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The prevalence of substance use globally is rising and is highest among men of reproductive age. In Africa, and South and Central America, cannabis use disorder is most prevalent and in Eastern and South-Eastern Europe, Central America, Canada and the USA, opioid use disorder predominates. Substance use might be contributing to the ongoing global decline in male fertility, and emerging evidence has linked paternal substance use with short-term and long-term adverse effects on offspring development and outcomes. This trend is concerning given that substance use is increasing, including during the COVID-19 pandemic. Preclinical studies have shown that male preconception substance use can influence offspring brain development and neurobehaviour through epigenetic mechanisms. Additionally, human studies investigating paternal health behaviours during the prenatal period suggest that paternal tobacco, opioid, cannabis and alcohol use is associated with reduced offspring mental health, in particular hyperactivity and attention-deficit hyperactivity disorder. The potential effects of paternal substance use are areas in which to focus public health efforts and health-care provider counselling of couples or individuals interested in conceiving., (© 2024. Springer Nature Limited.)

Background: With the growing availability of cannabis and the popularization of additional routes of cannabis use beyond smoking, including edibles, the prevalence of cannabis use in pregnancy is rapidly increasing. However, the potential effects of prenatal cannabis use on fetal developmental programming remain unknown., Results: We designed this study to determine whether the use of edible cannabis during pregnancy is deleterious to the fetal and placental epigenome. Pregnant rhesus macaques consumed a daily edible containing either delta-9-tetrahydrocannabinol (THC) (2.5 mg/7 kg/day) or placebo. DNA methylation was measured in 5 tissues collected at cesarean delivery (placenta, lung, cerebellum, prefrontal cortex, and right ventricle of the heart) using the Illumina MethylationEPIC platform and filtering for probes previously validated in rhesus macaque. In utero exposure to THC was associated with differential methylation at 581 CpGs, with 573 (98%) identified in placenta. Loci differentially methylated with THC were enriched for candidate autism spectrum disorder (ASD) genes from the Simons Foundation Autism Research Initiative (SFARI) database in all tissues. The placenta demonstrated greatest SFARI gene enrichment, including genes differentially methylated in placentas from a prospective ASD study., Conclusions: Overall, our findings reveal that prenatal THC exposure alters placental and fetal DNA methylation at genes involved in neurobehavioral development that may influence longer-term offspring outcomes. The data from this study add to the limited existing literature to help guide patient counseling and public health polices focused on prenatal cannabis use in the future., (© 2023. The Author(s).)

Objective: To determine whether discontinuation of delta-9-tetrahydrocannabinol (THC) use mitigates THC-associated changes in male reproductive health using a rhesus macaque model of daily THC edible consumption., Design: Research animal study., Setting: Research institute environment., Patient(s): Adult male rhesus macaques (age, 8-10 years; n = 6)., Intervention(s): Chronic daily THC edible administration at medically and recreationally relevant contemporary doses followed by cessation of THC use., Main Outcome Measure(s): Testicular volume, serum male hormones, semen parameters, sperm deoxyribonucleic acid (DNA) fragmentation, seminal fluid proteomics, and whole genome bisulfite sequencing of sperm DNA., Result(s): Chronic THC use resulted in significant testicular atrophy, increased gonadotropin levels, decreased serum sex steroid levels, changes in seminal fluid proteome, and increased DNA fragmentation with partial recovery after discontinuation of THC use. For every increase of 1 mg/7 kg/day in THC dosing, there was a significant decrease in the total testicular volume bilaterally by 12.6 cm 3 (95% confidence interval [CI], 10.6-14.5), resulting in a 59% decrease in volume. With THC abstinence, the total testicular volume increased to 73% of its original volume. Similarly, with THC exposure, there were significant decreases in the mean total testosterone and estradiol levels and a significant increase in the follicle-stimulating hormone level. With increasing THC dose, there was a significant decrease in the liquid semen ejaculate volume and weight of coagulum; however, no other significant changes in the other semen parameters were noted. After discontinuing THC use, there was a significant increase in the total serum testosterone level by 1.3 ng/mL (95% CI, 0.1-2.4) and estradiol level by 2.9 pg/mL (95% CI, 0.4-5.4), and the follicle-stimulating hormone level significantly decreased by 0.06 ng/mL (95% CI, 0.01-0.11). Seminal fluid proteome analysis revealed differential expression of proteins enriched for processes related to cellular secretion, immune response, and fibrinolysis. Whole genome bisulfite sequencing identified 23,558 CpGs differentially methylated in heavy-THC vs. pre-THC sperm, with partial restoration of methylation after discontinuation of THC use. Genes associated with altered differentially methylated regions were enriched for those involved in the development and function of the nervous system., Conclusion(s): This is the first study demonstrating that discontinuation of chronic THC use in rhesus macaques partially restores adverse impacts to male reproductive health, THC-associated sperm differentially methylated regions in genes important for development, and expression of proteins important for male fertility., (Copyright © 2023 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

The prevalence of males on testosterone therapy (TT) seeking vasectomy reversal (VR) is rising. As medical therapy (MT) to recover spermatogenesis after TT has been previously described, our study's objective is to present our institution's management and outcomes of VR in men previously on TT. We performed a retrospective case series of vasectomy patients on TT with subsequent VR by a single microsurgeon between March, 2010 and March, 2022. 14 men undergoing VR during the study period met inclusion criteria. The median age at VR was 43 years with a median obstructive interval of 11 years. Median time from MT to VR was 5 months. Post-operative semen analysis was performed in 10 men and all demonstrated patency. 2 patients had very low sperm counts secondary to continuing TT following VR contrary to medical advice and 5 men with patency achieved pregnancy. Our study noted a high rate of vasovasostomy (VV) (96%) and sustained patency despite a 12-year median obstructive interval. Our findings support favorable outcomes with less stringent VV indications after MT in patients previously on TT that desire VR. The use of MT reduces the recommended wait times for VR after TT discontinuation by more than half., (© 2022. The Author(s).)

