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Abstract Background In 1996, the National Cancer Institute hosted an international workshop to develop criteria to identify patients with colorectal cancer who should be offered microsatellite instability (MSI) testing due to an increased risk for Hereditary Nonpolyposis Colorectal Cancer (HNPCC). These criteria were further modified in 2004 and became known as the revised Bethesda Guidelines. Our study aimed to retrospectively evaluate the percentage of patients diagnosed with HNPCC tumors in 2004 who met revised Bethesda criteria for MSI testing, who were referred for genetic counseling within our institution. Methods All HNPCC tumors diagnosed in 2004 were identified by accessing CoPath, an internal database. Both the Tumor Registry and patients' electronic medical records were accessed to collect all relevant family history information. The list of patients who met at least one of the revised Bethesda criteria, who were candidates for MSI testing, was then cross-referenced with the database of patients referred for genetic counseling within our institution. Results A total of 380 HNPCC-associated tumors were diagnosed at our institution during 2004 of which 41 (10.7%) met at least one of the revised Bethesda criteria. Eight (19.5%) of these patients were referred for cancer genetic counseling of which 2 (25%) were seen by a genetics professional. Ultimately, only 4.9% of patients eligible for MSI testing in 2004 were seen for genetic counseling. Conclusion This retrospective study identified a number of barriers, both internal and external, which hindered the identification of individuals with HNPCC, thus limiting the ability to appropriately manage these high risk families.

To date, there are no efficacious translational solutions for end-stage urinary bladder dysfunction. Current surgical strategies, including urinary diversion and bladder augmentation enterocystoplasty (BAE), utilize autologous intestinal segments (e.g. ileum) to increase bladder capacity to protect renal function. Considered the standard of care, BAE is fraught with numerous short- and long-term clinical complications. Previous clinical trials employing tissue engineering approaches for bladder tissue regeneration have also been unable to translate bench-top findings into clinical practice. Major obstacles still persist that need to be overcome in order to advance tissue-engineered products into the clinical arena. These include scaffold/bladder incongruencies, the acquisition and utility of appropriate cells for anatomic and physiologic tissue recapitulation, and the choice of an appropriate animal model for testing. In this study, we demonstrate that the elastomeric, bladder biomechanocompatible poly(1,8-octamethylene-citrate-co-octanol) (PRS; synthetic) scaffold coseeded with autologous bone marrow-derived mesenchymal stem cells and CD34 + hematopoietic stem/progenitor cells support robust long-term, functional bladder tissue regeneration within the context of a clinically relevant baboon bladder augmentation model simulating bladder trauma. Partially cystectomized baboons were independently augmented with either autologous ileum or stem-cell-seeded small-intestinal submucosa (SIS; a commercially available biological scaffold) or PRS grafts. Stem-cell synergism promoted functional trilayer bladder tissue regeneration, including whole-graft neurovascularization, in both cell-seeded grafts. However, PRS-augmented animals demonstrated fewer clinical complications and more advantageous tissue characterization metrics compared to ileum and SIS-augmented animals. Two-year study data demonstrate that PRS/stem-cell-seeded grafts drive bladder tissue regeneration and are a suitable alternative to BAE., (© The Author(s) 2024. Published by Oxford University Press on behalf of National Academy of Sciences.)

A model is proposed to consider sexual climax in men, women, and animals as a unitary phenomenon. Sexual climax is a stereotyped rhythmic pattern of spinally generated neural activity in the autonomic and somatic nerves innervating pelvic organs. A column of neurons in the spinal cord of the male rat is strongly activated by ejaculation (sexual climax in the male). These neurons project to the thalamus and are therefore called lumbar spinothalamic cells (LSt cells). Comprehensive studies have demonstrated that the LSt cells constitute a central pattern generator of ejaculation. These findings have been extended to female animals. Further studies identified LSt cells in the lumbar spinal cord of men and women. Strong evidence indicates that the LSt cells mediate ejaculation in men. The climax model generalizes and extends these studies. It postulates that LSt cells in the lumbar spinal cord of humans and animals of both sexes generate climax. The LSt cells generate the neural activity driving the pelvic contractions and other responses of climax. The activity is transmitted to supraspinal sites to activate orgasm. The LSt cells receive excitatory and inhibitory projections from supraspinal sites. The descending projections reflect subjective arousal and inhibitions. Spinal sensory neurons from the genitals provide excitatory and inhibitory innervation to the LSt cells. These represent pleasurable and noxious sensations. The supraspinal and spinal excitatory and inhibitory inputs are integrated by the LSt. When the sum of the excitatory inputs, minus the sum of the inhibitory inputs reaches a threshold, the LSt cells generate sexual climax., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Topical photodynamic therapy (PDT) is widely used to treat superficial nonmelanoma skin cancer and dysplasia, and is generally well tolerated. However, as with all treatments, adverse effects may occur and awareness may facilitate approaches to prevention and management., Objectives: To review the available evidence relating to the adverse effects of topical PDT, to help inform recommendations in updated clinical guidelines produced by the British Association of Dermatologists and British Photodermatology Group, and the efficacy of preventative and therapeutic approaches., Methods: This review summarizes the published evidence related to the adverse effects of topical PDT and attempts to interpret this evidence in the context of patient risk and management., Results: Pain and discomfort during PDT are acute adverse effects, which can be minimized through the use of modified and low-irradiance PDT regimens and do not therefore usually limit successful treatment delivery. Other adverse effects include the risk of contact allergy to photosensitizer prodrugs, although this is rare but should be kept in mind, particularly for patients who have received multiple PDT treatments to larger areas. There are no other significant documented longer-term risks and, to date, no evidence of cumulative toxicity or photocarcinogenic risk., Conclusions: Topical PDT is usually well tolerated, reinforcing the utility of this important therapeutic option in dermatology practice. The main acute adverse effect of pain can typically be minimized through preventative approaches of modified PDT regimens. Other adverse effects are uncommon and generally do not limit treatment delivery., (© 2018 British Association of Dermatologists.)

