Patient-Reported Outcomes after Monitoring, Surgery, or Radiotherapy for Prostate Cancer.

BACKGROUND: Robust data on patient-reported outcome measures comparing treatments for clinically localized prostate cancer are lacking. We investigated the effects of active monitoring, radical prostatectomy, and radical radiotherapy with hormones on patient-reported outcomes. METHODS: We compared patient-reported outcomes among 1643 men in the Prostate Testing for Cancer and Treatment (ProtecT) trial who completed questionnaires before diagnosis, at 6 and 12 months after randomization, and annually thereafter. Patients completed validated measures that assessed urinary, bowel, and sexual function and specific effects on quality of life, anxiety and depression, and general health. Cancer-related quality of life was assessed at 5 years. Complete 6-year data were analyzed according to the intention-to-treat principle. RESULTS: The rate of questionnaire completion during follow-up was higher than 85% for most measures. Of the three treatments, prostatectomy had the greatest negative effect on sexual function and urinary continence, and although there was some recovery, these outcomes remained worse in the prostatectomy group than in the other groups throughout the trial. The negative effect of radiotherapy on sexual function was greatest at 6 months, but sexual function then recovered somewhat and was stable thereafter; radiotherapy had little effect on urinary continence. Sexual and urinary function declined gradually in the active-monitoring group. Bowel function was worse in the radiotherapy group at 6 months than in the other groups but then recovered somewhat, except for the increasing frequency of bloody stools; bowel function was unchanged in the other groups. Urinary voiding and nocturia were worse in the radiotherapy group at 6 months but then mostly recovered and were similar to the other groups after 12 months. Effects on quality of life mirrored the reported changes in function. No significant differences were observed among the groups in measures of anxiety, depression, or general health-related or cancer-related quality of life. CONCLUSIONS: In this analysis of patient-reported outcomes after treatment for localized prostate cancer, patterns of severity, recovery, and decline in urinary, bowel, and sexual function and associated quality of life differed among the three groups. (Funded by the U.K. National Institute for Health Research Health Technology Assessment Program; ProtecT Current Controlled Trials number, ISRCTN20141297 ; ClinicalTrials.gov number, NCT02044172 .).

Extreme Hardening of Pb at High Pressure and Strain Rate.

We study the high-pressure strength of Pb and Pb-4wt%Sb at the National Ignition Facility. We measure Rayleigh-Taylor growth of preformed ripples ramp compressed to ∼400 GPa peak pressure, among the highest-pressure strength measurements ever reported on any platform. We find agreement with 2D simulations using the Improved Steinberg-Guinan strength model for body-centered-cubic Pb; the Pb-4wt%Sb alloy behaves similarly within the error bars. The combination of high-rate, pressure-induced hardening and polymorphism yield an average inferred flow stress of ∼3.8 GPa at high pressure, a ∼250-fold increase, changing Pb from soft to extremely strong.

Characterizing the modulation of resting-state fMRI metrics by baseline physiology.

The blood-oxygenation level dependent (BOLD) functional magnetic resonance imaging (fMRI) signal is commonly used to assess functional connectivity across brain regions, particularly in the resting state (rs-fMRI). However, the BOLD fMRI signal is not merely a representation of neural activity, but a combination of neural activity and vascular response. These aspects of the BOLD signal are easily influenced by systemic physiology, potentially biasing BOLD-based functional connectivity measurements. In this work, we focus on the following physiological modulators of the BOLD signal: cerebral blood flow (CBF), venous blood oxygenation, and cerebrovascular reactivity (CVR). We use simulations and experiments to examine the relationship between the physiological parameters and rs-fMRI functional connectivity measurements in three resting-state networks: default mode network, somatosensory network and visual network. By using the general linear model, we demonstrate that physiological modulators significantly impact functional connectivity measurements in these regions, but in a manner that depends on the interplay between signal- and noise-driven correlations. Moreover, we find that the physiological effects vary by brain region and depend on the range of physiological conditions probed; the associations are more complex than previously reported. The results confirm that it is important to account for the effect of physiological modulators when comparing resting-state fMRI metrics. We note that such modulatory effects may be amplified by disease conditions, which will warrant future investigations.

Insights into the pathophysiology of catch-up compared with non-catch-up growth in children born small for gestational age: an integrated analysis of metabolic and transcriptomic data.

