Thresholds of adversity for endocrine disrupting substances: a conceptual case study.

For endocrine disrupting chemicals (EDC) the existence of "safe exposure levels", that is exposure levels that do not present an appreciable risk to human health is most controversially discussed, as is the existence of health-based reference values. Concerns have been especially raised that EDCs might not possess a threshold level such that no exposure level to EDCs can be considered safe. To explore whether or not threshold levels can be identified, we performed a screening exercise on 14 pesticidal and biocidal active substances previously identified as EDCs in the European Union. The respective substances are ideal subjects for case studies to review for endocrine activity and disruptive potential following well-defined regulatory assessment based on solid data to effectually establish adversity as consequence of endocrine disruption. Dimethomorph, metiram and propiconazole for which the weight of evidence demonstrating endocrine disruption was the strongest were used as subjects for further study. Epoxiconazole was additionally selected as its effects on the endocrine system are extensive. For all four substances, analysis of the toxicological data clearly indicated thresholds of adversity below which no adverse effects mediated through an endocrine mechanism were observed. Particular emphasis was placed on mechanistic considerations including homeostasis and the concept of adversity. As a proof of concept this study provides evidence that like other substances of toxicological concern EDCs have threshold levels for adversity. While for some EDCs the respective thresholds might indeed be very low this shows that, data allowing, for other EDCs sufficiently protective reference values can be derived.

Impact of Lifetime Obesity on Urinary Incontinence in the Women's Health Initiative.

PURPOSE: We assessed the impact of lifetime obesity on the development of urinary incontinence (UI). MATERIALS AND METHODS: Using data from the Women's Health Initiative, we evaluated the cumulative impact of obesity over a postmenopausal woman's lifetime on the development of UI. Analyses using logistic models assessed the relationship between overweight/obesity duration and the development of UI during the Women's Health Initiative study at year 3. RESULTS: Of the 15,420 women aged 50-79 years, 4,568 (30.0%) developed UI by year 3. When controlling for covariates, the duration of overweight years (OWY) and obese years (OBY) was significantly associated with overall UI. The number of OWY was associated with an increased risk of developing UI postmenopausally (OR 1.17, 95% CI 1.13-1.22) compared to those with 0 OWY. The number of OBY was associated with a higher risk of developing UI postmenopausally (OR 1.28, 95% CI 1.18-1.39). Severity of UI was also associated with higher OWY/OBY. Compared to participants who maintained normal weight, those who gained weight from age 18 to 50 years were more likely to report increased UI (OR 1.26, 95% CI 1.16-1.37), as did those who remained overweight/obese (OR 1.27, 95% CI 1.04-1.55). Those who lost weight reported no difference in rates of any UI. CONCLUSIONS: Chronic, increased body mass index status is associated with an elevated risk of UI later in life. Symptom severity also appears to be worsened with duration of increased body mass index status. Weight management should be supported throughout one's lifetime, as it may impact UI in later stages of life.

Adverse renal effects of NLRP3 inflammasome inhibition by MCC950 in an interventional model of diabetic kidney disease.

Activation of nucleotide-binding oligomerization domain-like receptor pyrin domain containing 3 (NLRP3) inflammasome has been reported in diabetic complications including diabetic kidney disease (DKD). However, it remains unknown if NLRP3 inhibition is renoprotective in a clinically relevant interventional approach with established DKD. We therefore examined the effect of the NLRP3-specific inhibitor MCC950 in streptozotocin-induced diabetic mice to measure the impact of NLRP3 inhibition on renal inflammation and associated pathology in DKD. We identified an adverse effect of MCC950 on renal pathology in diabetic animals. Indeed, MCC950-treated diabetic animals showed increased renal inflammation and macrophage infiltration in association with enhanced oxidative stress as well as increased mesangial expansion and glomerulosclerosis when compared with vehicle-treated diabetic animals. Inhibition of the inflammasome by MCC950 in diabetic mice led to renal up-regulation of markers of inflammation (Il1ß, Il18 and Mcp1), fibrosis (Col1, Col4, Fn1, α-SMA, Ctgf and Tgfß1) and oxidative stress (Nox2, Nox4 and nitrotyrosine). In addition, enhanced glomerular accumulation of pro-inflammatory CD68 positive cells and pro-oxidant factor nitrotyrosine was identified in the MCC950-treated diabetic compared with vehicle-treated diabetic animals. Collectively, in this interventional model of established DKD, NLRP3 inhibition with MCC950 did not show renoprotective effects in diabetic mice. On the contrary, diabetic mice treated with MCC950 exhibited adverse renal effects particularly enhanced renal inflammation and injury including mesangial expansion and glomerulosclerosis.

