William O. Brant

Brain‐Derived Neurotrophic Factor (BDNF) Acts Primarily via the JAK/STAT Pathway to Promote Neurite Growth in the Major Pelvic Ganglion of the Rat: Part 2

INTRODUCTIONnIdentification of the molecular mechanism of cavernous nerve regeneration is essential for future development of neuroprotective and regenerative strategies.nnnAIMnTo identify specific signal transduction pathway(s) associated with brain-derived neurotrophic factor (BDNF) enhanced cavernous nerve regeneration in an in vitro model.nnnMATERIALS AND METHODSnUsing 6-month-old male Fisher rats, inhibitors of four candidate signaling pathways were added to BDNF-treated explant cultures of major pelvic ganglia with attached cavernous nerve fragments. Study groups comprised of controls, BDNF alone at 50 ng/mL, or BDNF 50 ng/mL and inhibitors against MEK, PI3-K, PKA, and JAK/STAT pathways at increasing concentrations.nnnMAIN OUTCOME MEASUREnThe maximal neurite length for each tissue culture was measured and the mean maximal length +/- standard deviation was determined for all groups at 24, 36, and 48 hours.nnnRESULTSnThe JAK/STAT specific inhibitor AG490 significantly reduced BDNF-enhanced neurite growth. Maximum neurite lengths at 24, 36, and 48 hours for BDNF 50 ng/mL treated groups were 182.3, 348.1, and 528.1 microm, compared with AG490 at 25 microM (86.4, 165.1, 278.3 microm), 50 microM (78.8, 151.7, 235.3 microm), and 100 microM (71.83, 107.0, 219.6 microm) (P < 0.05). Neurite measures for BDNF with 25 and 50 microM U0126 (MEK pathway) were reduced to 402.0 and 424.3 microm at 48 hours, respectively (P < 0.05), likely reflecting an accessory molecular pathway. A similar observation was made for 100 uM LY294002 (PI3-K). No difference was observed for PKA inhibition.nnnCONCLUSIONnThe JAK/STAT pathway is the major signal-transduction pathway of BDNF-enhanced cavernous nerve growth in an in vitro rat model.

Gonadoblastoma and Turner Syndrome

PURPOSEnThe presence of a Y chromosome in the extrascrotal gonad of patients with intersex disorders has been associated with a high risk of GB and, potentially, GCT. Recently, modern sophisticated genotyping has revealed a subgroup of TS cases with a mosaic karyotype expressing a Y chromosome. We sought to evaluate this group of patients and address their risk of gonadoblastoma.nnnMATERIALS AND METHODSnWe reviewed the records and genotyping of all females newly diagnosed with TS between 1990 and 2002 at Childrens Hospital in Denver. All patients with TS and Y chromosome mosaicism underwent gonadectomy, and the specimens were evaluated for the presence of gonadoblastoma on histological analysis and to identify Y chromosome on genotyping.nnnRESULTSnA total of 192 girls with a clinical diagnosis of TS were identified between January 1990 and December 2002. Seven records were unavailable and 19 patients did not have karyotypic analyses available in the hospital charts. Of the remaining 166 patients 67 exhibited mosaic cell lines, of whom 8 had 45,X0/46,XY mosaic pattern and 59 had mosaic patterns without Y chromosomal elements. All 8 patients with Y mosaicism underwent uneventful laparoscopic gonadectomy on an outpatient basis. One patient observed to have bilateral dysgenetic gonads after gonadectomy was excluded from the study. Gonadoblastoma (bilateral 2 patients, unilateral 1) was detected in 3 of 7 patients (43%) with Y mosaicism.nnnCONCLUSIONSnIn our series 4.8% of evaluable patients with TS carried a 45,X0/46,XY karyotype. Gonadoblastoma can be evident even at an early age in streak gonads with Y mosaicism and may be bilateral. We recommend prophylactic laparoscopic gonadectomy of streak gonads in patients with TS who carry a Y mosaic genotype, because fertility is not an issue, surgical morbidity is minor and there may be a high potential for malignant transformation of gonadoblastomas in this population.

High scrotal (Bianchi) single-incision orchidopexy: a "tailored" approach to the palpable undescended testis.

Our aim was to evaluate the utility of the high scrotal orchidopexy (Bianchi) approach for palpable undescended testis (UDT) and to assess long-term follow-up. We reviewed the records of orchidopexies performed between 1999 and 2002. The patients were then categorized by intraoperative exam under anesthesia as to whether their testes were palpable or nonpalpable. All palpable UDT that were initially thought to be amenable to a single high scrotal approach (Bianchi) were then reviewed. These cases were then analyzed to assess the impact of patient age, initial location of the testis, and prior inguinal/scrotal surgery with respect to the necessity to convert to a standard two-incision technique, and to analyze success and complications at 6–12-week and 1-year follow-up. Two hundred and nineteen orchidopexies were performed on 204 patients over this 4-year period. There were 178 testes palpable, and the transscrotal approach was used in 85 patients (100 orchidopexies). The preoperative positions of the testes that were thought to be amenable to Bianchi technique included the following: gliding (19), secondary trapped (25), superficial inguinal pouch (42), and location within the inguinal canal (2), while the remaining 12 testes were ectopic. Six patients required conversion to a traditional inguinal approach because of insufficient cord length via the single incision to allow the testis to lie in the scrotum. All patent processes vaginalis were ligated via the scrotal incision, regardless of their size. All patients, except for one who had a testis in the superficial inguinal pouch, had palpable testes of stable size and in a dependent position at 6–12-week follow-up. Of the 62 children who returned for 1-year follow-up, all had findings identical to those at their initial 6-week visits, with no atrophy or secondary reascent. Postoperative complications included transient postoperative scrotal hematoma in a single patient. The single failure underwent a successful two-incision orchidopexy for secondary reascent and a resultant trapped testis. Children with primary palpable undescended, gliding, or trapped testes can be managed successfully through the transscrotal route in the majority of cases. With use of a tailored approach to the palpable UDT, an additional groin incision is necessary only for a minority of appropriately selected cases.