Background: Topical photodynamic therapy (PDT) is an established treatment option for low-risk basal cell carcinoma (BCC)., Objectives: To compare efficacy, cosmesis and tolerability of PDT for BCC with alternative treatments., Methods: MEDLINE, PubMed, Embase and CENTRAL databases were searched from inception until 1 September 2017. Included studies were randomized controlled trials (RCTs) of PDT for nodular (n) and superficial (s) BCC reporting at least one of the following outcomes: clearance at 3 months and sustained at 1 or 5 years; recurrence at ≥ 1 year; cosmesis; adverse events; tolerability., Results: From 2331 search results, 15 RCTs (2327 patients; 3509 BCCs) were included. PDT efficacy (5-year sustained clearance) was high but inferior to excisional surgery [nBCC pooled risk ratio (RR) 0·76; 95% confidence interval (CI) 0·63-0·91], and without re-treatment of partially responding lesions, was modestly inferior to imiquimod (sBCC: RR 0·81; 95% CI 0·70-0·95) and similar to fluorouracil (sBCC: RR 0·88; 95% CI 0·75-1·04). Five-year sustained clearance was inferior with conventional vs. fractionated PDT (sBCC: RR 0·76; 95% CI 0·68-0·84). PDT cosmesis was superior to surgery (sBCC: RR 1·68, 95% CI 1·32-2·14; nBCC: RR 1·82, 95% CI 1·19-2·80) and cryosurgery (BCC: RR 3·73, 95% CI 1·96-7·07), and without re-treatment of partially responding lesions was similar to imiquimod (sBCC: RR 1·01, 95% CI 0·85-1·19) and fluorouracil (sBCC: RR 1·04, 95% CI 0·88-1·24). Peak pain was higher but of shorter duration with PDT than topical treatments. Serious adverse reactions were rarer with PDT than imiquimod (sBCC: RR 0·05, 95% CI 0·00-0·84) and fluorouracil (sBCC: RR 0·11, 95% CI 0·01-2·04). Combination PDT regimens demonstrated reduced recurrence and improved cosmesis; however, results from these small studies were often nonsignificant., Conclusions: PDT is an effective treatment for low-risk BCC, with excellent cosmesis and safety. Imiquimod has higher efficacy than single-cycle PDT but more adverse effects. Highest efficacy is with excisional surgery. Fractionated and combination PDT options warrant further study., (© 2018 British Association of Dermatologists.)

Purpose: Lower urinary tract symptoms are a common finding in patients with chronic prostatitis/chronic pelvic pain syndrome. We previously reported that the mast cell-tryptase-PAR2 (protease activated receptor 2) axis has a critical role in the development of chronic pain in experimental autoimmune prostatitis, a mouse model of chronic prostatitis/chronic pelvic pain syndrome. Therefore, we examined whether PAR2 activation mediates lower urinary tract dysfunction., Materials and Methods: Functional cystometry was done in male B6 mice along with immunoblotting and immunohistochemistry for the expression of COL1A1 (collagen type I α I) and α-SMA (α-smooth muscle actin). Flow cytometry analysis was performed on single cell suspensions of the prostate, bladder, lymph nodes and spleen., Results: Experimental autoimmune prostatitis resulted in increased urinary voiding frequency and decreased bladder capacity 30 days after initiation. Concurrently, there was increased expression of COL1A1 and α-SMA in the prostates and bladders. In contrast, induction of experimental autoimmune prostatitis in PAR2 knockout mice did not result in altered urodynamics or increased markers of fibrosis in the prostate or the bladder. Single cell suspensions of the prostate, bladder, lymph nodes and spleen demonstrated that in the absence of PAR2 cellular inflammatory mechanisms were still initiated in experimental autoimmune prostatitis but PAR2 expression may be required to maintain chronic inflammation. Finally, antibody mediated PAR2 neutralization normalized urinary voiding frequency and bladder capacity, and attenuated chronic pelvic pain., Conclusions: PAR2 activation in the prostate may contribute to the development of lower urinary tract dysfunction through proinflammatory as well as profibrotic pathways., (Copyright © 2016 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Melanonychia is uncommon. We report the first case of histopathologic recurrence of a completely excised subungual congenital nevus that presented as congenital melanonychia., (© 2015 Wiley Periodicals, Inc.)

Introduction: The objective of this work is to examine if sensory innervation impacts lower urinary tract symptoms (LUTS). Onabotulinum toxin A (BoNTA) has been used for the treatment of overactive and neurogenic bladder and as a treatment for LUTS secondary to benign prostatic hyperplasia (BPH). The mechanism of how BoNTA impacts LUTS/BPH is unclear. In rats, BoNTA injection causes prostate denervation, apoptosis and atrophy. In clinical trials reduced prostate size and LUTS are observed inconsistently, suggesting a neurologic component. We will examine if BoNTA treatment inhibits substance P production in sensory nerve fibers in the rat prostate., Methods: Twenty Sprague Dawley rats were divided into four groups including 1X PBS (control, n=6), 2.5 units Onabotulinum toxin A (BoNTA, n=6), 5 units BoNTA (n=6) injected into both lobes of the ventral prostate (VP) and sham surgery (n=2). Rats were Euthanized after one week. Substance P and its receptor neurokinin 1 localization and quantification were performed by counting the number of stained neurons and nerve bundles, by semi-quantitative immunohistochemical analysis and by western analysis., Results: Substance P was localized in neuronal axons and bundles in the stroma of the VP but not in the epithelium. Receptor neurokinin 1 was identified in neuronal bundles of the stroma and in columnar epithelium of the VP ducts. Substance P decreased ~90% after BoNTA treatment (p=0.0001) while receptor neurokinin 1 did not change by IHC (p=0.213) or Western (p=0.3675)., Conclusions: BoNTA treatment decreases substance P in the rat VP.