The Anatomical Relationships in the Space of Retzius for Penile Implants: An MRI Analysis.

BACKGROUND: The 3-piece inflatable penile prosthesis includes an easy-to-use pump and fluid filled reservoir which is placed in either the space of Retzius (SOR) or in an alternative ectopic location. Reservoir placement in the SOR is a blind procedure despite the SOR being surrounded by many critical structures. To date only a handful of cadaveric studies have described the relevant anatomy. AIM: To use magnetic resonance imaging (MRI) as an in-vivo model to study relevant retropubic anatomy critical for SOR reservoir placement. METHODS: The study population included men with elevated prostate specific antigen or biopsy proven prostate cancer who (i) underwent pelvic MRI, (ii) without prior pelvic or inguinal surgery, and (iii) without pelvic radiation therapy. All MRIs were completed with a 3-Tesla scanner and endorectal coil. Both T1 and T2 weighted images were captured in both axial and sagittal planes. All images were reviewed by 2 independent reviewers under the supervision of a dedicated body MRI radiologist. Bladder volume was calculated using an ellipsoid formula. OUTCOMES: Relevant measurements included (i) the distance between the external inguinal ring (EIR) at the level of the pubic tubercle to the external iliac vein (EIV), (ii) the distance from the EIR at the pubic tubercle to the bladder (accounting for bladder volume) and (iii) the distance from the midline pubic symphysis to the bladder (accounting for bladder volume). Pearson correlation was used to determine correlated measurements. RESULTS: A total of 24 patients were included. Median participant age was 63 years (interquartile range, 59-66). The mean EIR-EIV distance was 3.0 ± 0.4 cm, the mean EIR-bladder distance was 1.8 ± 1.0 cm and the mean distance from the superior pubic symphysis to bladder was 0.9 ± 0.3 cm. There was a weak correlation between bladder volume and distance between the EIR and bladder (r = -0.30, P = .16). CLINICAL IMPLICATIONS: The use of MRI as an in-vivo model is a high-fidelity tool to study real time unaltered anatomy and allows for surgical preparation, diagnosis of anatomic variants and acts as a valuable teaching tool. STRENGTHS & LIMITATIONS: This is the first in-vivo model to report relevant retropubic anatomy in penile implant surgery. Our study is limited by sample size and inclusion of participants with no history of prior pelvic intervention. CONCLUSION: We demonstrate the utility of MRI as an in-vivo model, as opposed to cadaveric models, for the understanding of relevant retropubic anatomy for implant surgeons. Punjani N, Monteiro L, Sullivan J F et al. The Anatomical Relationships in the Space of Retzius for Penile Implants: An MRI Analysis. J Sex Med 2021;18:1830-1834.

Climacturia After Radical Prostatectomy: MRI-Based Predictors.

BACKGROUND: After radical prostatectomy (RP), climacturia is a prevalent and distressing problem. To date, no specific predictors have been identified. AIM: In this analysis, we sought to find associated pelvic magnetic resonance imaging (MRI) parameters. METHODS: We identified all men in our departmental database who (i) had climacturia post-RP, ≥3 episodes; (ii) underwent a pre-RP endorectal MRI; (iii) had no radiation or androgen deprivation therapy (ADT). Soft tissue and bony dimensions were measured by 2 raters blinded to clinical and pathological data. OUTCOMES: MRI parameters included the following: maximum height, width, and depth of prostate, prostate volume, urethral width and length, lower conjugate of pelvis, bony femoral width, outer and inner levator distances and thickness. Point-biserial correlations were run on univariate associations. Logistic regression was used for the multivariable model. RESULTS: 194 consecutive pre-RP MRI studies were reviewed (56 men with and 138 without climacturia). Mean age was 60 ± 7 years, average time post-RP at assessment, 7 ± 7 months. Of MRI parameters, urethral width (r = 0.13, P = .03) and lower conjugate (r = 0.12, P = .05) were associated with presence of persistent climacturia. 2 others met criteria for multivariable analysis, prostate depth and outer levator distance. Of the non-MRI parameters, none were significantly related to climacturia and only body mass index (BMI) met criteria for multivariable analysis. On multivariable analysis, only urethral width was associated with climacturia (OR = 1.23, 95% CI: 1.01-1.49, P = .04); the wider the urethra, greater the chance of climacturia. CLINICAL IMPLICATIONS: Improved ability to predict the occurrence of orgasm-associated incontinence in the preoperative setting. STRENGTHS AND LIMITATIONS: Limitations include the fact that the MRI endorectal probe may have distorted pelvic tissues during imaging and that our study population size was small. However, prospective data collection, blinded measurements by 2 trained readers, and rigorous statistical analysis should be considered strengths. CONCLUSION: By identifying preoperative risk factors, such as urethral width on MRI, we may be able to better understand the pathophysiology of this condition and furthermore may permit us to better counsel men regarding this postoperative outcome. Sullivan JF, Ortega Y, Matsushita K, et al. Climacturia After Radical Prostatectomy: MRI-Based Predictors. J Sex Med 2020;17:1723-1728.