Cannabis is the most commonly used federally illegal drug in the United States and the world, especially among people of reproductive age. In addition, the potency of cannabis products has increased significantly in the past decade. This is concerning because the available evidence suggests an adverse effect of cannabis exposure on male and female reproductive health. Exposure to cannabinoids may have differential impacts on female reproductive health across a woman's lifespan, from preconception to pregnancy, throughout lactation, and during menopause. Moreover, cannabis use has been associated with adverse effects on fetal outcomes and longer-term offspring health and developmental trajectories. Despite the prevalence of cannabis use, there is limited available evidence regarding its safety, especially in regard to reproductive health, pregnancy, and lactation. The biological effects of cannabis are mediated by the endocannabinoid system, and studies have reported the presence of cannabinoid receptors in the male and female reproductive tract, on sperm and the placenta, suggesting that the endocannabinoid system plays a role in regulating reproduction. Cannabis use can affect male and female fertility and has been associated with altered reproductive hormones, menstrual cyclicity, and semen parameters. Use of cannabis in male patients has also been associated with erectile dysfunction, abnormal spermatogenesis, and testicular atrophy. In female patients, cannabis use has been associated with infertility and abnormal embryo implantation and development. The main psychoactive component of cannabis, the delta-9-tetrahydrocannabinol, can also cross the placenta and has been detected in breast milk. Maternal cannabis use during pregnancy and lactation has been associated with adverse effects, including small-for-gestational-age infants, preterm birth, fetal neurodevelopmental consequences, and impaired offspring sociobehavioral and cognitive development. The prevalence of cannabis use for alleviating menopausal symptoms has also increased despite the limited information on its benefits and safety. Given that cannabis use is on the rise, it is critical to understand its impact on reproductive health and offspring developmental outcomes. This is an understudied but timely subject requiring much further information to guide healthcare providers and those interested in conceiving or who are pregnant and lactating, and those at the end of their reproductive time span., (Copyright © 2022. Published by Elsevier Inc.)

Objective: To investigate a novel transurethral hemostatic catheter device with an integrated chitosan endoluminal hemostatic dressing (CEHD). Development and implementation of this technology may help address bleeding following surgery such as transurethral resection of prostate (TURP). Bleeding remains the most common complication following TURP, leading to increased morbidity and hospitalization., Methods: Investigation of hemostasis, delivery, safety and efficacy of the CEHD device is conducted using Female Yorkshire swine (N = 23). Hemostatic efficacy of the CEHD (N = 12) is investigated against a control of gauze (N = 12) in a splenic injury model (3 swine). The delivery, safety, and efficacy of the CEHD device (N = 10) are investigated against Foley-catheter control (N = 10) for 7 days using a swine bladder-neck-injury model., Results: In the splenic injury study, 9/12 CEHD dressings successfully achieved hemostasis within 150 seconds (mean 83 seconds) vs success of 6/12 (mean 150 seconds) for gauze (P = .04). In the 7-day study, the CEHD was successfully deployed in 10/10 animals and all dressings were tolerated without histologic or clinical adverse effect. Hemostasis of the CEHD device was found to be noninferior to control catheters. Noninferiority is attributed to low bleeding rates in the swine bladder neck injury model., Conclusion: This investigation successfully demonstrated the feasibility of transurethral deployment of the CEHD in vivo. Routine use of safe and slowly dissolvable CEHDs could reduce the rate of complications and hospitalizations associated with bleeding and blood loss in TURP procedures. Further investigation is warranted., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: To determine the dose-dependent effect of delta-9-tetrahydrocannabinol (THC) exposure on male testes and reproductive health in a nonhuman primate model., Design: Research animal study., Setting: Research institute., Animal(s): Adult male rhesus macaques 8-10 years of age (n = 6)., Intervention(s): Daily edible THC at medically and recreationally relevant doses., Main Outcome Measure(s): Testicular volume and epididymal head width, serum levels of inhibin B, albumin, total testosterone, prolactin, follicle-stimulating hormone, estradiol, and luteinizing hormone; semen volume; and sperm motility, morphology, and concentration., Result(s): For each 1 mg/7 kg/day increase in THC dosing, there was a marked loss in total bilateral testicular volume of 11.8 cm 3 (95% confidence interval [CI]: 8.3-15.4). In total, average bilateral testicular volume decreased by 58%. Significant dose-response decreases in mean total testosterone level by 1.49 ng/mL (95% CI: 0.83-2.15) and in estradiol level by 3.8 pg/mL (95% CI: 2.2-5.4) were observed, but significant increases in the levels of follicle-stimulating hormone by 0.06 ng/mL (95% CI: 0.02-0.10), luteinizing hormone by 0.16 ng/mL (95% CI: 0.08-0.25), and prolactin by 7.4 ng/mL (95% CI: 3.4-11.3) were observed. There were no statistically significant changes in semen parameters., Conclusion(s): In rhesus macaques, chronic exposure to THC resulted in significant dose-response testicular atrophy, increased serum gonadotropin levels, and decreased serum sex steroids, suggestive of primary testicular failure. Further studies are needed to determine if reversal of these observed adverse effects would occur if THC was discontinued and for validation of thefindings in a human cohort., (Copyright © 2021 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Purpose of Review: Recent widespread legalization changes have promoted the availability of marijuana and its increased potency and perceived safety. The limited evidence on reproductive and perinatal outcomes from marijuana exposure is enough to warrant concern and action. The objective of this review is to provide a current and relevant summary of the recent literature surrounding this topic., Recent Findings: The available published studies on the effect of marijuana exposure on reproductive health and pregnancy outcomes are conflicting. Human studies are often observational or retrospective and confounded by self-report and polysubstance use. However, the current, limited evidence suggests that marijuana use adversely affects male and female reproductive health. Additionally, prenatal marijuana exposure has been reported to be associated with an increased risk of preterm birth and small for gestational age infants., Summary: With the increasing prevalence of marijuana use, there is an urgent need for evidence-driven recommendations and guidelines for couples interested in conception, affected by infertility or who are expecting. At this time, no amount of marijuana use during conception or pregnancy is known to be well tolerated and the limited available evidence suggests that the safest choice is to abstain., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To compare racial differences in male fertility history and treatment., Design: Retrospective review of prospectively collected data., Setting: North American reproductive urology centers., Patient(s): Males undergoing urologist fertility evaluation., Intervention(s): None., Main Outcome Measure(s): Demographic and reproductive Andrology Research Consortium data., Result(s): The racial breakdown of 6,462 men was: 51% White, 20% Asian/Indo-Canadian/Indo-American, 6% Black, 1% Indian/Native, <1% Native Hawaiian/Other Pacific Islander, and 21% "Other". White males sought evaluation sooner (3.5 ± 4.7 vs. 3.8 ± 4.2 years), had older partners (33.3 ± 4.9 vs. 32.9 ± 5.2 years), and more had undergone vasectomy (8.4% vs. 2.9%) vs. all other races. Black males were older (38.0 ± 8.1 vs. 36.5 ± 7.4 years), sought fertility evaluation later (4.8 ± 5.1 vs. 3.6 ± 4.4 years), fewer had undergone vasectomy (3.3% vs. 5.9%), and fewer had partners who underwent intrauterine insemination (8.2% vs. 12.6%) compared with all other races. Asian/Indo-Canadian/Indo-American patients were younger (36.1 ± 7.2 vs. 36.7 ± 7.6 years), fewer had undergone vasectomy (1.2% vs. 6.9%), and more had partners who underwent intrauterine insemination (14.2% vs. 11.9%). Indian/Native males sought evaluation later (5.1 ± 6.8 vs. 3.6 ± 4.4 years) and more had undergone vasectomy (13.4% vs. 5.7%)., Conclusion(s): Racial differences exist for males undergoing fertility evaluation by a reproductive urologist. Better understanding of these differences in history in conjunction with societal and biologic factors can guide personalized care, as well as help to better understand and address disparities in access to fertility evaluation and treatment., (Copyright © 2021 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To determine the dose-dependent effect of contemporary marijuana exposure on female menstrual cyclicity and reproductive endocrine physiology in a nonhuman primate model., Design: Research animal study., Setting: Research institute environment., Animals: Adult female rhesus macaques (6-12 years of age; n = 8)., Interventions: Daily delta-9-tetrahydrocannabinol (THC) edible at medically and recreationally relevant contemporary doses., Main Outcome Measures: Menstrual cycle length (MCL), anti-Müllerian hormone, prolactin, basal follicle-stimulating hormone (FSH), estradiol (E2) and progesterone, luteinizing hormone (LH), and thyroid-stimulating hormone., Results: The average before THC weight was 6.9 kg (standard deviation, 0.8), and at the highest THC dosing, the average weight was 7.2 kg (standard deviation, 0.8). With increasing THC dosing, MCL and FSH concentrations increased, while basal E2 concentration was stable. The average MCL concentration increased 4.0 days for each mg/7 kg/day of THC (95% CI, 1.4-6.6 days). Follicle-stimulating hormone concentration increased significantly with increasing THC dose, 0.34 ng/mL for each mg/7 kg/day of THC (95% CI, 0.14-0.57 ng/mL). No significant trends were observed between THC dosing and average basal progesterone, anti-Müllerian hormone, prolactin, LH, or thyroid-stimulating hormone concentrations., Conclusions: In rhesus macaques, a dose response toward increased MCL and basal FSH concentrations but plateau of basal E2 and LH concentrations was observed with increasing THC dosing, suggesting ovulatory dysfunction. Further studies are needed to determine the effects of a longer duration of exposure and whether the significant increase in MCL and FSH concentrations results in reduced fecundity.

