Testosterone replacement therapy does not promote priapism in hypogonadal men with sickle cell disease: 12-month safety report.

Hypogonadism, which is highly prevalent in men with sickle cell disease (SCD), affects quality of life and causes great morbidity. The safety of testosterone replacement therapy (TRT) in SCD in relation to priapism episodes is relatively unknown. Our aim was to monitor the safety of TRT in a cohort of seven hypogonadal men with SCD. Testosterone undecanoate (Nebido) 1 g was administered intramuscularly to adult men with homozygous SCD (Hb SS) having hypogonadism [serum total testosterone ≤12.0 nmol/L (346 ng/dL), reference range 12.5-38.1 nmol/L (360-1098 ng/dL)] for 12 months. Serum total testosterone, haemoglobin, haematocrit, renal and liver function tests, glucose and PSA measurements were done at baseline and 12-month follow-up. Trough serum total testosterone, haemoglobin and haematocrit were measured three monthly. Priapism events and adverse drug events were assessed every 3 months. International Index of Erectile Function (IIEF), Androgen Deficiency in the Ageing Male (ADAM) and World Health Organization Quality of Life (WHOQOL) questionnaires were administered at baseline, 6 and 12 months. Seven men with a mean age of 34.4 years were treated. Median total testosterone increased from 10.6 to 11.2 nmol/L (p = 0.46). Median serum lactate dehydrogenase levels decreased from 1445 to 1143.5 IU/L (p < 0.05), while all other laboratory indices remained stable. Injection site pain was the most frequently reported adverse event, with no increases in painful crises, hypersensitivity or oedema. After TRT, there was no significant increase in priapism frequency. Median questionnaire scores were increased for the IIEF (46-68, p = 0.018), reduced for ADAM (5.0-2.0, p = 0.016) and unchanged for WHOQOL (98-103, p = 0.086). TRT using testosterone undecanoate with eugonadal intent for hypogonadism appears to be safe in men with SCD. This treatment does not appear to promote priapism occurrences and rather it possibly improves sexual function. Future prospective evaluations in larger groups of hypogonadal men with SCD are necessary to confirm these findings.

Drug ligand-induced activation of translocator protein (TSPO) stimulates steroid production by aged brown Norway rat Leydig cells.

Translocator protein (TSPO; 18 kDA) is a high-affinity cholesterol-binding protein that is integrally involved in cholesterol transfer from intracellular stores into mitochondria, the rate-determining step in steroid formation. Previous studies have shown that TSPO drug ligands are able to activate steroid production by MA-10 mouse Leydig tumor cells and by mitochondria isolated from steroidogenic cells. We hypothesized herein that the direct, pharmacological activation of TSPO might induce aged Leydig cells, which are characterized by reduced T production, to produce significantly higher levels of T both in vitro and in vivo. To test this, we first examined the in vitro effects of the TSPO selective and structurally distinct drug ligands N,N-dihexyl-2-(4-fluorophenyl)indole-3-acetamide (FGIN-1-27) and benzodiazepine 4'-chlorodiazepam (Ro5-4864) on steroidogenesis by Leydig cells isolated from aged (21-24 months old) and young adult (3-6 months old) Brown Norway rats. The ligands stimulated Leydig cell T production significantly, and equivalently, in cells of both ages, an effect that was significantly inhibited by the specific TSPO inhibitor 5-androsten-3,17,19-triol (19-Atriol). Additionally, we examined the in vivo effects of administering FGIN-1-27 to young and aged rats. In both cases, serum T levels increased significantly, consistent with the in vitro results. Indeed, serum T levels in aged rats administered FGIN-1-27 were equivalent to T levels in the serum of control young rats. Taken together, these results indicate that although there are reduced amounts of TSPO in aged Leydig cells, its direct activation is able to increase T production. We suggest that this approach might serve as a therapeutic means to increase steroid levels in vivo in cases of primary hypogonadism.

Modeling sporulation of Fusicladium carpophilum on nectarine twig lesions: relative humidity and temperature effects.