Benign prostatic hyperplasia (BPH) is a serious health concern and is an underlying cause of lower urinary tract symptoms (LUTS) in many men. In affected men, LUTS/BPH is believed to result from benign proliferation of the prostate resulting in bladder outlet obstruction. Postnatal growth of the prostate is controlled via growth factor and endocrine mechanisms. However, little attention had been given to the function of the autonomic nervous system in prostate growth and differentiation. Nerve growth factor (NGF) is a prostatic mitogen that has a trophic role in autonomic sensory end organ interaction. In this study, we examine how the autonomic nervous system influences prostate growth as a function of age by quantifying NGF in the rat ventral prostate (VP) after pelvic ganglionectomy. Unilateral pelvic ganglionectomy was performed on postnatal days 30 (P30), 60 and 120 Sprague-Dawley rats in comparison to sham controls (n=39). Semiquantitative RT-PCR, Western blotting and immunohistochemical analysis for NGF were performed on denervated, intact (contralateral side) and sham control VP 7 days after surgery. Ngf RNA expression was significantly increased in the denervated and intact hyperplastic VP. Western blotting showed age-dependent increases in NGF protein at P60 in the contralateral intact VP. NGF was localized in the nerves, basal cells and columnar epithelium of the prostatic ducts. Denervation causes age-dependent increases in NGF in the VP, which is a potential mechanism by which the autonomic nervous system may regulate prostate growth and lead to BPH/LUTS.

Leptin decreases food intake and increases energy expenditure. Leptin administration into the CNS of mice or rats increases alveolar ventilation and dysfunction in leptin signaling has been implicated in the hypoventilation that can accompany obesity. An increase in CO(2) chemosensitivity has been implicated in this response but it is unclear whether ventilation is augmented when PCO(2) is maintained constant. We examined the effects of intravenous leptin to test the hypothesis that systemic leptin administration in isoflurane anesthetized, mechanically ventilated and vagotomized rats would lead to a sustained increase in respiratory motor output that was independent of changes in end-tidal PCO(2), body temperature or lung inflation pressure (an indicator of overall lung and chest wall compliance). In anesthetized Sprague-Dawley rats with end-tidal PCO(2), lung compliance and rectal temperature maintained constant, injection of a bolus of leptin (0.25 mg, 0.5 mg/ml, i.v.), followed over the next 1 h by the intravenous infusion of an additional 0.25 mg, elicited a progressive increase in the peak amplitude of integrated phrenic nerve discharge lasting at least 1 h beyond the end of the infusion. The increase peaked at 90 min at 58.3 ± 5.7% above baseline. There was an associated increase in the slope of the phrenic response to increasing inspired CO(2). There was also a moderate and sustained decrease in arterial pressure 9 ± 1.3 mmHg at 120 min, with no associated change in heart rate. These data indicate that leptin elicits a sustained increase in respiratory motor output that outlasts the administration leptin via a mechanism that does not require alterations in arterial PCO(2), body temperature, or systemic afferent feedback via the vagus nerves. This stimulation may help to prevent obesity-related hypoventilation.

The incidence of phototoxicity as a side effect of ciprofloxacin appears to be increased in patients with cystic fibrosis compared to the general population (approximately 2.4%). We used an interview-based questionnaire to determine the incidence of such phototoxic skin reactions in cystic fibrosis patients. Results from 105 respondents revealed the incidence of ciprofloxacin-induced phototoxicity in the adult cystic fibrosis population in Northern Ireland to be 48.4% with only 66% of the patients recalling being given sun care information beforehand. We concluded that the incidence of phototoxicity is increased in patients with cystic fibrosis and that it is important for all to receive good sun care information prior to taking ciprofloxacin given the high risk of developing phototoxic rash., (© 2012 John Wiley & Sons A/S.)

Introduction: A population of lumbar spinothalamic cells (LSt cells) has been demonstrated to play a pivotal role in ejaculatory behavior and comprise a critical component of the spinal ejaculation generator. LSt cells are hypothesized to regulate ejaculation via their projections to autonomic and motor neurons in the lumbosacral spinal cord., Aim: The current study tested the hypothesis that ejaculatory reflexes are dependent on LSt cells via projections within the lumbosacral spinal cord., Methods: Male rats received intraspinal injections of neurotoxin saporin conjugated to substance P analog, previously shown to selectively lesion LSt cells. Two weeks later, males were anesthetized and spinal cords were transected. Subsequently, males were subjected to ejaculatory reflex paradigms, including stimulation of the dorsal penile nerve (DPN), urethrogenital stimulation or administration of D3 agonist 7-OH-DPAT. Electromyographic recordings of the bulbocavernosus muscle (BCM) were analyzed for rhythmic bursting characteristic of the expulsion phase of ejaculation. In addition, a fourth commonly used paradigm for ejaculation and erections in unanesthetized, spinal-intact male rats was utilized: the ex copula reflex paradigm., Main Outcome Measures: LSt cell lesions were predicted to prevent rhythmic bursting of BCM following DPN, urethral, or pharmacological stimulation, and emissions in the ex copula paradigm. In contrast, LSt cell lesions were not expected to abolish erectile function as measured in the ex copula paradigm., Results: LSt cell lesions prevented rhythmic contractions of the BCM induced by any of the ejaculatory reflex paradigms in spinalized rats. However, LSt cell lesions did not affect erectile function nor emissions determined in the ex copula reflex paradigm., Conclusions: These data demonstrate that LSt cells are essential for ejaculatory, but not erectile reflexes, as previously reported for mating animals. Moreover, LSt cells mediate ejaculation via projections within the spinal cord, presumably to autonomic and motor neurons., (© 2011 International Society for Sexual Medicine.)