INTRODUCTION To evaluate the educational value of transplant rotation in urology residency. In the United States, exposure to kidney transplantation during urology residency has declined significantly over the past few decades. At our institution, transplantation has been a core component of urology residency since its inception in 1959., Materials and Methods: A 15-question anonymous survey was developed. The first 8 questions queried demographics and the last 7 were a set of questions with a Likert Scale response. The survey was electronic- mailed to past and current urology residents who had completed the transplant rotation, dating back to 1972., Results: A total of 61 out of 98 (62%) individuals responded. The majority (59%) were general urologists, and one (2%) had completed a transplant fellowship. In their practices, 17% performed kidney transplants and 28% performed donor nephrectomies. Overall, 100% responded that the skills learned on the transplant rotation were beneficial for urology training, 100% had learned valuable vascular surgical techniques, and 93% felt that urology residents should have clinical transplant experience during their training. There was no statistical difference between the younger and older graduates in Likert scale responses., Conclusion: The majority of graduates did not perform transplants in their practice, yet, all of responders agreed that the skills learned on the transplant rotation were beneficial and 93% expressed that urology residents should have clinical transplant experience during residency. Kidney transplantation should be an integral part of urology residency training.

INTRODUCTION Perioperative stroke and myocardial infarction are uncommon but devastating thromboembolic complications. There is no comprehensive study detailing these complications for urologic procedures. The primary aim of this study is to determine which urologic procedures and patients carry the highest risk of perioperative stroke and myocardial infarction., Materials and Methods: The National Surgical Quality Improvement Program data set was reviewed from 2008-2017. Procedures coded under the urology specialty were included and patients who had a perioperative stroke or myocardial infarction were identified. CPTs were stratified into clinically relevant procedure groups. Two multivariable logistic regression analyses were performed to determine preoperative and procedural risk factors for developing perioperative stroke or myocardial infarction. A multivariable logistic regression analysis was performed to determine the association between these complications and 30-day mortality., Results: A total of 281,744 cases were included, identifying 392 strokes (0.14%) and 1,016 myocardial infarctions (0.36%). Age ≥ 70, hypertension, and disseminated cancer were the strongest preoperative risk factors for perioperative stroke or myocardial infarction. Cystectomy was the highest risk urologic procedure (stroke: OR 3.3, 95%CI 2.3-4.8; MI: OR 7.2, 95%CI 5.6-9.1). Thirty-day mortality was dramatically worse for patients who had a perioperative stroke or myocardial infarction., Conclusions: Perioperative stroke and myocardial infarction were confirmed to be uncommon but devastating complications of urologic surgery, with incidence of 0.14% and 0.36%, respectively. Cystectomy was the highest risk urologic procedure. Perioperative stroke and myocardial infarction were strongly associated with age ≥ 70, hypertension, and disseminated cancer.