The production of conidia by Fusicladium carpophilum on twig lesions was quantitatively modeled as a function of temperature and duration of high relative humidity. During peak sporulation periods in 2007, 2008, and 2009, 1-year-old twigs bearing abundant overwintering lesions were removed from a heavily infected 'Redgold' nectarine orchard, placed in trays at high relative humidity (>95%), and incubated at eight constant temperatures for seven durations, resulting in a factorial design of 56 treatment combinations. Conidia numbers were estimated with a hemacytometer. Results from a six-stage modeling process indicated that, at any given temperature, spore production during high relative humidity periods increased in a monomolecular- to Gompertz-like pattern. The Richards model, with shape parameters of 0.79 to 0.90, was found to provide the best overall fit. When the asymptote and rate parameters were derived as functions of temperature using Gaussian and quadratic models, respectively, the duration of high relative humidity and temperature described 90 to 94% of the variation in conidia production. Predictions of the final models were highly correlated with observed levels of sporulation (r > 0.94; P < 0.0001), indicating an excellent fit to the data. The optimum temperature for sporulation, based on fitting a Gaussian model to the maximum sporulation levels at each temperature, was 17.9 to 20.2°C, with an overall average of 18.8°C. The derived models give a quantitative description of sporulation by F. carpophilum and may have potential use in simulators and forecasting systems.

Avanafil for the treatment of erectile dysfunction.

Erectile dysfunction is a prevalent condition afflicting millions of men worldwide and can have disastrous effects on a couple's quality of life. With the understanding of the physiology of erections and the discovery of cGMP-specific 3',5'-cyclic phosphodiesterase (PDE5) inhibitors, therapy for erectile dysfunction was revolutionized, and this class of medication became the first-line treatment option for this widespread condition. Despite the ease of use, efficacy and tolerability of the available PDE5 inhibitors, many men discontinue their use, usually related to lack of efficacy or development of adverse events. As such, research into the development of other medications within this drug class is extensive. Avanafil is a novel PDE5 inhibitor with favorable pharmacokinetic and pharmacodynamic profiles with good tolerability and limited adverse events. It was recently approved and launched in Korea, and is currently under review by the U.S. Food and Drug Administration. Its efficacy and purported role in the treatment for erectile dysfunction are reviewed here.

Increased expression of nestin in the major pelvic ganglion following cavernous nerve injury.

In an effort to identify neuronal repair mechanisms of the major pelvic ganglion (MPG), we evaluated changes in the expression of nestin, an intermediate filament protein and neural stem cell marker following cavernous nerve crush injury (CNI). We utilized two groups of Sprague Dawley rats: (i) sham and (ii) bilateral CNI. Erectile responses to cavernous nerve stimulation (CNS) were determined at 48 h in a subset of rats. The MPG was isolated and removed at 48 h after CNI, and nestin immunolocalization, protein levels and RNA expression were evaluated. At 48 h, erectile responses to CNS in CNI rats were substantially reduced (P<0.05; ∼70% decrease in intracavernous pressure/mean arterial pressure) compared with sham surgery controls. This coincided with a dramatic 10-fold increase (P<0.05) in nestin messenger RNA expression and protein levels in the MPG of rats with CNI. Immunoflourescence microscopy demonstrated that nestin upregulation after CNI occurred within the ganglion cell bodies and nerve fibers of the MPG. In conclusion, CNI induces nestin in the MPG. These data suggest that nestin may be involved in the regenerative process of the cavernous nerve following crush injury.

eNOS-uncoupling in age-related erectile dysfunction.

Aging is associated with ED. Although age-related ED is attributed largely to increased oxidative stress and endothelial dysfunction in the penis, the molecular mechanisms underlying this effect are not fully defined. We evaluated whether endothelial nitric oxide synthase (eNOS) uncoupling in the aged rat penis is a contributing mechanism. Correlatively, we evaluated the effect of replacement with eNOS cofactor tetrahydrobiopterin (BH(4)) on erectile function in the aged rats. Male Fischer 344 'young' (4-month-old) and 'aged' (19-month-old) rats were treated with a BH(4) precursor sepiapterin (10 mg/kg intraperitoneally) or vehicle for 4 days. After 1-day washout, erectile function was assessed in response to electrical stimulation of the cavernous nerve. Endothelial dysfunction (eNOS uncoupling) and oxidative stress (thiobarbituric acid reactive substances, TBARS) were measured by conducting western blot in penes samples. Erectile response was significantly reduced in aged rats, whereas eNOS uncoupling and TBARS production were significantly increased in the aged rat penis compared with young rats. Sepiapterin significantly improved erectile response in aged rats and prevented increase in TBARS production, but did not affect eNOS uncoupling in the penis of aged rats. These findings suggest that aging induces eNOS uncoupling in the penis, resulting in increased oxidative stress and ED.

Effect of QoI Fungicides on Colonization and Sporulation of Monilinia fructicola on Peach Fruit and Blossom Blight Cankers.