Introduction: The sexual reflex ejaculation is controlled by a spinal ejaculation generator located in the lumbosacral spinal cord. A population of spinothalamic (LSt) neurons forms a key component of this generator, as manipulations of LSt cells either block or trigger ejaculation. However, it is currently unknown which afferent signals contribute to the activation of LSt cells and ejaculation., Aim: The current study tested the hypothesis that glutamate, via activation of N-Methyl-D-aspartic acid (NMDA) receptors in LSt cells, is a key regulator of ejaculation., Methods: Expression of phosphorylated NMDA receptor subunit 1 (NR1) was investigated following mating, or following ejaculation induced by electrical stimulation of the dorsal penile nerve (DPN) in anesthetized, spinalized male rats. Next, the effects of intraspinal delivery of NMDA receptor antagonist AP-5 on DPN stimulation-induced ejaculation were examined. Moreover, the ability of intraspinal delivery of NMDA to trigger ejaculation was examined. Finally, the site of action of NMDA was determined by studying effects of NMDA in male rats with LSt cell-specific lesions., Main Outcome Measures: Expression of NR1 and phosphorylated NR1 in LSt cells was analyzed. Electromyographic recordings of the bulbocavernosus muscle (BCM) were recorded in anesthetized, spinalized rats following stimulation of the DPN and delivery of AP-5 or NMDA., Results: Results indicate that the NR1 receptors are activated in LSt cells following ejaculation in mating animals or induced by DPN stimulation in anesthetized, spinalized animals. Moreover, NR1 activation in LSt cells is an essential trigger for rhythmic BCM bursting, as DPN stimulation-induced reflexes were absent following administration of NMDA receptor antagonist in the L3-L4 spinal area, and were triggered by NMDA. NMDA effects were dependent on intact LSt cells and were absent in LSt-lesioned males., Conclusion: These results demonstrate that glutamate, via activation of NMDA receptors in LSt cells, is a key afferent signal for ejaculation., (© 2011 International Society for Sexual Medicine.)

SHH plays a significant role in peripheral nerve regeneration and has clinical potential to be used as a regenerative therapy for the CN in prostatectomy patients and in other patients with neuropathy of peripheral nerves. Efforts to regenerate the cavernous nerve (CN), which provides innervation to the penis, have been minimally successful, with little translation into improved clinical outcomes. We propose that, Sonic hedgehog (SHH), is critical to maintain CN integrity, and that SHH delivered to the CN by novel peptide amphiphile (PA) nanofibers, will promote CN regeneration, restore physiological function, and prevent penile morphology changes that result in erectile dysfunction (ED). We performed localization studies, inhibition of SHH signaling in the CN, and treatment of crushed CNs with SHH protein via linear PA gels, which are an innovative extended release method of delivery. Morphological, functional and molecular analysis revealed that SHH protein is essential to maintain CN architecture, and that SHH treatment promoted CN regeneration, suppressed penile apoptosis and caused a 58% improvement in erectile function in less than half the time reported in the literature. These studies show that SHH has substantial clinical application to regenerate the CN in prostatectomy and diabetic patients, that this methodology has broad application to regenerate any peripheral nerve that SHH is necessary for maintenance of its structure, and that this nanotechnology method of protein delivery may have wide spread application as an in vivo delivery tool in many organs., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Introduction: Erectile dysfunction (ED) is a serious medical condition that affects 16-82% of prostate cancer patients treated by radical prostatectomy and current treatments are ineffective in 50-60% of prostatectomy patients. The reduced efficacy of treatments makes novel therapeutic approaches to treat ED essential. The secreted protein Sonic hedgehog (SHH) is a critical regulator of penile smooth muscle and apoptosis that is decreased in cavernous nerve (CN) injury and diabetic ED models. Past studies using Affi-Gel beads have shown SHH protein to be effective in suppressing apoptosis caused by CN injury., Aim: We hypothesize that SHH protein delivered via novel peptide amphiphile (PA) nanofibers will be effective in suppressing CN injury-induced apoptosis., Methods: Adult Sprague Dawley rats (n=50) were used to optimize PA injection in vivo. PA with SHH protein (n=16) or bovine serum albumin (BSA) (control, n=14) was injected into adult rats that underwent bilateral CN cut. Rats were sacrificed at 2, 4, and 7 days. Alexa Fluor-labeled SHH protein was used to determine the target of SHH signaling (n=3)., Main Outcome Measures: Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and semiquantitative immunohistochemical analysis for SHH protein and cluster differentiation protein three (CD3) were performed., Results: SHH-PA caused a 25% and 16% reduction in apoptosis at 4 and 7 days after CN injury and a 9.3% and 19% increase in SHH protein at 4 and 7 days after CN injury. CD3 protein was not observed in SHH-PA-treated penis. In vitro, 73% of SHH protein diffused from PA within 6 days. Labeled SHH was observed in smooth muscle., Conclusions: PA technology is effective in delivering SHH protein to the penis and SHH is effective in suppressing CN injury-induced apoptosis. These results suggest substantial translational potential of this methodology and show that only a short duration of SHH treatment is required to impact the apoptotic index., (© 2010 International Society for Sexual Medicine.)