Background: Relative value units (RVUs) are the measure of value used in US Medicare reimbursement. Medicare determines physician work RVUs (wRVUs) from the Relative Value Update Committee (RUC) for a procedure based on operative time, technical skill and effort, mental effort and judgment, and stress. In theory, work RVUs should account for the complexity and operative time involved in a procedure. The aim of this study was to assess whether major procedures for treatment of benign prostatic enlargement (BPE) are fairly compensated based on complexity and operative time in the RVU system and compare them with the intended reimbursement. Methods: The American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database and the Centers for Medicare and Medicaid Services (CMS) Medicare Physician Fee Schedule were queried from 2015 to 2017. Single, current, procedural terminology codes associated with BPE treatments were included: transurethral resection of the prostate (TURP), photovaporization of the prostate (PVP), holmium laser enucleation of the prostate (HoLEP), retropubic simple prostatectomy (RSP), and suprapubic simple prostatectomy (SSP). The CMS operative times and the NSQIP real data were used in turn to calculate separate values for wRVUs per hour (wRVUs/hr) of operative time. The wRVUs/hr derived from CMS operative times represent RUC-estimated wRVUs/hr and wRVUs/hr derived from NSQIP represent actual wRVUs/hr. Results: A total of 27,664 cases were included from the NSQIP dataset. Median wRVU was 15.3 (interquartile range [IQR] 12.2-15.3), median operative time 50 minutes (IQR 33-74), and median wRVUs/hr 17.0 (IQR 11.6-26.2). RUC-estimated wRVUs/hr were TURP 12.2, PVP 12.2, RSP 9, SSP 9.3, and HoLEP 7.3. The actual wRVUs/hr were TURP 19.1, PVP 15.5, RSP 10.2, HoLEP 9.4, and SSP 7.6. Conclusions: Laser enucleation and simple prostatectomy are highly complex and efficacious procedures for treating BPE, yet the current payment schedule assigns these procedures the least amount of wRVUs/hr. Financial incentives for performing BPE surgeries are clearly misaligned.

Background: The microscopic characteristics of vasal fluid at time of vasectomy reversal (VR) guide operative decision making and predict fertility outcomes. The proteomic profile of this vasal fluid has not been described or correlated with the microscopic fluid appearance. To characterize the vasal fluid proteome at time of VR and evaluate the variation of the vasal fluid proteome with respect to microscopic presence of sperm., Methods: A prospective cohort study was conducted enrolling twenty-five men undergoing VR for infertility and/or pain at a University-affiliated hospital. Vasal fluid samples obtained at time of VR were grouped based on presence of sperm on light microscopy at time of VR. Proteomic profiles were generated using liquid chromatography/ tandem mass spectrometry, and MS/MS protein spectral counts compared between individuals and treatment groups, controlling for less than 5% protein false discovery rate (FDR). Proteins were matched with the human swissprot database using the Comet search engine, and categorized by Gene Ontology (GO) terms., Results: There was large variability between the 46 vasal fluid samples collected, with 1,692 unique proteins detected. The three most abundant proteins were Lactotransferrin, Cysteine-rich secretory protein 1, A-kinase anchor protein 4. There was no correlation between the proteome and microscopic sperm presence. Prevalent GO terms included viral process, signal transduction, innate immune response, protein folding and spermatogenesis., Conclusions: We describe the proteome and the most common proteins in vasal fluid at time of VR. Numerable sperm, testis and epididymis specific proteins were present even in the absence of sperm on microscopy. Further evaluation is needed to determine if a protein biomarker may better guide operative decision making and predict VR fertility outcomes., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tau-20-703). The authors have no conflicts of interest to declare., (2020 Translational Andrology and Urology. All rights reserved.)

Objective: To characterize spermatogenesis in the estrogenized transgender patient., Materials and Methods: This is a retrospective, single-center, cross-sectional study. Seventy-two transgender women underwent gender-affirming orchiectomy between May 2015 and January 2017. All were on long-term (>1 year) cross-sex hormonal therapy prior to orchiectomy. Patient data were obtained via chart review. Histologic analysis was performed by a pathology resident under the supervision of a genitourinary pathologist. The main outcome is histologic presence of germ cells and presence of spermatids (a proxy for preserved spermatogenesis) in orchiectomy specimens., Results: There were 141 pathologic specimens available for analysis. Germ cells were present in 114 out of 141 (81%) testicles. Spermatids were present in 57 (40%) testicles. Presence of germ cells was associated with older age (43 vs 35 years, P = .007) and increased testicular weight (28.6 g vs 19.3 g, P <.001). Presence of spermatids was associated with increased weight (31.5 g vs 23.3 g, P <.001) and volume (20.3 mL vs 12.6 mL, P <.001). There was a linear correlation between testis volume and preserved spermatogenesis (Pearson's r = 0.448, P <.001)., Conclusion: Despite long-term hormone therapy, the majority (80%) of transgender women have germ cells present in the testicle. Spermatogenesis is preserved in approximately 40% of these individuals. Duration of hormonal therapy did not affect the degree of preservation of germ cells or spermatogenesis but starting hormonal treatment at a younger age may be associated with decreased germ cells in the testicle. Volume of testicles predict presence of preserved spermatogenesis., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: To characterize the referral patterns and characteristics of men presenting for infertility evaluation using data obtained from the Andrology Research Consortium., Design: Standardized male infertility questionnaire., Setting: Male infertility centers., Patient(s): Men presenting for fertility evaluation., Intervention(s): Not applicable., Main Outcome Measure(s): Demographic, infertility history, and referral data., Result(s): The questionnaires were completed by 4,287 men, with a mean male age of 40 years ± 7.4 years and female partners age of 37 years ± 4.9 years. Most were Caucasian (54%) with other races being less commonly represented (Asian 18.6%, and African American 5.5%). The majority (59.7%) were referred by a reproductive gynecologist, 19.4% were referred by their primary care physician, 4.2% were self-referred, and 621 (14.5%) were referred by "other." Before the male infertility investigation, 12.1% of couples had undergone intrauterine insemination, and 4.9% of couples had undergone in vitro fertilization (up to six cycles). Among the male participants, 0.9% reported using finasteride (5α-reductase inhibitor) at a dose used for androgenic alopecia, and 1.6% reported exogenous testosterone use., Conclusion(s): This broad North American patient survey shows that reproductive gynecologists are the de facto gateway for most male infertility referrals, with most men being assessed in the male infertility service being referred by reproductive endocrinologists. Some of the couples with apparent male factor infertility are treated with assisted reproductive technologies before a male factor investigation. The survey also identified potentially reversible causes for the male infertility including lifestyle factors such as testosterone and 5α-reductase inhibitor use., (Copyright © 2019 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To provide pregnancy and live birth rates from a contemporary series of vasectomy reversals in men with female partners aged ≥35 years and to correlate the results with IVF., Setting: Tertiary academic referral center., Design: Retrospective comparative study of prospectively collected database., Patient(s): Two hundred forty-six men who underwent vasectomy reversal for fertility with female partner aged ≥35 years., Intervention(s): Vasovasostomy or vasoepididymostomy., Main Outcome Measure(s): Correlation of pregnancy and live birth rate of this cohort by age groups with most recently published pregnancy and live birth rate per IVF cycle., Result(s): One hundred thirty-six men who underwent vasectomy reversal between 2006 and 2014 met our inclusion criteria. Overall pregnancy and live birth rates were 35% and 30%, respectively. Subgroup analysis by female age groups (35-37, 38-40, >40 years) demonstrated pregnancy and live birth rates comparable to those per IVF cycle by age groups according to a recently published (2015) national report., Conclusion(s): Vasectomy reversal should be strongly considered in men with a partner aged ≤40 years. Additionally, vasectomy reversal can be considered in carefully selected patients even with a partner aged >40 years., (Copyright © 2018 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Malignant Leydig cell tumor is a rare entity that has been previously described as rapidly progressive and uniformly fatal. We present the case of a malignant Leydig cell tumor that presented 14 years after orchiectomy with an isolated retroperitoneal metastasis. Our patient underwent a retroperitoneal lymph node dissection and has been free of recurrence or progression at 12 months of follow up. Additionally, we describe the symptomatic hormone dysfunction experienced by our patient as a result of his tumor.