Management of Climacturia During Inflatable Penile Prosthesis Surgery.

Radical prostatectomy, the preferred treatment option for organ-confined prostate cancer, is associated with a wide variety of sexual dysfunctions including erectile and orgasmic dysfunctions. Climacturia is a type of orgasmic dysfunction that has been reported to occur in 20-60% of men after radical prostatectomy. Several treatment strategies for climacturia have been evaluated and recommended including behavioral changes, use of special devices, medications, specialized therapies, and surgeries. Inflatable penile prosthesis implantation might be the treatment of choice when conservative management approaches fail to treat erectile dysfunction. In this review article, the different options and approaches for the management of climacturia during inflatable penile prosthesis surgery will be discussed.

Clinical predictors and risk factors for vaginal mesh extrusion.

PURPOSES: Our study aims to enhance the accuracy of the clinical diagnosis in patients with vaginal mesh extrusion following transvaginal mesh placement for pelvic organ prolapse using significant clinical parameters and risk factors. METHODS: All patients who underwent vaginal mesh removal were retrospectively reviewed from January 2000 to May 2014. Eligible patients were divided into two groups according to the presence of vaginal mesh extrusion. RESULTS: A total of 862 patients, 798 were included. 357 (44.7%) had evidence of vaginal mesh extrusion, and 441 (55.3%) had no evidence of vaginal mesh extrusion. The mean age of the vaginal mesh extrusion group was slightly higher than in the group without vaginal mesh extrusion (58.7 ± 11.2 vs. 56.4 ± 11.5, respectively; p = 0.002). From multivariate analysis, the significant clinical correlations for vaginal mesh extrusion were vaginal bleeding [60 (16.9) vs. 14 (3.2%), p < 0.001], hispareunia [48 (13.5) vs. 15 (3.4%), OR = 4.163, p < 0.001], and vaginal discharge [45 (12.6) vs. 18 (4.1%), p = 0.001]. The risk factors were multiple mesh implantations [218 (67.06) vs. 175 (39.68%), p < 0.001] and menopause [314 (88) vs. 364 (82.7%), p = 0.145]. Demographic data, including BMI, sexual activity, vaginal atrophy, both local and systemic hormonal use, smoking status, and hysterectomy status, were not significantly different, as well as the clinical symptoms including dyspareunia, vaginal infection, and symptomatic vaginal bulge. CONCLUSIONS: Vaginal bleeding, hispareunia, and vaginal discharge were the most significant clinical predictors for raising suspicion of vaginal mesh extrusion. Multiple mesh implantations were a significant risk factor for extrusion.

TSPO in a murine model of Sandhoff disease: presymptomatic marker of neurodegeneration and disease pathophysiology.