Introduction: Ejaculation is a reflex controlled by a spinal ejaculation generator located in the lumbosacral spinal cord responsible for the coordination of genital sensory with autonomic and motor outputs that regulate ejaculation. In the male rat, a population of lumbar spinothalamic cells (LSt cells) comprises an essential component of the spinal ejaculation generator. LSt cells are activated with ejaculation, but the nature of the signal transduction pathways involved in this activation is unknown. Moreover, it is unknown if LSt cell activation is required for expression of ejaculation., Aim: The current study tested the hypothesis that ejaculatory reflexes are triggered via activation of the mitogen-activated protein (MAP) kinase signaling pathway in the LSt cells., Methods: Expression of phosphorylated extracellular signal-related kinases 1 and 2 (pERK) was investigated following mating behavior, or following ejaculation induced by electrical stimulation of the dorsal penile nerve (DPN) in anesthetized, spinalized male rats. Next, the effects of intrathecal or intraspinal delivery of Mitogen-activated protein/extracellular signal-regulated kinase (MEK) inhibitor U0126 on DPN stimulation-induced ejaculation was examined., Main Outcome Measures: Expression of pERK in LSt cells and associated areas was analyzed. Electromyographic recordings of the bulbocavernosus muscle were recorded in anesthetized, spinalized rats., Results: Results indicate that the MAP kinase signaling pathway is activated in LSt cells following ejaculation in mating animals or induced by DPN stimulation in anesthetized, spinalized animals. Moreover, ERK activation in LSt cells is an essential trigger for ejaculation, as DPN stimulation-induced reflexes were absent following administration of MEK inhibitor in the L3-L4 spinal area., Conclusion: These data provide insight into the nature of the signal transduction pathways involved in the activation of ejaculation through LSt cells. The data demonstrate that ERK activation in LSt cells is essential for ejaculation and contribute to a more detailed understanding of the spinal generation of ejaculation.

Background: Aquagenic wrinkling of the palms (AWP) is a rare condition characterised by the development of oedema and excessive wrinkling of the palms following exposure to water. It has frequently been associated with cystic fibrosis (CF). Early reports of AWP have only been case reports or small case series; there has only been one reported prevalence study of AWP in a CF population., Objective: To determine the incidence and characteristics of AWP in the adult CF population in Northern Ireland., Methods: 105 CF patients were interviewed. The patients were asked whether they noticed excess wrinkling of the hands when exposed to water. If they answered 'yes', further questions were asked regarding clinical characteristics. The atopic status, CF genotype and drug history were recorded for each patient. Formal testing of 7 patients was carried out., Results: Out of the 105 patients who were interviewed, 43 (41%) described AWP. Of the 43 patients with AWP, 20 were male and 23 were female. There was no association of AWP with genotype, atopy or concomitant drug intake., Conclusion: AWP appears to have an equal sex incidence, and the high number of cases in the population studied would suggest that this condition is underreported., (Copyright © 2010 S. Karger AG, Basel.)

Multicentre randomized controlled studies now demonstrate high efficacy of topical photodynamic therapy (PDT) for actinic keratoses, Bowen's disease (BD) and superficial basal cell carcinoma (BCC), and efficacy in thin nodular BCC, while confirming the superiority of cosmetic outcome over standard therapies. Long-term follow-up studies are also now available, indicating that PDT has recurrence rates equivalent to other standard therapies in BD and superficial BCC, but with lower sustained efficacy than surgery in nodular BCC. In contrast, current evidence does not support the use of topical PDT for squamous cell carcinoma. PDT can reduce the number of new lesions developing in patients at high risk of skin cancer and may have a role as a preventive therapy. Case reports and small series attest to the potential of PDT in a wide range of inflammatory/infective dermatoses, although recent studies indicate insufficient evidence to support its use in psoriasis. There is an accumulating evidence base for the use of PDT in acne, while detailed study of an optimized protocol is still required. In addition to high-quality treatment site cosmesis, several studies observe improvements in aspects of photoageing. Management of treatment-related pain/discomfort is a challenge in a minority of patients, and the modality is otherwise well tolerated. Long-term studies provide reassurance over the safety of repeated use of PDT.

An 8-year-old boy presented with eczematous skin lesions, recurrent otitis media and unexplained pyrexias. X-linked agammaglobulinaemia was diagnosed and treatment commenced with intravenous immunoglobulin replacement therapy. X-linked agammaglobulinaemia (XLA) is a primary immunodeficiency syndrome associated with a deficiency of B lymphocytes, caused by a defect in the expression of Bruton's tyrosine kinase. It affects only boys and usually presents before the age of 2 years with recurrent bacterial sinopulmonary infections. IgG levels are usually <2 g/L (normal range 5.4-16.1) and IgM and IgA are usually undetectable. The commonest cutaneous features of XLA are pyogenic skin infections; however, eczema can occur with increased frequency. We report a child who presented with multiple discrete eczematous lesions who subsequently developed eczematous exacerbations several days after administration of intravenous immunoglobulin (IVIg) replacement therapy.

Thirty to eighty-seven percent of patients treated by radical prostatectomy experience erectile dysfunction (ED). The reduced efficacy of treatments in this population makes novel therapeutic approaches to treat ED essential. We propose that abundant apoptosis observed in penile smooth muscle when the cavernous nerve (CN) is cut (mimicking the neural injury which can result from prostatectomy) is a major contributing factor to ED development. We hypothesize that decreased Sonic hedgehog (SHH) signaling is a cause of ED in neurological models of impotence by increasing apoptosis in penile smooth muscle. We examined this hypothesis in a bilateral CN injury model of ED. We found that the active form of SHH protein was significantly decreased 1.2-fold following CN injury, that SHH inhibition causes a 12-fold increase in smooth muscle apoptosis in the penis, and that SHH treatment at the time of CN injury was able to decrease CN injury-induced apoptosis (1-3-fold) in a dose-dependent manner. These results show that SHH stabilizes the alterations of the corpora cavernosal smooth muscle following nerve injury.