Introduction: To determine the factors used to make the decision between vasovasostomy (VV) and vasoepididymostomy (VE) by leaders performing microsurgical vasectomy reversal using a questionnaire., Materials and Methods: An online questionnaire was sent to all members of the Society for the Study of Male Reproduction (SSMR), a male reproduction subspecialty society of the AUA, using the SurveyMonkey platform., Results: Sixty-seven surgeons responded to the questionnaire (27% of SSMR members). Of which 72% of members performed less than 50 vasectomy reversals per year. Also, 71% of members stated that less than 20% of their vasectomy reversals are vasoepididymostomies. When evaluating epididymal fluid at the time of reversal, 87% would perform a VE for pasty fluid, 66% with creamy fluid without sperm heads and 55% with no or scant fluid. With respect to banking sperm, 36% take sperm or testicular tissue at the time of VE while 37% sometimes take sperm mostly depending on the couple's preference. The Berger end-to-side with intussusception VE technique is used by the majority of members (78%). The presence of intact sperm or sperm parts determined the location in the epididymis for anastomosis for 55% and 19% of members respectively. Postoperative semen testing after a VE is evaluated first between 6 weeks to 3 months for 64%. The procedure is considered a failure between 6 to 12 months for 34% and 12 to 18 months for another 48% if no sperm is seen on semen analysis., Conclusions: Most members perform a VE with pasty fluid or creamy fluid without sperm heads. Three out of four members are using the Berger end-to-side intussusception technique to perform their VE. More studies are needed to determine the optimal circumstances to perform a VE as there is significant variation in responses even among members of the SSMR.