Translocator protein (18 kDa), formerly known as the peripheral benzodiazepine receptor (PBR), has been extensively used as a biomarker of active brain disease and neuroinflammation. TSPO expression increases dramatically in glial cells, particularly in microglia and astrocytes, as a result of brain injury, and this phenomenon is a component of the hallmark response of the brain to injury. In this study, we used a mouse model of Sandhoff disease (SD) to assess the longitudinal expression of TSPO as a function of disease progression and its relationship to behavioral and neuropathological endpoints. Focusing on the presymptomatic period of the disease, we used ex vivo [(3)H]DPA-713 quantitative autoradiography and in vivo [(125)I]IodoDPA-713 small animal SPECT imaging to show that brain TSPO levels markedly increase prior to physical and behavioral manifestation of disease. We further show that TSPO upregulation coincides with early neuronal GM2 ganglioside aggregation and is associated with ongoing neurodegeneration and activation of both microglia and astrocytes. In brain regions with increased TSPO levels, there is a differential pattern of glial cell activation with astrocytes being activated earlier than microglia during the progression of disease. Immunofluorescent confocal imaging confirmed that TSPO colocalizes with both microglia and astrocyte markers, but the glial source of the TSPO response differs by brain region and age in SD mice. Notably, TSPO colocalization with the astrocyte marker GFAP was greater than with the microglia marker, Mac-1. Taken together, our findings have significant implications for understanding TSPO glial cell biology and for detecting neurodegeneration prior to clinical expression of disease.

Deformity stabilization and improvement in men with untreated Peyronie's disease.

OBJECTIVE: To define predictors of the deformity stabilisation and improvement in men with untreated Peyronie's disease (PD). PATIENTS AND METHODS: The study population consisted of patients with PD-associated uniplanar curvature, who opted for no treatment and were followed for at least 12 months. All patients had deformity assessment (DA) performed on initial presentation and at follow-up. Stabilisation of PD was defined as no change between DAs (±10°), while improvement and progression were defined as ≥10° change. Patients were subdivided into different groups based on time to presentation: ≤6 months (A), 7-12 months (B), and 13-18 months (C). Multivariable analysis was used to define predictors of stabilisation and improvement. RESULTS: In all, 176 men met the inclusion criteria. The mean age was 54 years, with a mean (sd) PD duration of 9 (12) months and mean curvature of 42 (27)°. In all, 67% of the entire population had no change in deformity over time, 12% improved with a mean (sd) change of 27 (14)°, and 21% worsened with a mean (sd) change of 22 (11)°. On multivariate analysis, predictors of stabilisation included: time to presentation of >6 months (odds ratio [OR] 2.4, P < 0.01), per decade increase in age (OR 1.5, P < 0.05), and age (r = 0.32, P < 0.05). Predictors of improvement included: time to presentation of ≤6 months (OR 4.1, P < 0.001), and per decade decrease in age (OR 2.1, P < 0.01). CONCLUSIONS: In men with uniplanar curvature, PD stabilisation and improvement rates change with time-to-presentation and patient age. These data may aid in counselling patients with PD.

Comparison of laparoendoscopic single site (LESS) and conventional laparoscopic donor nephrectomy at a single institution.

UNLABELLED: WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: Most transplant centres harvest living donor kidneys via a conventional laparoscopic surgical approach. Laparoendoscopic single-site donor nephrectomy (LESS-DN) is a relatively novel minimally invasive approach that allows the surgery to be performed via a single incision. This technique may be advantageous in decreasing surgical morbidity and improving cosmetic outcomes, thus plausibly reducing the barriers to kidney donation. The study demonstrates the safety and feasibility of LESS-DN in a large consecutive series of kidney donors. Comparative analysis between LDN and LESS-DN showed that there was a significant decrease in intra-operative blood loss and allograft warm ischaemia time in the LESS-DN group, but also a significant increase in operating time. Other peri-operative outcomes were similar between the two approaches. Evaluation of the LESS-DN cases alone revealed that, the operating times did not significantly change through the course of the series. Using this outcome as a surrogate for technical difficulty suggests a relatively shallow learning curve for LESS-DN. OBJECTIVE: To present a comparative analysis of peri-operative outcomes for >200 cases of conventional laparoscopic donor nephrectomy (LDN) and laparoendoscopic single site donor nephrectomy (LESS-DN). PATIENTS AND METHODS: From 2006 to 2011, 213 donor nephrectomies were performed by two surgeons (R.E.L and W.A.M.) at a tertiary transplant centre. The approach changed from conventional LDN to LESS-DN over the course of the series. The two approaches were compared retrospectively and evaluated for differences in peri-operative outcomes. Statistical significance was assessed using Student's t-test and chi-squared analysis. RESULTS: A total of 111 patients underwent LDN and 102 patients underwent LESS-DN. Total operating time was significantly longer in the LESS-DN group (206.1 vs 181.9 min, P < 0.001), but LESS-DN resulted in less intra-operative blood loss (61.5 mL vs 85.9 mL, P < 0.001) and shorter warm ischaemia times (4.4 vs 5.0 min, P = 0.01). There were no significant differences in analgesic requirements, subjective pain scores, length of hospital stay, postoperative graft function, or donor's postoperative glomerular filtration rate between the two approaches. Complication rates were low regardless of the approach, and there were no major complications (>grade II) in the LESS-DN group. CONCLUSIONS: In experienced hands, LESS-DN results in peri-operative outcomes similar to those of conventional LDN without compromising donor safety, while providing a desirable cosmetic result. For surgeons familiar with LDN, transitioning to the LESS approach using this technique appears to have a relatively short learning curve.