Small for gestational age (SGA) children exhibiting catch-up (CU) growth have a greater risk of cardiometabolic diseases in later life compared with non-catch-up (NCU) SGA children. The aim of this study was to establish differences in metabolism and gene expression profiles between CU and NCU at age 4-9 years. CU children (n=22) had greater height, weight and body mass index standard deviation scores along with insulin-like growth factor-I (IGF-I) and fasting glucose levels but lower adiponectin values than NCU children (n=11; all P<0.05). Metabolic profiling demonstrated a fourfold decrease of urine myo-inositol in CU compared with NCU (P<0.05). There were 1558 genes differentially expressed in peripheral blood mononuclear cells between the groups (P<0.05). Integrated analysis of data identified myo-inositol related to gene clusters associated with an increase in insulin, growth factor and IGF-I signalling in CU children (P<0.05). Metabolic and transcriptomic profiles in CU SGA children showed changes that may relate to cardiometabolic risk.

Trigeminal neuralgia diffusivities using Gaussian process classification and merged group tractography.

ABSTRACT: Imaging of trigeminal neuralgia (TN) has demonstrated key diffusion tensor imaging-based diffusivity alterations in the trigeminal nerve; however, imaging has primarily focused on the peripheral nerve segment because of previous limitations in reliably segmenting small fiber bundles across multiple subjects. We used Selective Automated Group Integrated Tractography to study 36 subjects with TN (right-sided pain) and 36 sex-matched controls to examine the trigeminal nerve (fifth cranial nerve [CN V]), pontine decussation (TPT), and thalamocortical fibers (S1). Gaussian process classifiers were trained by scrolling a moving window over CN V, TPT, and S1 tractography centroids. Fractional anisotropy (FA), generalized FA, radial diffusivity, axial diffusivity, and mean diffusivity metrics were evaluated for both groups, analyzing TN vs control groups and affected vs unaffected sides. Classifiers that performed at greater-than-or-equal-to 70% accuracy were included. Gaussian process classifier consistently demonstrated bilateral trigeminal changes, differentiating them from controls with an accuracy of 80%. Affected and unaffected sides could be differentiated from each other with 75% accuracy. Bilateral TPT could be distinguished from controls with at least 85% accuracy. TPT left-right classification achieved 98% accuracy. Bilateral S1 could be differentiated from controls, where the affected S1 radial diffusivity classifier achieved 87% accuracy. This is the first TN study that combines group-wise merged tractography, machine learning classification, and analysis of the complete trigeminal pathways from the peripheral fibers to S1 cortex. This analysis demonstrates that TN is characterized by bilateral abnormalities throughout the trigeminal pathway compared with controls and abnormalities between affected and unaffected sides. This full pathway tractography study of TN demonstrates bilateral changes throughout the trigeminal pathway and changes between affected and unaffected sides.

Standardizing T1-w/T2-w ratio images in trigeminal neuralgia to estimate the degree of demyelination in vivo.

BACKGROUND: Novel magnetic resonance (MR) imaging techniques have led to the development of T1-w/T2-w ratio images or "myelin-sensitive maps (MMs)" to estimate and compare myelin content in vivo. Currently, raw image intensities in conventional MR images are unstandardized, preventing meaningful quantitative comparisons. We propose an improved workflow to standardize the MMs, which was applied to patients with classic trigeminal neuralgia (CTN) and trigeminal neuralgia secondary to multiple sclerosis (MSTN), to assess the validity and feasibility of this clinical tool. METHODS: T1-w and T2-w images were obtained for 17 CTN patients and 17 MSTN patients using a 3 T scanner. Template images were obtained from ICBM152. Multiple sclerosis (MS) plaques in the pons were labelled in MSTN patients. For each patient image, a Gaussian curve was fitted to the histogram of its intensity distribution, and transformed to match the Gaussian curve of its template image. RESULTS: After standardization, the structural contrast of the patient image and its histogram more closely resembled the ICBM152 template. Moreover, there was reduced variability in the histogram peaks of the gray and white matter between patients after standardization (p < 0.001). MM intensities were decreased within MS plaques, compared to normal-appearing white matter (NAWM) in MSTN patients (p < 0.001) and its corresponding regions in CTN patients (p < 0.001). CONCLUSIONS: Images intensities are calibrated according to a mathematic relationship between the intensities of the patient image and its template. Reduced variability among histogram peaks allows for interpretation of tissue-specific intensity and facilitates quantitative analysis. The resultant MMs facilitate comparisons of myelin content between different regions of the brain and between different patients in vivo. MM analysis revealed reduced myelin content in MS plaques compared to its corresponding regions in CTN patients and its surrounding NAWM in MSTN patients. Thus, the standardized MM serves as a non-invasive, easily-automated tool that can be feasibly applied to clinical populations for quantitative analyses of myelin content.