The goal of work-up of lower urinary tract symptoms is to establish the severity and cause of lower urinary tract symptoms and to predict with certainty which patients will respond to which treatments. Clinical guidelines exist to guide urologists in decision-making. All patients need a medical history with a validated symptom score, a physical examination, and a urinalysis. Prostate-specific antigen, postvoid urine residual, and peak urine flow rate provide additional information at little cost. For more invasive testing high-level data are lacking and guidelines defer to the urologist. Even the most extensive work-up is imperfect, and thus the attempt to balance costs with benefits of invasive testing., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: Renal autotransplantation is an infrequently performed procedure. It has been used to manage complex ureteral disease, vascular anomalies and chronic kidney pain. We reviewed our 27-year experience with this procedure., Materials and Methods: This is a retrospective, observational study of 51 consecutive patients who underwent renal autotransplantation, including 29 at Oregon Health and Science University between 1986 and 2013, and 22 at Virginia Mason Medical Center between 2007 and 2012. Demographics, indications, operative details and followup data were collected. Early (30 days or less) and late (greater than 30 days) complications were graded according to the Clavien-Dindo system. Factors associated with complications and pain recurrence were evaluated using a logistic regression model., Results: The 51 patients underwent a total of 54 renal autotransplants. Median followup was 21.5 months. The most common indications were loin pain hematuria syndrome/chronic kidney pain in 31.5% of cases, ureteral stricture in 20.4% and vascular anomalies in 18.5%. Autotransplantation of a solitary kidney was performed in 5 patients. Laparoscopic nephrectomy was performed in 23.5% of cases. Median operative time was 402 minutes and median length of stay was 6 days. No significant difference was found between preoperative and postoperative plasma creatinine (p = 0.74). Early, high grade complications (grade IIIa or greater) developed in 14.8% of patients and 12.9% experienced late complications of any grade. Two graft losses occurred. Longer cold ischemia time was associated with complications (p = 0.049). Of patients who underwent autotransplantation for chronic kidney pain 35% experienced recurrence and 2 underwent transplant nephrectomy. No predictors of pain recurrence were identified., Conclusions: The most common indications for renal autotransplantation were loin pain hematuria syndrome/chronic kidney pain, ureteral stricture and vascular anomalies in descending order. Kidney function was preserved postoperatively and 2 graft losses occurred. At a median followup of 13 months pain resolved in 65% of patients who underwent the procedure. Complication rates compared favorably with those of other major urological operations and cold ischemia time was the only predictor of postoperative complications., (Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Objectives: To determine the incidence of calcified Peyronie's disease plaque that cannot be cut with a blade in a 100-case series and to describe the use of a soft tissue-protecting bone saw for plaque incision., Methods: Chart reviews were done of all surgically treated Peyronie's disease patients at our center between October 1996 and December 2012. 100 cases were included. We evaluated our novel technique of tissue-protecting bone saw surgical use., Results: 100 consecutive patients underwent surgery for Peyronie's disease, and 6 required transverse bone saw plaque incision due to the severity of calcification that could not be cut with a blade. Four of those 6 underwent grafting procedures with porcine submucosal intestinal substance (SIS) and 2 underwent placement of inflatable penile prosthesis (IPP) after plaque incision. There were no surgical complications. Both IPP patients had functioning prosthesis 4 and 7.3 years after surgery. One SIS-graft patient required re-operation for more proximal curvature 11 months later and ultimately required multiple plaque incisions and an IPP., Conclusion: Densely calcified plaques occurred in 6% of a surgical series of Peyronie's disease patients. The vibrating bone saw is a novel technique to incise calcified plaques before grafting or IPP placement., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: To review our institution's experience and success with vasectomy reversal to treat postvasectomy pain syndrome (PVPS) over the last 20 years., Materials and Methods: A single surgeon (E.F.F.) performed all the vasectomy reversals. We identified 123 procedures done for PVPS treatment and were able to contact 76 patients. We sent surveys or conducted phone interviews inquiring about satisfaction, levels of pain preoperatively and postoperatively, and the need for additional procedures for pain. Thirty-one patients completed phone or written surveys. In addition, we compared the location of vasectomy among patients presenting for pain to that of fertile patients., Results: Thirty-one men had vasectomy reversal for postvasectomy pain, with median age of 38 years (range, 31-55 years), of which 26 underwent vasovasostomy (VV). Seven patients required epididymovasostomy (EV) on at least 1 side based on intraoperative findings. Eighty-two percent of patients reported improvement in their pain at 3.2 months (±3.4 months) after vasectomy reversal. Thirty-four percent patients had complete resolution of all pain. Mean pain score before procedure was 6.4 (±2.4), decreasing to a median of 2.7 (±2.7) afterward. There was a 59% improvement in pain scores (P <.001). Two patients required additional procedures for continued pain, one orchiectomy and one epididymectomy. Four patients required an additional reversal procedure, one a repeat VV at 1 year and 3 an EV at 1, 5, and 9 years, respectively. Follow-up ranged from 1 to 19 years, with a mean follow-up of 8.4 years. We found no relationship between vasectomy location and pain., Conclusion: Vasectomy reversal, through the use of both VV and EV, can provide long-term relief from PVPS., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose: We compared fertility outcomes with gross and microscopic fluid findings at vasectomy reversal at a high volume vasectomy reversal center., Materials and Methods: A retrospective study of a prospective database was performed. All vasectomy reversals were performed by a single surgeon (EFF) between 1978 and 2011. The clinical pregnancy rate was self-reported or determined via patient mailers. Patient and operative findings were determined through database review. We classified vasal fluid as opalescent, creamy, pasty or clear. Intraoperative light microscopy was used to determine if sperm or sperm parts were present and if they were motile. Multivariate analysis was performed evaluating patient age, partner age, years after vasectomy, type of surgery, and gross and microscopic fluid analysis., Results: A total of 2,947 microsurgical vasectomy reversals were reviewed after we excluded reversals performed for post-vasectomy pain. We determined the pregnancy status of 902 (31%) cases. On univariate analysis with respect to pregnancy the presence of motile sperm at vasovasostomy neared statistical significance (p=0.075) and there was no difference between bilateral vs unilateral motile sperm. Gross fluid appearance was not statistically significant but we found the order of pregnancy success to be opalescent, creamy, clear then pasty fluid. On multivariate analysis only female partner age and sperm heads only or no sperm seen on light microscopy had statistical significance (p <0.05)., Conclusions: The presence of motile sperm at vasectomy reversal approaches statistical significance on univariate analysis as a factor that affects clinical pregnancy rates. On multivariate analysis female partner age and microscopic findings of sperm heads only or no sperm are inversely related to pregnancy rates. These data will help counsel couples after vasectomy reversal and reinforce the importance of female partner age., (Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: We reviewed fertility outcomes of vasectomy reversal at a high surgical volume center in men with the same female partner as before vasectomy., Materials and Methods: We retrospectively studied a prospective database. All vasectomy reversals were performed by a single surgeon (EFF). Patients who underwent microsurgical vasectomy reversal and had the same female partner as before vasectomy were identified from 1978 to 2011. Pregnancy and live birth rates, procedure type (bilateral vasovasostomy, bilateral vasoepididymostomy, unilateral vasovasostomy or unilateral vasoepididymostomy), patency rate, time from reversal and spouse age were evaluated., Results: We reviewed the records of 3,135 consecutive microsurgical vasectomy reversals. Of these patients 524 (17%) who underwent vasectomy reversal had the same female partner as before vasectomy. Complete information was available on 258 patients (49%), who had a 94% vas patency rate. The clinical pregnancy rate was 83% by natural means compared to 60% in our general vasectomy reversal population (p <0.0001). On logistic regression analysis controlling for female partner and patient ages, years from vasectomy and vasectomy reversal with the same female partner the OR was 2 (p <0.007). Average time from vasectomy was 5.7 years. Average patient and female partner age at reversal was 38.9 and 33.2 years, respectively., Conclusions: Outcomes of clinical pregnancy and live birth rates are higher in men who undergo microsurgical vasectomy reversal with the same female partner. These outcomes may be related to a shorter interval from vasectomy, previous fertility and couple motivation., (Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Objective: To report a series of penile fractures, describing preoperative evaluation, surgical repair, and long-term outcomes., Patients and Methods: Medical records from Northwestern Memorial Hospital and Oregon Health & Science University from 2002 to 2011 were reviewed. Clinical presentation, preoperative evaluation, time from injury, mechanism and site of injury, and presence of urethral injury were assessed. Outcomes including erectile dysfunction, penile curvature, and voiding symptoms were evaluated using International Prostate Symptom Score and International Index of Erectile Function scores., Results: Twenty-nine patients with 30 separate episodes of penile fractures presenting to the emergency room were identified. Mean patient age was 43 ± 9.6 years. The time from presentation to the initiation of surgery was 5.5 ± 4.4 hours. Mechanism of injury was intercourse in 26 of 30 fractures with the remaining attributed to masturbation or "rolling over." Immediate surgical repair was offered to all patients. Twenty-seven patients underwent surgery. Urethral injury was noted in 5 of the 27. The site of fracture was at the proximal shaft in 11, mid shaft in 12, and distal shaft in 4 patients. The mean follow-up period was 14.3 ± 15.8 weeks. Nine patients reported new mild erectile dysfunction or penile curvature. One patient reported new irritative voiding symptoms., Conclusion: The most common mechanism of penile fracture was from sexual intercourse, and frequent concomitant urethral injuries were observed. The frequency of concomitant urethral injury was higher than in previous studies. Although we observed high incidence of erectile dysfunction or penile curvature with early surgical repair, we retain it as the favored approach., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Purpose: It was theorized that the use of permanent contraceptive methods may vary with economic conditions. We evaluated the relationship between vasectomy/vasectomy reversal frequencies at several large referral centers and national economic indicators during 2 recessions spanning 2001 to 2011., Materials and Methods: We performed an institutional review board approved, retrospective chart review to identify the number of vasectomies/vasectomy reversals per month at several large referral centers from January 2001 to July 2011. The rates of these procedures were pooled, correlated with national economic data and analyzed in a multivariate linear regression model., Results: A total of 4,599 vasectomies and 1,549 vasectomy reversals were performed at our institutions during the study period. The number of vasectomies per month positively correlated with the unemployment rate (r=0.556, p<0.001) and personal income per capita (r=0.276, p=0.002). The number of reversals per month negatively correlated with the unemployment rate (r=-0.399, p<0.001) and personal income per capita (r=-0.305, p<0.001). Neither vasectomy nor vasectomy reversal frequency significantly correlated with the inflation rate or the S&P 500®. Regression models confirmed that the unemployment rate explained more of the variance in vasectomy/vasectomy reversal frequencies than other indicators., Conclusions: We noted a correlation between the number of vasectomies/vasectomy reversals performed at our institutions and national economic indicators. The strongest association was with the unemployment rate. This points to the importance of financial pressure on family planning decisions., (Copyright © 2014 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