Background: Glomuvenous malformations (GVMs) are rare bluish lesions that can affect the skin and mucosal surfaces. They represent defects in vasculogenesis. Lesions can occur sporadically or in an autosomal dominant mode of inheritance. Recent studies have shown that mutations in the glomulin gene (GLMN) on chromosome 1p21-22 are responsible for familial GVMs., Objectives: To search for mutations in GLMN in Irish families with GVMs., Methods: We identified four Irish families with GVMs and confirmed linkage to chromosome 1p21-22 in these cases. We sequenced the glomulin gene in all affected and unaffected members of the families. Results Linkage analysis showed that affected individuals from the families shared a common haplotype. Mutation analysis revealed a delAAGAA mutation in exon 3 of the glomulin gene in all four families with GVMs., Conclusions: We confirm that mutations in the glomulin gene are responsible for GVMs and suggest a founder Irish mutation in the glomulin gene in four Irish families.

Background: Psoriasis is a genetically determined inflammatory skin disease. It is now recognized that narrow band TL-01 phototherapy is an effective treatment for psoriasis. However, ultraviolet (UV) exposure induces p53 mutations in keratinocytes and repeated exposure of skin to UV radiation results in clonal expansion of these initiated p53-mutant cells within the epidermis., Aim: The present study aims to examine epidermal p53 expression in the skin of psoriatic patients at different time points following TL-01 phototherapy., Methods: Skin samples from patients suffering from plaque-type psoriasis, collected before, during and at the final stages of TL-01 phototherapy were examined for p53 expression by immunohistochemistry., Results/conclusion: Our results showed an increase in p53 expressing keratinocytes following TL-01 phototherapy. Some of these cells were arranged spatially, as conical clones arising from putative stem cell compartments, suggesting that the chronic TL-01 treatment might have triggered cell growth and clonal expansion, an important step in initiating skin carcinogenesis.

Photopheresis or extracorporeal photochemotherapy (ECP) is a novel immunomodulatory therapy which involves separation of the patient's leucocyte-rich plasma, followed by ex vivo administration of a photosensitizer and ultraviolet A radiation, before reinfusion. ECP has been used successfully for the treatment of cutaneous T-cell lymphoma (CTCL: Sézary syndrome), graft-versus-host disease (GVHD) and cardiac transplant rejection. ECP has a dose-sparing effect on concurrent immunosuppressive therapy. The procedure induces apoptosis of the irradiated lymphocytes, but the exact mechanism by which ECP exerts its therapeutic effect in these different conditions is uncertain. The treatment has very few adverse effects and in particular is not associated with an increased incidence of opportunistic infections. The evidence for the efficacy of ECP has been appraised by a combined British Photodermatology Group and U.K. Skin Lymphoma Group workshop on the basis of evidence published up to the end of 2001 and on the consensus of best practice. There is fair evidence for the use of ECP in erythrodermic CTCL and steroid-refractory GVHD, but randomized controlled studies are needed. There is good evidence supporting the use of ECP in preventing cardiac rejection following transplantation. Randomized controlled trials have also shown a therapeutic benefit in type 1 diabetes mellitus, but the inconvenience associated with the procedure outweighed the clinical benefit. There is fair evidence not to use ECP for the treatment of systemic sclerosis and multiple sclerosis, and good evidence not to use ECP for other forms of CTCL.

Ejaculation is a reflex mediated by a spinal control center, referred to as a spinal ejaculation generator. During intercourse, the spinal ejaculation generator integrates the sensory inputs that are necessary to trigger ejaculation. At the time of ejaculation, it coordinates the sympathetic, parasympathetic, and somatic outflow to induce the two phases of ejaculation, i.e. emission and expulsion. It also provides the brain with signals related to the occurrence of ejaculation. Experimental and clinical data evidenced that these functions were devoted to neurons located in the lumbosacral cord. We recently characterized a population of spinothalamic neurons in the lumbar spinal cord of male rats (LSt cells) that constitutes an integral part of the spinal ejaculation generator. LSt cells send projections to the autonomic nuclei and motoneurons involved in the emission and expulsion phase, and they receive sensory projections from the pelvis. LSt cells are activated with ejaculation, but not following other components of sexual behavior, and lesions of LSt cells completely ablate ejaculatory function. These data support a pivotal role for the LSt cells in the control of ejaculation.

The sinusoid anatomy of the penis is complex and requires complicated interaction between smooth muscle and endothelium in order to maintain homeostasis in the adult. The morphogen, Sonic hedgehog (Shh), is a crucial regulator of these processes, along with its down stream targets patched (Ptc), Hox, bone morphogenetic proteins (BMP's), vascular endothelial growth factor (VEGF) and nitric oxide synthase (NOS). Shh is critical for patterning and establishing tissue identity of the penis during embryonic development, is a crucial regulator of penile postnatal differentiation of the sinusoid morphology of the corpora cavernosa, and plays a fundamental role in maintaining sinusoidal structures pertinent to erectile function in the adult rat. Shh and its targets are active in human penes, and decreased in human diabetic penes in parallel with observations in the rat, thus lending clinical significance to the role of abnormal Shh signaling in erectile dysfunction (ED). Application of exogenous Shh protein to rat corpora cavernosa, induces VEGF and NOS proteins, suggesting a potential mechanism through which decreased Shh protein can cause ED. The studies outlined in this review provide in depth analysis of the Shh pathway and signal transduction, its role in penile development, how Shh signaling is altered in a rat model of ED and neuropathy, how abnormal Shh signaling can cause ED, and the clinical significance of the Shh pathway to human ED. These studies will provide valuable insight, at the molecular level, into understanding the mechanisms that under lie ED and lead to new treatment strategies for diabetic impotence.