High resolution >40 keV x-ray radiography using an edge-on micro-flag backlighter at NIF-ARC.

Radiography of low-contrast features in high-density materials evolving on a nanosecond timescale requires a bright photon source in the tens of keV range with high temporal and spatial resolution. One application for sources in this category is the study of dynamic material strength in samples compressed to Mbar pressures at the National Ignition Facility, high-resolution measurements of plastic deformation under conditions relevant to meteor impacts, geophysics, armor development, and inertial confinement fusion. We present radiographic data and the modulation transfer function (MTF) analysis of a multi-component test object probed at ∼100 keV effective backlighter energy using a 5 µm-thin dysprosium foil driven by the NIF Advanced Radiographic Capability (ARC) short-pulse laser (∼2 kJ, 10 ps). The thin edge of the foil acts as a bright line-projection source of hard x rays, which images the test object at 13.2× magnification into a filtered and shielded image plate detector stack. The system demonstrates a superior contrast of shallow (5 µm amplitude) sinusoidal ripples on gold samples up to 90 µm thick as well as enhanced spatial and temporal resolution using only a small fraction of the laser energy compared to an existing long-pulse-driven backlighter used routinely at the NIF for dynamic strength experiments.

Regulatory network analysis of Paneth cell and goblet cell enriched gut organoids using transcriptomics approaches.

The epithelial lining of the small intestine consists of multiple cell types, including Paneth cells and goblet cells, that work in cohort to maintain gut health. 3D in vitro cultures of human primary epithelial cells, called organoids, have become a key model to study the functions of Paneth cells and goblet cells in normal and diseased conditions. Advances in these models include the ability to skew differentiation to particular lineages, providing a useful tool to study cell type specific function/dysfunction in the context of the epithelium. Here, we use comprehensive profiling of mRNA, microRNA and long non-coding RNA expression to confirm that Paneth cell and goblet cell enrichment of murine small intestinal organoids (enteroids) establishes a physiologically accurate model. We employ network analysis to infer the regulatory landscape altered by skewing differentiation, and using knowledge of cell type specific markers, we predict key regulators of cell type specific functions: Cebpa, Jun, Nr1d1 and Rxra specific to Paneth cells, Gfi1b and Myc specific for goblet cells and Ets1, Nr3c1 and Vdr shared between them. Links identified between these regulators and cellular phenotypes of inflammatory bowel disease (IBD) suggest that global regulatory rewiring during or after differentiation of Paneth cells and goblet cells could contribute to IBD aetiology. Future application of cell type enriched enteroids combined with the presented computational workflow can be used to disentangle multifactorial mechanisms of these cell types and propose regulators whose pharmacological targeting could be advantageous in treating IBD patients with Crohn's disease or ulcerative colitis.

Current strategies for monitoring men with localised prostate cancer lack a strong evidence base: observational longitudinal study.

BACKGROUND: The UK National Institute for Health and Clinical Excellence (NICE) guidance recommends conservative management of men with 'low-risk' localised prostate cancer, monitoring the disease using prostate-specific antigen (PSA) kinetics and re-biopsy. However, there is little evidence of the changes in PSA level that should alert to the need for clinical re-assessment. METHODS: This study compares the alerts resulting from PSA kinetics and a novel longitudinal reference range approach, which incorporates age-related changes, during the monitoring of 408 men with localised prostate cancer. Men were monitored by regular PSA tests over a mean of 2.9 years, recording when a man's PSA doubling time fell below 2 years, PSA velocity exceeded 2 ng ml(-1) per year, or when his upper 10% reference range was exceeded. RESULTS: Prostate-specific antigen doubling time and PSA velocity alerted a high proportion of men initially but became unresponsive to changes with successive tests. Calculating doubling time using recent PSA measurements reduced the decline in response. The reference range method maintained responsiveness to changes in PSA level throughout the monitoring. CONCLUSION: The increasing unresponsiveness of PSA kinetics is a consequence of the underlying regression model. Novel methods are needed for evaluation in cohorts currently being managed by monitoring. Meanwhile, the NICE guidance should be cautious.

"Older Adults with ASD: The Consequences of Aging." Insights from a series of special interest group meetings held at the International Society for Autism Research 2016-2017.