Ameliorating diabetes-associated atherosclerosis and diabetic nephropathy through modulation of soluble guanylate cyclase.

Diabetes mellitus (DM) is an independent risk factor for micro- and macrovascular complications such as nephropathy and atherosclerosis respectively, which are the major causes of premature morbidity and mortality in Type 1 and Type 2 diabetic patients. Endothelial dysfunction is the critical first step of vascular disease and is characterized by reduced bioavailability of the essential endothelial vasodilator, nitric oxide (NO), coupled with an elevation in inflammation and oxidative stress. A novel pathway to bolster NO activity is to upregulate soluble guanylate cyclase (sGC), an enzyme responsible for mediating the protective actions of NO. Two classes of sGC modulators exist, activators and stimulators, with differing sensitivity to oxidative stress. In this study, we investigated the therapeutic effects of the sGC stimulator BAY 41-2272 (Bay 41) and the sGC activator BAY 60-2770 (Bay 60) on endpoints of atherosclerosis and renal disease as well as inflammation and oxidative stress in diabetic Apolipoprotein E knockout (ApoE-/-) mice. We hypothesized that under oxidative conditions known to accompany diabetes, sGC activation might be more efficacious than sGC stimulation in limiting diabetic vascular complications. We demonstrate that Bay 60 not only significantly decreased nitrotyrosine staining (P < 0.01) and F4/80 positive cells by 75% (P < 0.05), but it also significantly reduced total plaque area (P < 0.05) and improved endothelial function (P < 0.01). Our data suggest an important anti-atherogenic role for Bay 60 accompanied by reduced oxidative stress and inflammation under diabetic settings. Treatment with the stimulator Bay 41, on the other hand, had minimal effects or caused no changes with respect to cardiovascular or renal pathology. In the kidneys, treatment with Bay 60 significantly lessened urinary albuminuria, mesangial expansion and nitrotyrosine staining under diabetic conditions. In summary, our head-to-head comparator is the first preclinical study to show that a sGC activator is more efficacious than a sGC stimulator for the treatment of diabetes-associated vascular and renal complications.

Cardiovascular characterisation of a novel mouse model that combines hypertension and diabetes co-morbidities.

Epidemiologic data suggest that the prevalence of hypertension in patients with diabetes mellitus is ∼1.5-2.0 times greater than in matched non-diabetic patients. This co-existent disease burden exacerbates cardiac and vascular injury, leading to structural and functional changes to the myocardium, impaired cardiac function and heart failure. Oxidative stress and persistent low-grade inflammation underlie both conditions, and are identified as major contributors to pathological cardiac remodelling. There is an urgent need for effective therapies that specifically target oxidative stress and inflammation to protect against cardiac remodelling. Animal models are a valuable tool for testing emerging therapeutics, however, there is a notable lack of appropriate animal models of co-morbid diabetes and hypertension. In this study, we describe a novel preclinical mouse model combining diabetes and hypertension to investigate cardiac and vascular pathology of co-morbid disease. Type 1 diabetes was induced in spontaneously hypertensive, 8-week old, male Schlager (BPH/2) mice via 5 consecutive, daily injections of streptozotocin (55 mg/kg in citrate buffer; i.p.). Non-diabetic mice received citrate buffer only. After 10 weeks of diabetes induction, cardiac function was assessed by echocardiography prior to post-mortem evaluation of cardiomyocyte hypertrophy, interstitial fibrosis and inflammation by histology, RT-PCR and flow cytometry. We focussed on the oxidative and inflammatory stress pathways that contribute to cardiovascular remodelling. In particular, we demonstrate that markers of inflammation (monocyte chemoattractant protein; MCP-1), oxidative stress (urinary 8-isoprostanes) and fibrosis (connective tissue growth factor; CTGF) are significantly increased, whilst diastolic dysfunction, as indicated by prolonged isovolumic relaxation time (IVRT), is elevated in this diabetic and hypertensive mouse model. In summary, this pre-clinical mouse model provides researchers with a tool to test therapeutic strategies unique to co-morbid diabetes and hypertension, thereby facilitating the emergence of novel therapeutics to combat the cardiovascular consequences of these debilitating co-morbidities.