Three studies were conducted to examine the curative activity of azoxystrobin, trifloxystrobin, and pyraclostrobin + boscalid against Monilinia fructicola, causal agent of brown rot on peach. In the first study, 'Autumnglo' peach trees were treated with each of the three fungicides both before and after fruit inoculation. In the second study, the effects of fungicide active ingredient, rate/volume, and inoculation timing were examined on inoculated 'Suncrest' peach fruit. Results of these studies showed that sporulating area, on average across all treatments, was reduced by 15.9, 42.4, and 0.4% for azoxystrobin, trifloxystrobin, and pyraclostrobin + boscalid, respectively. In any single treatment, trifloxystrobin provided the greatest benefit with two consecutive sprays, reducing sporulating area by 53 to 60%. In contrast to sporulation activity, the three fungicides exhibited less of an inhibitory effect on fruit colonization. When applied at maximum labeled rates in the various treatments, azoxystrobin, trifloxystrobin, and pyraclostrobin + boscalid reduced colony growth, on average, by 12.3, 7.5, and 7.4%, respectively. Because the pathogen was inoculated into the mesocarp, this low level of activity against colonization may be due to a lack of deeper systemic movement of the fungicides into fruit tissue. In the final study, the three fungicides were examined for their antisporulant activity on blossom blight twig cankers. Unlike results observed on fruit, significant reductions in spore production on cankers were observed for all three fungicides. Azoxystrobin, trifloxystrobin, and pyraclostrobin + boscalid provided 56, 71, and 53% reductions, respectively, in the number of conidia produced per unit canker length. Overall results of these studies indicated that quinone outside inhibitor fungicides, in addition to their known protectant activity, also possess varying levels of curative activity against M. fructicola. In particular, trifloxystrobin demonstrated good antisporulant activity on both fruit infections and cankers.

Stem and endothelial progenitor cells in erection biology.

Erectile dysfunction (ED) is defined as the consistent inability to obtain or maintain an erection for satisfactory sexual relations. The past 20 years of basic science research on erection physiology has been devoted to investigating the pathogenesis of ED and has led to the conclusion that ED is predominately a disease of vascular origin with dramatic changes occurring in the endothelium. Research has also led to an understanding of the biochemical factors and intracellular mechanisms responsible for corporal smooth muscle contraction and relaxation and the influence of endothelium-derived relaxing factors. The development of methods to deliver both stem and endothelial cells to the penis has kindled a keen interest in treating ED with gene- and cell-based therapies. In this paper, erection physiology and stem cell biology is reviewed, and the potential application of novel cell-based therapies for the treatment of ED is discussed.

Endothelial dysfunction in diabetic erectile dysfunction.

Erectile dysfunction (ED) is highly prevalent in diabetes mellitus. Pathophysiological mechanisms underlying diabetes-associated ED are in large part due to endothelial dysfunction, which functionally refers to the inability of the endothelium to produce vasorelaxing messengers and to maintain vasodilation and vascular homeostasis. The precise mechanisms leading to endothelial dysfunction in the diabetic vasculature, including the penis, are not yet fully understood. Hyperglycemia affects endothelial nitric oxide synthase activity and nitric oxide production/bioavailability, nitric oxide-independent relaxing factors, oxidative stress, production and/or action of hormones, growth factors and/or cytokines, and generation and activity of opposing vasoconstrictors. Considering recent advances in the field of vascular biology and diabetes, the emphasis in this review is placed on the mechanisms of hyperglycemia-induced endothelial dysfunction in the pathophysiology of diabetes-associated ED.

Novel nitric oxide signaling mechanisms regulate the erectile response.

Nitric oxide (NO) is a physiologic signal essential to penile erection, and disorders that reduce NO synthesis or release in the erectile tissue are commonly associated with erectile dysfunction. NO synthase (NOS) catalyzes production of NO from L-arginine. While both constitutively expressed neuronal NOS (nNOS) and endothelial NOS (eNOS) isoforms mediate penile erection, nNOS is widely perceived to predominate in this role. Demonstration that blood-flow-dependent generation of NO involves phosphorylative activation of penile eNOS challenges conventional understanding of NO-dependent erectile mechanisms. Regulation of erectile function may not be mediated exclusively by neurally derived NO: Blood-flow-induced fluid shear stress in the penile vasculature stimulates phosphatidyl-inositol 3-kinase to phosphorylate protein kinase B, which in turn phosphorylates eNOS to generate NO. Thus, nNOS may initiate cavernosal tissue relaxation, while activated eNOS may facilitate attainment and maintenance of full erection.