A special interest group (SIG) entitled "Older Adults with ASD: The Consequences of Aging" was held at the International Society for Autism Research (INSAR) annual meetings in 2016 and 2017. The SIG and subsequent meetings brought together, for the first time, international delegates who were members of the autistic community, researchers, practitioners and service providers. Based on aging autism research that is already underway in UK, Europe, Australia and North America, discussions focussed on conceptualising the parameters of aging when referring to autism, and the measures that are appropriate to use with older adults when considering diagnostic assessment, cognitive factors and quality of life in older age. Thus, the aim of this SIG was to progress the research agenda on current and future directions for autism research in the context of aging. A global issue on how to define 'aging' when referring to ASD was at the forefront of discussions. The 'aging' concept can in principle refer to all developmental transitions. However, in this paper we focus on the cognitive and physical changes that take place from mid-life onwards. Accordingly, it was agreed that aging and ASD research should focus on adults over the age of 50 years, given the high rates of co-occurring physical and mental health concerns and increased risk of premature death in some individuals. Moreover, very little is known about the cognitive change, care needs and outcomes of autistic adults beyond this age. Discussions on the topics of diagnostic and cognitive assessments, and of quality of life and well-being were explored through shared knowledge about which measures are currently being used and which background questions should be asked to obtain comprehensive and informative developmental and medical histories. Accordingly, a survey was completed by SIG delegates who were representatives of international research groups across four continents, and who are currently conducting studies with older autistic adults. Considerable overlap was identified across different research groups in measures of both autism and quality of life, which pointed to combining data and shared learnings as the logical next step. Regarding the background questions that were asked, the different research groups covered similar topics but the groups differed in the way these questions were formulated when working with autistic adults across a range of cognitive abilities. It became clear that continued input from individuals on the autism spectrum is important to ensure that questionnaires used in ongoing and future are accessible and understandable for people across the whole autistic spectrum, including those with limited verbal abilities.

Impact of motivational interviewing on outcomes of an adolescent obesity treatment: results from the MI Values randomized controlled pilot trial.

The aim of this study is to examine outcomes from MI Values, a motivational interviewing (MI) intervention implemented adjunctive to obesity treatment. Adolescents (n = 99; 73% African American; 74% female; mean body mass index [BMI] percentile = 98.9 ± 1.2) were randomized to receive two MI sessions or education control. All adolescents participated in structured behavioural weight management treatment. Baseline, 3- and 6-month assessments of anthropometrics, dietary intake and physical activity were obtained. Both groups had significant reductions in BMI z-scores and energy intake and increased physical activity at 3 and 6 months (P < 0.05). MI participants reported greater reductions in 3-month energy intake compared with controls. Participation in MI is associated with reduction in energy intake, consistent with better adherence to dietitian visits previously reported from MI Values. MI might be an effective adjunct to adolescent obesity treatment; future research is needed to determine if motivational interviewing can enhance BMI outcomes, via greater adherence to behavioural intervention.

Fatigue Intervention by Nurses Evaluation--the FINE Trial. A randomised controlled trial of nurse led self-help treatment for patients in primary care with chronic fatigue syndrome: study protocol. [ISRCTN74156610].

BACKGROUND: Chronic fatigue syndrome, also known as ME (CFS/ME), is a condition characterised primarily by severe, disabling fatigue, of unknown origin, which has a poor prognosis and serious personal and economic consequences. Evidence for the effectiveness of any treatment for CFS/ME in primary care, where most patients are seen, is sparse. Recently, a brief, pragmatic treatment for CFS/ME, based on a physiological dysregulation model of the condition, was shown to be successful in improving fatigue and physical functioning in patients in secondary care. The treatment involves providing patients with a readily understandable explanation of their symptoms, from which flows the rationale for a graded rehabilitative plan, developed collaboratively with the therapist. The present trial will test the effectiveness and cost-effectiveness of pragmatic rehabilitation when delivered by specially trained general nurses in primary care. We selected a client-centred counselling intervention, called supportive listening, as a comparison treatment. Counselling has been shown to be as effective as cognitive behaviour therapy for treating fatigue in primary care, is more readily available, and controls for supportive therapist contact time. Our control condition is treatment as usual by the general practitioner (GP). METHODS AND DESIGN: This study protocol describes the design of an ongoing, single-blind, pragmatic randomized controlled trial of a brief (18 week) self-help treatment, pragmatic rehabilitation, delivered by specially trained nurse-therapists in patients' homes, compared with nurse-therapist delivered supportive listening and treatment as usual by the GP. An economic evaluation, taking a societal viewpoint, is being carried out alongside the clinical trial. Three adult general nurses were trained over a six month period to deliver the two interventions. Patients aged over 18 and fulfilling the Oxford criteria for CFS are assessed at baseline, after the intervention, and again one year later. Primary outcomes are self-reported physical functioning and fatigue at one year, and will be analysed on an intention-to-treat basis. A qualitative study will examine the interventions' mechanisms of change, and also GPs' drivers and barriers towards referral.