Peyronie's disease in teenagers.

INTRODUCTION: Peyronie's disease (PD) is commonly seen in middle-aged men, and little is known about this condition in teenagers. AIM: To investigate the characteristics of PD in teenagers. METHODS: The findings were compared between patients with the disease who were teenagers with those over 40 years of age. Statistical analyses were conducted to define differentiating features between these two groups. MAIN OUTCOME MEASURES: The demographics, clinical features, and associated comorbidities of patients with PD were reviewed. RESULTS: Thirty-two teenaged males were evaluated for PD in a single institution over a 10-year period. The median age for our cohort was 18 (15-19) years. Forty-five percent of patients had already been seen by another urologist, and 28% had been told they did not have PD. The mean duration of PD before seeking medical care in our cohort was 3 ± 1 months. Sixteen percent of patients reported antecedent penile trauma, half of which happened during coitus or masturbation, and 18% of patients had hemoglobin (Hb) A1c levels > 5%. Dupuytren's contracture was not seen in this population. Twenty-two percent of patients presented with penile pain. Subsequent ED was seen in 37% of patients. Multiple noncontiguous plaques were seen in 37% of patients. Twelve percent were previously treated with vitamin E, while another 12% had previous intralesional verapamil. High distress was reported by 94% of patients. Thirty-four percent sought medical attention for anxiety/mood disorder, and 28% had a negative encounter with a sexual partner related to PD. All of the 32 patients had penile curvature with a mean of 32 ± 12 degrees. Seventy-two percent of the patients had dorsal curvature while 22% had an associated deformity. Using duplex Doppler ultrasound, 12% had a calcified plaque, while none of the patients had abnormal hemodynamics. When compared with PD in adults, teenagers had greater than seven times the prevalence of multiple noncontiguous plaques (37% vs. 5%). Also, the prevalence of HbA1c level > 5% was higher in the teenagers as well (18% vs. 5%). CONCLUSIONS: PD does occur in teenagers often causing high distress levels. Compared to older adults, teenagers often present earlier, and more commonly have elevated HbA1c level and increased number of plaques at presentation.

Animal models of diabetes-associated vascular diseases: an update on available models and experimental analysis.

Diabetes is a chronic metabolic disorder associated with the accelerated development of macrovascular (atherosclerosis and coronary artery disease) and microvascular complications (nephropathy, retinopathy and neuropathy), which remain the principal cause of mortality and morbidity in this population. Current understanding of cellular and molecular pathways of diabetes-driven vascular complications, as well as therapeutic interventions has arisen from studying disease pathogenesis in animal models. Diabetes-associated vascular complications are multi-faceted, involving the interaction between various cellular and molecular pathways. Thus, the choice of an appropriate animal model to study vascular pathogenesis is important in our quest to identify innovative and mechanism-based targeted therapies to reduce the burden of diabetic complications. Herein, we provide up-to-date information on available mouse models of both Type 1 and Type 2 diabetic vascular complications as well as experimental analysis and research outputs. LINKED ARTICLES: This article is part of a themed issue on Preclinical Models for Cardiovascular disease research (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.5/issuetoc.

Translocator protein (18 kDa)/peripheral benzodiazepine receptor specific ligands induce microglia functions consistent with an activated state.

In the brain, translocator protein (18 kDa) (TSPO), previously called peripheral benzodiazepine receptor (PBR), is a glial protein that has been extensively used as a biomarker of brain injury and inflammation. However, the functional role of TSPO in glial cells is not well characterized. In this study, we show that the TSPO-specific ligands R-PK11195 (PK) and Ro5-4864 (Ro) increased microglia proliferation and phagocytosis with no effect on migration. Both ligands increased reactive oxygen species (ROS) production, and this effect may be mediated by NADPH-oxidase. PK and Ro also produced a small but detectable increase in IL-1ß release. We also examined the effect of PK and Ro on the expression of proinflammatory genes and cytokine release in lipopolysaccharide (LPS) and adenosine triphosphate (ATP) activated microglia. PK or Ro had no effect on LPS-induced increase of pro-inflammatory genes, but they both decreased the ATP-induced increase of COX-2 gene expression. Ro, but not PK, enhanced the LPS-induced release of IL-1ß. However, Ro decreased the ATP-induced release of IL-1ß and TNF-α, and PK decreased the ATP-induced release of TNF-α. Exposure to Ro in the presence of LPS increased the number of apoptotic microglia, an effect that could be blocked by PK. These findings show that TSPO ligands modulate cellular functions consistent with microglia activation. Further, when microglia are activated, these ligands may have therapeutic potential by reducing the expression of pro-inflammatory genes and cytokine release. Finally, Ro-like ligands may be involved in the elimination of activated microglia via apoptosis.