Neurturin enhances the recovery of erectile function following bilateral cavernous nerve crush injury in the rat

Background The molecular mechanisms responsible for the survival and preservation of function for adult parasympathetic ganglion neurons following injury remain incompletely understood. However, advances in the neurobiology of growth factors, neural development, and prevention of cell death have led to a surge of clinical interest for protective and regenerative neuromodulatory strategies, as surgical therapies for prostate, bladder, and colorectal cancers often result in neuronal axotomy and debilitating loss of sexual function or continence. In vitro studies have identified neurturin, a glial cell line-derived neurotrophic factor, as a neuromodulator for pelvic cholinergic neurons. We present the first in vivo report of the effects of neurturin upon the recovery of erectile function following bilateral cavernous nerve crush injury in the rat. Methods In these experiments, groups (n = 8 each) consisted of uninjured controls and animals treated with injection of albumin (blinded crush control group), extended release neurotrophin-4 or neurturin to the site of cavernous nerve crush injury (100 μg per animal). After 5 weeks, recovery of erectile function (treatment effect) was assessed by cavernous nerve electrostimulation and peak aortic pressures were measured. Investigators were unblinded to specific treatments after statistical analyses were completed. Results Erectile dysfunction was not observed in the sham group (mean maximal intracavernous pressure [ICP] increase of 117.5 ± 7.3 cmH2O), whereas nerve injury and albumin treatment (control) produced a significant reduction in ICP elevation of 40.0 ± 6.3 cmH2O. Neurturin facilitated the preservation of erectile function, with an ICP increase of 55% at 62.0 ± 9.2 cmH2O (p < 0.05 vs control). Extended release neurotrophin-4 did not significantly enhance recovery of erectile function with an ICP change of 46.9 ± 9.6. Peak aortic blood pressures did not differ between groups. No significant pre- and post-treatment weight differences were observed between control, neurotrophin-4 and neurturin cohorts. All animals tolerated the five-week treatment course. Conclusion Treatment with neurturin at the site of cavernous nerve crush injury facilitates recovery of erectile function. Results support further investigation of neurturin as a neuroprotective and/or neuroregenerative agent facilitating functional recovery after cavernous or other pelvic autonomic nerve injuries.

Vascular Surgery for Erectile Dysfunction

Erectile dysfunction (ED) is common and potentially devastating. Men often complain that although the various modalities of treatment are potentially effective, they are not “natural” because they require assistance from a pill, injection, or device and do not allow for the same level of spontaneity that was previously enjoyed. Rather than symptom management, men desire a cure. With the exception of reversible endocrinopathies, no other available treatments address this fundamental desire. Because ED often has a vascular component, it is reasonable that practitioners have tried to develop surgical methods to re-establish penile vascular integrity. This chapter reviews penile vascular anatomy and arteriogenic and venogenic causes of ED. It then reviews various means of evaluation as well as surgical approaches and their associated outcomes and complications.

Peyronie’s Disease: Etiology and Treatment

In 1743, Francois Gigot de la Peyronie described the fibrous penile plaques that we now associate with his name. These plaques have been characterized histologically (Brock et al. 1997), ultrastructurally (Hirano et al. 1997), and, to some degree, molecularly (El-Sakka et al. 1997b; Hirano et al. 1997; Magee et al. 2002). Although there is no universal consensus on the definition, most authors describe Peyronie’s disease as some combination of penile pain, deformity, and/or palpable plaque (Mulhall et al. 2004; Zargooshi 2004). In general, the penile deformity adopts a dorsal curvature although the manifestation may be protean. One series described 46% dorsal curvature, 29% lateral, and 9% ventral, with the remained being mixed or a combination of curvatures (Kadioglu et al. 2002). Although curvature is the most common deformity, other malformations can occur, including penile shortening, hinging, and indentations or bottle-neck configurations. Additionally, erectile dysfunction is a common (20–40%) associated finding; this may be generalized or localized (i.e., flaccidity limited to distal to the lesion).

Future Therapies Applicable to Post-radical Pelvic Surgery Patients

Despite advances in operative technique and pharmacotherapy, erectile function is compromised in a significant proportion of men undergoing radical pelvic surgery for prostate, bladder, and colorectal malignancies. Strategies to decrease the incidence or severity of post-operative erectile dysfunction may include pre-operative optimization of erectile function, risk factors, and/or other protective maneuvers, elimination or modulation of neural, vascular and corporal smooth muscle injury, and the use of novel pharmacotherapies. In this chapter, future strategies to optimize the recovery of erectile function, and ultimately increase patient quality of life, are outlined.