Dissociation of antiviral and antitumor immunity in resistance to Marek's disease.

Immunization of chickens either with gluteral-dehyde-inactivated chicken kidney cells infected with Marek's disease (MD) virus or with glutaraldehyde-inactivated cells of MD lymphoma-derived continuous lymphoblastoid cell lines protected against MD. The former type of immunity was associated with an immunologic suppression of virus replication and virus antigen production after challenge with virulent virus, but lymphocytes specifically cytotoxic to cells bearing MD tumor antigens were not detected. In the latter type of immunity, virus multiplication was not affected; some evidence of the stimulation of cell-mediated antitumor immunity was found. The results supported the view that immunity to MD may be directed against either virus-specific or tumor-specific antigens and that in natural resistance to MD both mechanisms may be operative.

Nature of genetic resistance to Marek's disease in chickens.

Infection of line 6 resistant and line 7 susceptible chickens with Marek's disease virus (MDV) resulted in a depressed phytohemagglutinin (PHA) response and the presence of Marek's disease (MD) tumor-associated surface antigen (MATSA) in the spleens. At 6-10 weeks after infection, recovery in PHA response, diminution in the number of MATSA cells, and the presence of significant anti-MATSA immunity were observed in line 6 but not in line 7 chickens. Both lines had antibody-dependent cell-mediated antiviral immunity, but T-cell-mediated antiviral immunity was detected only in line 6 and the surviving line 7 chickens. Lymphoproliferative lesions were found only in line 7 chickens, an virus titers were significantly higher in line 7 than in line 6 chickens and embryos. Lymphoid organ weights and the number of lymphocytes of line 6 were significantly lower than those of line 7. These data suggests that resistance to MD in line 6 chickens was due to a) a deficiency in the aggregate number of target lymphocytes, b) a restriction in the ability to lymphocytes to nonproductively replicate MDV, and c) the involvement of cellular antiviral and antitumor immune responses.

Motivational interviewing targeting diet and physical activity improves adherence to paediatric obesity treatment: results from the MI†Values randomized controlled trial.

BACKGROUND: Adherence is a challenge in obesity treatment. Motivational interviewing (MI) may promote patient adherence. MI Values is a randomized controlled trial of MI implemented as an adjunct to an adolescent obesity treatment [Teaching Encouragement Exercise Nutrition Support (T.E.E.N.S.)]. OBJECTIVE: Assess effects of MI Values on T.E.E.N.S. attrition and adherence. METHODS: Participants were randomized to MI (n = 58) or control (n = 41). At weeks 1 and 10, MI participants had brief MI sessions; controls viewed health education videos. All participants continued with T.E.E.N.S. (biweekly dietitian and behavioural support visits; 3 times per week supervised physical activity). Assessments were repeated at baseline, 3 and 6 months. T-tests and chi-square analyses examined T.E.E.N.S. attrition and adherence by group. RESULTS: Adolescents (N = 99) were primarily African-American (73%) females (74%); age = 13.8 ± 1.8 years, body mass index percentile = 98.0 ± 1.2. Compared with controls, MI participants had greater 3-month adherence overall (89.2% vs. 81.0%, P = 0.040), and to dietitian (91.3% vs. 84.0%; P = 0.046) and behavioural support (92.9% vs. 85.2%; P = 0.041) visits, and greater 6-month adherence overall (84.4% vs. 76.2%, P = 0.026) and to behavioural support visits (87.5% vs. 78.8%, P = 0.011). CONCLUSIONS: MI enhanced adherence to this obesity intervention. MI Values is the first study to examine the impact of MI on treatment adherence among obese, primarily African-American adolescents.

Preclinical comparison in AR4-2J tumor-bearing mice of four radiolabeled 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-somatostatin analogs for tumor diagnosis and internal radiotherapy.