Defining predictors of response to intralesional verapamil injection therapy for Peyronie's disease.

OBJECTIVE: • To assess factors that predict penile curvature responses to intralesional verapamil (ILV) injection therapy for men with Peyronie's disease (PD). PATIENTS AND METHODS: • Men with PD for <1 year were assessed at baseline and after 3 months of bi-monthly ILV-injection therapy. Curvature was assessed at the time of maximum penile rigidity. • Univariate relationships were tested with correlation or chi-square analyses. • Multivariate analyses included logistic and linear regression. • We analysed curvature improvement, defined as a decrease of ≥10 ° from baseline. Additionally, the relationship between curvature outcomes and patient age and degree of baseline penile curvature were assessed. RESULTS: • Data from 131 men were included and the rates of penile curvature change were:26% improved, 12% worsened, and 62% stable. • Age (r=-0.24, P < 0.01) and larger baseline penile curvature (r= 0.33, P < 0.01) were associated with improved curvature on univariate analysis. • On multivariate analysis (logistic regression), both age [odds ratio (OR) 0.93, P < 0.01, 95%CI 0.89-0.97] and larger baseline penile curvature (OR 1.07, P < 0.01, 95%CI 1.04-1.11) were associated with improvements in curvature after ILV-injection therapy. • Improvements in curvature were associated with age (≤40 years vs >40 years; OR 0.27, P < 0.05, 95%CI 0.10-0.75) and degree of penile curvature at baseline (≤30 ° vs >30 °; OR 9.12, P < 0.01, 95%CI 1.94-42.84) when dichotomized as indicated. CONCLUSION: • Younger age and larger baseline penile curvature were predictive of favourable curvature outcomes. • Analysis of dichotomized variables suggests that age and baseline curvature thresholds may be important to consider when deciding on ILV as a therapeutic strategy for PD.

Erectile dysfunction after plaque incision and grafting: short-term assessment of incidence and predictors.

INTRODUCTION: Plaque incision and grafting (PIG) surgery for Peyronie's disease (PD) is a recognized management strategy. One of the recognized complications of PIG surgery is the development of postoperative erectile dysfunction (ED). AIM: To determine the incidence of ED after PIG surgery and attempt to define predictors of ED development. METHODS: All patients underwent preoperative cavernosometry. Grafting was performed with either cadaveric pericardium (Tutoplast) or intestinal submucosa (Surgisis). Prior to 2006, the procedure used an H-type incision, whereas after this date, the Egydio approach has been used. MAIN OUTCOME MEASURES: Men undergoing PIG completed preoperative and 6-month postoperative International Index of Erectile Function (IIEF) questionnaires. RESULTS: 56 patients were analyzed. Mean patient and partner ages were 57 ± 22 and 54 ± 18 years, respectively. Mean duration of PD at the time of PIG was 22 ± 9 months. Seventy-five percent had curvature alone, 11% had hourglass/indentation deformity, and the remainder had combined curvature/indentation. Mean preoperative curvature was 52 ± 23°. Fifty-two had grafting with Tutoplast, while four had grafting with Surgisis. All men at baseline were capable of generating a penetration rigidity erection. Preoperatively, 50% of men had cavernosal insufficiency and 21% had venous leak (baseline and postoperative erectile function [EF] domain scores were 23 ± 4 and 17 ± 9, respectively [P < 0.01]). Forty-six percent of men experienced a ≥6-point decrease in EF domain score after PIG. The predictors of a ≥6-point reduction in IIEF-EF domain score on multivariable analysis were degree of preoperative curvature, type of plaque incision, patient age, and baseline venous leak. Conclusions. Almost one-half of men had significant reduction in their erectile rigidity after PIG. Reduction was predicted by larger baseline curvature, the Egydio plaque incision technique, older patient age, and the presence of venous leak at baseline. Based on these data, we discourage older men, those with venous leak, and those with profound curvature from considering PIG surgery.