There is an emerging evolution in the understanding of the relationship between the prostate and testosterone. It has long been generally believed that with testosterone replacement therapy (TRT), increasing serum testosterone levels led to prostatic growth and worsening of voiding dysfunction and associated complications. A new theory, the Saturation Model of Testosterone and its effect on the Prostate has gained attention. This theory suggests that the prostate's response to increasing levels of serum testosterone reaches a limit beyond which there is minimal effect. This model predicts that testosterone replacement therapy occurs above this saturation point, and replacing testosterone to eugonadal levels should not worsen prostate related benign disease. We evaluated the recent published data, with an emphasis on clinical studies done within the last 3 years, for the effects of testosterone supplementation on benign prostatic disease.

Purpose: Survival to reproductive age among men with cancer has steadily increased and yet cancer therapy and cancer itself may carry the risk of infertility. Since 2006, we have used a formalized fertility preservation program with expedited fertility care at our institution. We assessed the impact of this program by comparing the frequency of sperm cryopreservation and patient characteristics before and after its implementation., Materials and Methods: Men 18 to 55 years old diagnosed with cancer at our institution from 2002 to 2010 were included in our study. We retrospectively reviewed patient charts to identify those who were offered and subsequently used fertility preservation services before and after program formalization., Results: From 2002 to 2010 at our institution 4,818 men 18 to 55 years old were diagnosed with cancer, of whom 411 were offered fertility preservation consultation and 249 underwent sperm cryopreservation. Since program implementation, the annual number of men receiving fertility preservation consultation and undergoing sperm cryopreservation increased by 2.4 and 2.7-fold, respectively, while the total number diagnosed with cancer remained fairly constant. Upon substratifying patients into the more conventional reproductive age range of 18 to 40 years 23.4% of all men with cancer in this group were offered consultation before formalization vs 43.3% after formalization (p <0.05). The overall sperm use and discard rates were 8.4% and 14.8%, respectively., Conclusions: A formalized institutional fertility preservation program significantly increased the overall number and percent of male patients with cancer who received fertility preservation consultation and pursued sperm cryopreservation. These increases were seen in men with all types of cancer and across all demographics assessed at our institution., (Copyright © 2012 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Preconditioning induces ischemic tolerance, which confers robust protection against ischemic damage. We show marked protection with polyinosinic polycytidylic acid (poly-IC) preconditioning in three models of murine ischemia-reperfusion injury. Poly-IC preconditioning induced protection against ischemia modeled in vitro in brain cortical cells and in vivo in models of brain ischemia and renal ischemia. Further, unlike other Toll-like receptor (TLR) ligands, which generally induce significant inflammatory responses, poly-IC elicits only modest systemic inflammation. Results show that poly-IC is a new powerful prophylactic treatment that offers promise as a clinical therapeutic strategy to minimize damage in patient populations at risk of ischemic injury.

In canine colon, M2/M3 muscarinic receptors are coupled to extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein (MAP) kinases. We tested the hypothesis that this coupling is mediated by enzymes of the phosphatidylinositol (PI) 3-kinase family. RT-PCR and Western blotting demonstrated expression of two isoforms, PI 3-kinase-alpha and PI 3-kinase-gamma. Muscarinic stimulation of intact muscle strips (10 microM ACh) activated PI 3-kinase-gamma, ERK and p38 MAP kinases, and MAP kinase-activated protein kinase-2, whereas PI 3-kinase-alpha activation was not detected. Wortmannin (25 microM) abolished the activation of PI 3-kinase-gamma, ERK, and p38 MAP kinases. MAP kinase inhibition was a PI 3-kinase-gamma-specific effect, since wortmannin did not inhibit recombinant activated murine ERK2 MAP kinase, protein kinase C, Raf-1, or MAP kinase kinase. In cultured muscle cells, newborn calf serum (3%) activated PI 3-kinase-alpha and PI 3-kinase-gamma isoforms, ERK and p38 MAP kinases, and stimulated chemotactic cell migration. Using wortmannin and LY-294002 to inhibit PI 3-kinase activity and PD-098059 and SB-203580 to inhibit ERK and p38 MAP kinases, we established that these enzymes are functionally important for regulation of chemotactic migration of colonic myocytes.

The signal transduction pathways regulating smooth-muscle gene expression and production of cytokines in response to proinflammatory mediators are undefined. Cultured human bronchial smooth-muscle cells were treated for 20 h with a cytokine cocktail containing interleukin (IL)-1beta, tumor necrosis factor-alpha, and interferon-gamma. A complementary DNA expression array containing 588 genes was used to follow cytokine-stimulated gene expression. The expression and secretion of the cytokines IL-1beta, IL-6, and IL-8 significantly increased after 20 h of stimulation as measured by relative reverse transcriptase/ polymerase chain reaction, enzyme-linked immunosorbent assay, and Western blotting techniques. Expression of IL-6 and IL-8 was sensitive to SB203580, the specific inhibitor of p38 mitogen-activated protein (MAP) kinase and PD98059, an inhibitor of MAP kinase kinase. Expression of IL-1beta was sensitive only to PD98059. Together, these results demonstrate that the p38 and extracellular signal-regulated protein kinase MAP kinase pathways are required for proinflammatory mediator- induced cytokine expression in airway myocytes. The generation of chemokines and cytokines in airway smooth muscle also provides evidence that smooth-muscle cells have the ability to contribute to the inflammatory response.