Photochemotherapy (psoralen/UVA (PUVA)) is an efficient therapeutic tool for a wide range of skin diseases. Concern, however, exists regarding the long-term carcinogenic effects of this treatment modality and, as a consequence, is being used less frequently. PUVA remains an important treatment in our therapeutic armamentarium but must be used with caution in those patients with risk factors and cumulative dose exposure must be limited. PUVA-induced cancers show features in common with skin cancers induced by immunosuppressed organ transplant recipients. Tumours in the latter group of individuals are, however, much more aggressive and difficult to manage.

Ejaculation is a reflex mediated by a spinal control center, referred to as a spinal ejaculation generator. This spinal ejaculation generator coordinates sympathetic, parasympathetic and motor outflow to induce the two phases of ejaculation, i.e., emission and expulsion. In addition, the spinal ejaculation generator integrates this outflow with inputs that are related to the summation of sexual activity prior to ejaculation that are required to trigger ejaculation. Recently, a group of spinothalamic neurons in the lumbar spinal cord (LSt cells) were demonstrated to comprise an integral part of the spinal ejaculation generator. Specifically, lesions of LSt cells completely ablate ejaculatory function. Moreover, LSt cells are activated following ejaculation, but not following other components of sexual behavior. Furthermore, based on their relationship with autonomic nuclei, motoneurons and genital sensory inputs, LSt cells are also in the ideal anatomical position to integrate sensory inputs and autonomic and motor outflow. Additionally, the spinal ejaculation generator is under inhibitory and excitatory influence of supraspinal sites, including the nucleus paragigantocellularis (nPGi), the paraventricular nucleus of the hypothalamus (PVN) and the medial preoptic area (MPOA). Finally, sensory information related to ejaculation is processed in the spinal cord and brain, possibly contributing to the rewarding properties of ejaculation. One candidate pathway for relay of ejaculation-related cues consists of LSt cells and their projections to the parvocellular subparafascicular thalamic nucleus. Moreover, neural activation specifically related to ejaculation is observed in the brain and may reflect of processing of ejaculation-related sensory cues.

Lower urinary tract symptoms (LUTS) and sexual dysfunction are highly prevalent in aging men. Both conditions also are significant contributors to overall quality of life. New data have emerged to indicate potential links in epidemiological, physiologic, pathophysiologic, and treatment aspects of these two entities. There are numerous publications based on sophisticated community and clinical-based data, suggesting a strong and consistent association between LUTS and erectile dysfunction (ED). The association is supported by the consistent linear relationship of more severe LUTS with more severe ED. The link between ED and LUTS has biologic plausibility given the four leading theories of how these diseases inter-relate.

Erectile dysfunction (ED) is a common and debilitating pathological development that affects up to 75% of diabetic males. Neural stimulation is a crucial aspect of the normal erection process. Nerve injury causes ED and disrupts signaling of the Sonic hedgehog (Shh) cascade in the smooth muscle of the corpora cavernosa. Shh and targets of its signaling establish normal corpora cavernosal morphology during postnatal differentiation of the penis and regulate homeostasis in the adult. Interruption of the Shh cascade in the smooth muscle of the corpora cavernosa results in extensive changes in corpora cavernosal morphology that lead to ED. Our hypothesis is that the neuropathy observed in diabetics causes morphological changes in the corpora cavernosa of the penis that result in ED. Disruption of the Shh cascade may be involved in this process. We tested this hypothesis by examining morphological changes in the penis, altered gene and protein expression, apoptosis, and bromodeoxyuridine incorporation in the BB/WOR rat model of diabetes. Extensive smooth muscle and endothelial degradation was observed in the corpora cavernosa of diabetic penes. This degradation accompanied profound ED, significantly decreased Shh protein in the smooth muscle of the corpora cavernosa, and increased penile Shh RNA expression in the intact penis (nerves, corpora, and urethra). Localization and expression of Shh targets were also disrupted in the corpora cavernosa. Increasing our understanding of the molecular mechanisms that regulate Shh signaling may provide valuable insight into improving treatment options for diabetic impotence.

Background: Previous studies have demonstrated the ultraviolet (UV)-sparing effect of combining topical calcipotriol with broadband UVB in the treatment of psoriasis., Objectives: To determine if the combination of narrowband TL01 UVB phototherapy and topical calcipotriol produces the same UVB-sparing effect., Methods: This was a randomized, placebo-controlled, blinded clinical trial. Fifty psoriasis patients were recruited, 25 of whom were randomized into the active group who received TL01 phototherapy together with twice-daily application of calcipotriol cream 50 microg g(-1). The control group received TL01 phototherapy and twice-daily application of a topical emollient as placebo. TL01 phototherapy was given three times per week starting at 70% minimal erythema dose with 20% increments as tolerated for up to approximately 20 sessions. Patients were assessed using the Psoriasis Area and Severity Index (PASI) and Psoriasis Disability Index (PDI). They were evaluated at treatment sessions 8, 14 and 20, and followed up at 5 and 10 weeks post-treatment. Statistical analysis was performed using a two-tailed t-test., Results: There were no significant differences in demographic characteristics and baseline PASI and PDI scores between the two groups. The mean PASI score declined significantly (P < 0.01) for both groups after treatment. The difference in mean PASI score reduction from baseline between the two groups was only significant during the first eight sessions, with a net reduction of 3.6 (95% confidence interval 1.0-6.2, P = 0.008) in the active group relative to the control group. The mean PDI score declined significantly (P < 0.05) for both groups, but there was no statistical difference in mean PDI score reduction between the two groups (P = 0.8) at the end of treatment. The mean cumulative UVB dose for the active group was significantly lower (P < 0.02) at 16 204 mJ cm-2 compared with 21 082 mJ cm-2 for the control group., Conclusions: We conclude that combining TL01 phototherapy with topical calcipotriol cream has a UVB-sparing effect.