Specific NLRP3 Inhibition Protects Against Diabetes-Associated Atherosclerosis.

Low-grade persistent inflammation is a feature of diabetes-driven vascular complications, in particular activation of the Nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome to trigger the maturation and release of the inflammatory cytokine interleukin-1ß (IL-1ß). We investigated whether inhibiting the NLRP3 inflammasome, through the use of the specific small-molecule NLRP3 inhibitor MCC950, could reduce inflammation, improve vascular function, and protect against diabetes-associated atherosclerosis in the streptozotocin-induced diabetic apolipoprotein E-knockout mouse. Diabetes led to an approximately fourfold increase in atherosclerotic lesions throughout the aorta, which were significantly attenuated with MCC950 (P < 0.001). This reduction in lesions was associated with decreased monocyte-macrophage content, reduced necrotic core, attenuated inflammatory gene expression (IL-1ß, tumor necrosis factor-α, intracellular adhesion molecule 1, and MCP-1; P < 0.05), and reduced oxidative stress, while maintaining fibrous cap thickness. Additionally, vascular function was improved in diabetic vessels of mice treated with MCC950 (P < 0.05). In a range of cell lines (murine bone marrow-derived macrophages, human monocytic THP-1 cells, phorbol 12-myristate 13-acetate-differentiated human macrophages, and aortic smooth muscle cells from humans with diabetes), MCC950 significantly reduced IL-1ß and/or caspase-1 secretion and attenuated leukocyte-smooth muscle cell interactions under high glucose or lipopolysaccharide conditions. In summary, MCC950 reduces plaque development, promotes plaque stability, and improves vascular function, suggesting that targeting NLRP3-mediated inflammation is a novel therapeutic strategy to improve diabetes-associated vascular disease.

Cumulative dietary risk assessment of chronic acetylcholinesterase inhibition by residues of pesticides.

A retrospective cumulative risk assessment of dietary exposure to pesticide residues was conducted for chronic inhibition of acetylcholinesterase. The pesticides considered in this assessment were identified and characterised in a previous scientific report on the establishment of cumulative assessment groups of pesticides for their effects on the nervous system. The exposure assessments used monitoring data collected by Member States under their official pesticide monitoring programmes in 2016, 2017 and 2018, and individual food consumption data from 10 populations of consumers from different countries and from different age groups. Exposure estimates were obtained by means of a two-dimensional probabilistic model, which was implemented in SAS ® software. The characterisation of cumulative risk was supported by an uncertainty analysis based on expert knowledge elicitation. For each of the 10 populations, it is concluded with varying degrees of certainty that cumulative exposure to pesticides contributing to the chronic inhibition of acetylcholinesterase does not exceed the threshold for regulatory consideration established by risk managers.

Predicting delay in presentation in men with Peyronie's disease.

INTRODUCTION: Many men with Peyronie's disease (PD) delay presentation to a urologist. The reasons for this are unclear. AIM: To define the differences in men who present early compared to those presenting in a delayed fashion and to determine predictors of delayed presentation. METHODS: A retrospective analysis of all patients presenting for the first medical evaluation of PD. All patients underwent a standard history and physical examination and had a standardized deformity assessment. Demographic and PD parameters were recorded. MAIN OUTCOME MEASURES: Statistical comparison was used to define factors that were different between early and delayed presenters and multivariable analysis was used to define predictors of presentation >12 months. RESULTS: 482 patients were analyzed, 61% presenting ≤12 months, 39% >12 months. Mean patient age was 52 ± 13 years and mean duration of PD was 17 ± 30 months. Mean measured curvature was 42° ± 19°. Multivariable analysis revealed that delayed presentation patients were significantly more likely to be older (odds ratio [OR] = 4.0), to be in long-term relationships (OR = 3.6), to have dorsal curvature (OR = 2.5), to have curvature <45° (OR = 3.3), to be heterosexual (OR = 2.0), and to have simple deformity (OR = 1.5). CONCLUSIONS: One-third of men with PD presented in a delayed fashion and they tended to be older, to be in long-term relationships, to have dorsal curvature, or to have simple deformity.