Somatostatin analogs labeled with radionuclides are of considerable interest in nuclear oncology as diagnostic or therapeutic tools for somatostatin receptor (SSTR)-expressing tumors. We investigated the suitability of DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) as a replacement for the widely used diethylenetriaminepentaacetic acid, to enable stable labeling of somatostatin analogs with both therapeutic (90Y) and diagnostic (111In) radionuclides. The three clinically relevant somatostatin agonists, octreotide, vapreotide, and lanreotide, together with the newly designed Tyr3-octreotide (TyrOc), were conjugated to DOTA and labeled with 90Y or 111In. For all DOTA-somatostatin analogs tested, irrespective of the incorporated radionuclide, we observed favorable biodistribution profiles in AR4-2J tumor-bearing mice: 1) a rapid clearance from all SSTR-negative tissues except kidney; 2) a specific uptake in SSTR-positive tissues, including tumor; and 3) an excellent tumor penetration. The main route of excretion was via the kidneys. Nevertheless, DOTATOC was clearly superior to the other DOTA-somatostatin analogs tested, as well as OctreoScan, as indicated by the highest tumor-to-nontarget-tissue ratio, including the tumor-to-SSTR-positive-tissue ratios. The presence of different SSTR subtypes in the SSTR-positive tissues possibly contributes to these differential uptakes. We assume that the very favorable behavior of DOTATOC in our mouse model makes this radioligand very promising for future applications in nuclear oncology.

Unanswered questions in screening for prostate cancer.

Prostate cancer fulfils some of the conditions required of a disease that might be managed by population screening. In a cohort of 50- to 60-year-old men, carrying out a rectal examination and prostate specific antigen (PSA) test will detect clinically suspicious areas within the prostate in approximately 5%, and approximately 10% will have a raised PSA. We are however unsure which of the prostate cancers that are known to be present in approximately 30-40% of men aged over 60 years will be detected. Eventually after such screening, around 4% of men with an otherwise normal prostate will be found to have prostate cancers. The use of rectal examination may increase the number of tumours found, but will reduce compliance. The use of free/total PSA ratios will reduce the number of unnecessary biopsies at the expense of missing some tumours. Of more concern, we remain uncertain how effective aggressive local treatment is in altering the natural history of the disease. The risk of a 50-year-old man with a 25 year life expectancy of having microscopic cancer is 42%, of having clinically evident cancer is 9.5%, and of dying of prostate cancer 2.9%. Only a small proportion of cancers known to be present become clinically evident: more men die with prostate cancer than of it. Screening will identify some men with cancer who will not benefit from treatment. It is unclear whether screening would be followed by a reduction in morbidity and mortality. Recent data suggest a screening effect has been observed in the USA with: an increase in incidence, a decrease in men with distant metastases. The small decrease in mortality recently observed (many times smaller than the increase in incidence) may be confounded by inappropriate 'attribution' of cause of death, the detection of men with better prognosis distant metastatic disease responsive to hormonal ablation and changes in social factors such as diet. Future changes may incorporate molecular markers that might aid identification of men best treated aggressively because of a risk of progression. Tests to identify genetic pre-disposition may also allow targeted screening. New treatments and early chemoprevention or dietary strategies will again shift the ground on which these arguments are being rehearsed. The most urgent evidence required concerns the effectiveness of treatment strategies.

Evidence against vasoactive intestinal polypeptide as the relaxant neurotransmitter in human cavernosal smooth muscle.

1. The putative role of vasoactive intestinal polypeptide (VIP) as the relaxant neurotransmitter in human cavernosal smooth muscle has been studied in isolated tissue preparations. 2. Consistent neurogenic relaxations were evoked by electrical field stimulation (EFS; 2-64 pulses/train, 0.8 ms pulse duration, 10 Hz). VIP (0.1-3 microM) relaxed cavernosal smooth muscle in a dose-dependent fashion. Relaxant responses to both EFS and VIP were reduced in tissue from impotent men. 3. Neurogenic relaxant responses were not diminished in the presence of the VIP-inactivating peptidase, alpha-chymotrypsin (alpha-CT, 2 units ml-1). In contrast VIP-induced relaxations were completely abolished. 4. Inhibition of nitric oxide synthase by NG-nitro-L-arginine (30 microM), and of guanylate cyclase by methylene blue (50 microM) caused highly significant reductions of neurogenic relaxant responses whereas VIP-evoked relaxations were unaffected. 5. It is concluded that VIP-evoked relaxations are not mediated by the NO-guanosine 3':5'-cyclic monophosphate (cyclic GMP) pathway and that VIP release is not essential for neurogenic relaxation of human cavernosal smooth muscle. VIP does not therefore act as the major relaxant neurotransmitter in this tissue.