Purpose: We focused on the post-radical prostatectomy model to advance the understanding of neurogenic erectile dysfunction. We attempted to identify previously undescribed molecular changes via gene discovery methods using GeneChip (Affymetrix, Santa Clara, California) microarray technology., Materials and Methods: Five male adult 120-day-old Sprague-Dawley rats underwent bilateral cavernous nerve neurectomy. Five age matched controls were prepared simultaneously. The penises were harvested on postoperative day 2 and snap frozen in liquid nitrogen. RNA was prepared and pooled into cut and uncut groups. Synthesis of cRNA was performed according to the GeneChip technical manual. Microarray analysis was performed on a U34A Rat Array (Affymetrix). This array has approximately 8,800 gene probe sets, approximately 6,600 known genes and approximately 2,200 estimated sequence transcripts., Results: Dramatic results were found during GeneChip microarray expression analysis. A total of 126 candidate genes were noted to be altered based on the magnitude of expression change using rigorous statistical criteria, including 47 that were down-regulated and 79 that were up-regulated. Among the many significant changes seen 1 dominant class of genes was the submandibular rat genes. Submandibular rat 1 (SMR1) was down-regulated 82.5 fold. Other genes in this family were down-regulated 226 and 90 times. This result was confirmed by reverse transcriptase-polymerase chain reaction and Western blot analyses. These assays verified decreases in SMR1 at multiple time points after surgery., Conclusions: Impressive and previously unrecognized genetic changes are being intensely investigated as they are being unmasked by GeneChip technology. We have identified and begun the investigation of 1 interesting family of genes, namely submandibular gland proteins. The role of SMR as a clinically relevant change in penile and/or urethral function following cavernous nerve injury is speculative.

Purpose: We evaluated neurogenic erectile dysfunction, focusing on the post-radical prostatectomy model. We investigated changes in DNA, protein and apoptotic cells of the rat penis after denervation. Gross morphometry was measured to elucidate the impact of chemical changes., Materials and Methods: Postpubertal male Sprague-Dawley rats were randomized to bilateral or unilateral cavernous nerve transection, or sham operation. Wet weight, DNA content and protein content were measured. Tissue sections were stained for apoptosis by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling and the apoptotic index was calculated. Dual staining was performed for endothelial and smooth muscle cells to identify apoptotic cells., Results: Penile wet weight was significantly decreased at all time points after bilateral neurotomy (p <0.0005). Unilateral neurotomy allowed much greater preservation of penile weight. DNA content was significantly decreased in bilaterally denervated penes and unchanged in unilaterally operated penes. Protein content was not significantly altered in the bilateral or unilateral cohorts. Bilateral neurotomy induced significant apoptosis, while unilateral surgery caused significantly less apoptosis. Each population had apoptotic clustering just beneath the tunica albuginea, which was mostly smooth muscle cells., Conclusions: These data suggest the importance of neural integrity to maintain penile homeostasis. The loss in penile weight was consistent with the anecdotal experience of many clinicians. Decreased DNA content may have been due to significant levels of apoptosis in smooth muscle cells. Preserved protein content may suggest an increase in extracellular protein, as postulated in corporeal fibrosis. The subtunical population of apoptotic smooth muscle cells revealed a mechanism for veno-occlusive dysfunction observed after radical prostatectomy. These effects were significantly moderated in the unilateral model, reinforcing the critical nature of neural integrity.

The penis is unique in that it undergoes morphogenesis and differentiation primarily in the postnatal period. For complex structures such as the penis to be made from undifferentiated precursor cells, proliferation, differentiation, and patterning are required. This process involves coordinated activity of multiple signals. Sonic hedgehog (Shh) forms part of a regulatory cascade that is essential for growth and morphogenesis of many tissues. It is hypothesized that the penis utilizes regulatory mechanisms similar to those of the limb and accessory sex organs to pattern penile postnatal morphogenesis and differentiation and that the Shh cascade is critical to this process. To test this hypothesis, Shh, BMP-4, Ptc, and Hoxa-10 localization and function were examined in Sprague-Dawley rat penes by means of quantitative reverse transcription polymerase chain reaction, in situ hybridization, immunohistochemistry, and Western blotting. These genes were expressed in the penis during postnatal morphogenesis in a spatially and temporally restricted manner in adjacent layers of the corpora cavernosal sinusoids. The function of Shh and BMP-4 is to establish and maintain corpora cavernosal sinusoids. The data suggest that Ptc and Hoxa-10 are also important in penile morphogenesis. The continuing function of Shh and targets of its signaling in maintaining penile homeostasis in the adult is significant because disruption of Shh signaling affects erectile function. This is the first report that demonstrates the significant role that Shh plays in establishing and maintaining penile homeostasis and how this relates to erectile function. These studies provide valuable insight that may be applied to improve treatment options for erectile dysfunction.

Recent research on the neural control of female sexual function is reviewed. The control of female genital responses has not been extensively studied and significant gaps in our knowledge remain. Sexual arousal is largely the product of spinal level reflexes. A network of interneurons processes the sensory information and generate complex patterns of activities that are then distributed to the autonomic and somatic efferents. The spinal reflexive systems are under inhibitory and excitatory control from the brainstem and hypothalamic sites. Further research is necessary to identify the mechanisms underlying female sexual function, the pathogenesis of sexual dysfunctions and their possible treatment.