Mitogen-activated protein (MAP) kinases signal to proteins that could modify smooth muscle contraction. Caldesmon is a substrate for extracellular signal-related kinases (ERK) and p38 MAP kinases in vitro and has been suggested to modulate actin-myosin interaction and contraction. Heat shock protein 27 (HSP27) is downstream of p38 MAP kinases presumably participating in the sustained phase of muscle contraction. We tested the role of caldesmon and HSP27 phosphorylation in the contractile response of vascular smooth muscle by using inhibitors of both MAP kinase pathways. In intact smooth muscle, PD-098059 abolished endothelin-1 (ET-1)-stimulated phosphorylation of ERK MAP kinases and caldesmon, but p38 MAP kinase activation and contractile response remained unaffected. SB-203580 reduced muscle contraction and inhibited p38 MAP kinase and HSP27 phosphorylation but had no effect on ERK MAP kinase and caldesmon phosphorylation. In permeabilized muscle fibers, SB-203580 and a polyclonal anti-HSP27 antibody attenuated ET-1-dependent contraction, whereas PD-098059 had no effect. These results suggest that ERK MAP kinases phosphorylate caldesmon in vivo but that activation of this pathway is unnecessary for force development. The generation of maximal force may be modulated by the p38 MAP kinase/HSP27 pathway.

Phosphorylation of h-caldesmon has been proposed to regulate airway smooth muscle contraction. Both extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein (MAP) kinases phosphorylate h-caldesmon in vitro. To determine whether both enzymes phosphorylate caldesmon in vivo, phosphorylation-site-selective antibodies were used to assay phosphorylation of MAP kinase consensus sites. Stimulation of cultured tracheal smooth muscle cells with ACh or platelet-derived growth factor increased caldesmon phosphorylation at Ser789 by about twofold. Inhibiting ERK MAP kinase activation with 50 microM PD-98059 blocked agonist-induced caldesmon phosphorylation completely. Inhibiting p38 MAP kinases with 25 microM SB-203580 had no effect on ACh-induced caldesmon phosphorylation. Carbachol stimulation increased caldesmon phosphorylation at Ser789 in intact tracheal smooth muscle, which was blocked by the M(2) antagonist AF-DX 116 (1 microM). AF-DX 116 inhibited carbachol-induced isometric contraction by 15 +/- 1.4%, thus dissociating caldesmon phosphorylation from contraction. Activation of M(2) receptors leads to activation of ERK MAP kinases and phosphorylation of caldesmon with little or no functional effect on isometric force. P38 MAP kinases are also activated by muscarinic agonists, but they do not phosphorylate caldesmon in vivo.

Smooth muscle cells are exposed to growth factors and cytokines that contribute to pathological states including airway hyperresponsiveness, atherosclerosis, angiogenesis, smooth muscle hypertrophy, and hyperplasia. A common feature of several of these conditions is migration of smooth muscle beyond the initial boundary of the organ. Signal transduction pathways activated by extracellular signals that instigate migration are mostly undefined in smooth muscles. We measured migration of cultured tracheal myocytes in response to platelet-derived growth factor, interleukin-1beta, and transforming growth factor-beta. Cellular migration was blocked by SB203580, an inhibitor of p38(MAPK). Time course experiments demonstrated increased phosphorylation of p38(MAPK). Activation of p38(MAPK) resulted in the phosphorylation of HSP27 (heat shock protein 27), which may modulate F-actin polymerization. Inhibition of p38(MAPK) activity inhibited phosphorylation of HSP27. Adenovirus-mediated expression of activated mutant MAPK kinase 6b(E), an upstream activator for p38(MAPK), increased cell migration, whereas overexpression of p38alpha MAPK dominant negative mutant and an HSP27 phosphorylation mutant blocked cell migration completely. The results indicate that activation of the p38(MAPK) pathway by growth factors and proinflammatory cytokines regulates smooth muscle cell migration and may contribute to pathological states involving smooth muscle dysfunction.

There is relatively little known about expression and activation of p38 mitogen-activated protein kinases (MAPKs) through G protein-linked, seven-transmembrane-spanning (STM) receptors in mammalian smooth muscle. To investigate the role of p38 MAPK in smooth muscle, we cloned and sequenced the p38 MAPK expressed in canine smooth muscles. A full-length clone of the canine p38 MAPK expressed in colonic smooth muscle was obtained by RT-PCR. The deduced amino acid sequence revealed 99% identity to the human p38 MAPK and differed from the human enzyme in only two conservative substitutions. The deduced molecular mass of the canine p38 MAPK is 41.2 kDa, with a calculated isoelectric point of 5.41. Canine p38 MAPK was found to be expressed in colonic, tracheal, and vascular smooth muscles and underwent increased tyrosine phosphorylation in response to motor neurotransmitters, acetylcholine (ACh) and neurokinin A (NKA), in colonic smooth muscle. There was an eightfold increase in p38 MAPK phosphorylation after a 10-min incubation with ACh and a threefold increase with NKA. We also identified a p38 immunoreactive kinase activity isolated from colonic smooth muscle homogenate by Mono Q chromatography. Partially purified p38 MAPK and activated recombinant p38 MAPK (Mpk2) phosphorylated both the known p38 MAPK substrate ATF2, as well as porcine stomach h-caldesmon in vitro. The results suggest that elements of the "stress-response" pathway may be coupled to transcriptional control as well as to cytoskeletal and possibly contractile protein phosphorylation in mammalian smooth muscle.

This paper models general survival and the distribution of tumor onset times for various tumors in the data base of control animals developed by the National Toxicology Program. For general survival, a modified Weibull model is shown to give an adequate fit for both Fischer 344 rats and C57BL/6 X C3H F1, mice. In addition, data from control animals in a lifetime study of asbestos are used to support the extension of these survival curves beyond 2 years in Fischer rats. The distributions of tumor onset times are modeled using a two-parameter Weibull model. For many common tumor types, this model yielded a very good fit to the data. Finally, a summary measure of the contribution of a tumor to mortality is given.