Glycaemic control and risk of incident urinary incontinence in women with Type 1 diabetes: results from the Diabetes Control and Complications Trial and Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study.

AIMS: To study the impact of glycaemic control on urinary incontinence in women who participated in the Diabetes Control and Complications Trial (DCCT; 1983-1993) and its observational follow-up study, the Epidemiology of Diabetes Interventions and Complications (EDIC; 1994-present). METHODS: Study participants were women who completed, at both years 10 (2003) and 17 (2010) of the EDIC follow-up, the urological assessment questionnaire (UroEDIC). Urinary incontinence was defined as self-reported involuntary leakage of urine that occurred at least weekly. Incident urinary incontinence was defined as weekly urinary incontinence present at EDIC year 17 but not at EDIC year 10. Multivariable regression models were used to examine the association of incident urinary incontinence with comorbid prevalent conditions and glycaemic control (mean HbA1c over the first 10 years of EDIC). RESULTS: A total of 64 (15.3%) women with Type 1 diabetes (mean age 43.6 ± 6.3 years at EDIC year 10) reported incident urinary incontinence at EDIC year 17. When adjusted for clinical covariates (including age, DCCT cohort assignment, DCCT treatment arm, BMI, insulin dosage, parity, hysterectomy, autonomic neuropathy and urinary tract infection in the last year), the mean EDIC HbA1c was associated with increased odds of incident urinary incontinence (odds ratio 1.03, 95% CI 1.01-1.06 per mmol/mol increase; odds ratio 1.41, 95% CI 1.07-1.89 per % HbA1c increase). CONCLUSIONS: Incident urinary incontinence was associated with higher HbA1c levels in women with Type 1 diabetes, independent of other recognized risk factors. These results suggest the potential for women to modify their risk of urinary incontinence with improved glycaemic control. (Clinical Trials Registry no: NCT00360815 and NCT00360893).

Effect of endothelial cell-based iNOS gene transfer on cavernosal eNOS expression and mouse erectile responses.

Inducible nitric oxide synthase (iNOS) gene transfer is reported to augment erectile responses in rats, although it is also shown to impair vasorelaxation in cerebral arteries. We investigated the effect of endothelial cell-based iNOS gene transfer on endothelial NOS (eNOS) expression and mouse erectile responses. Human coronary artery endothelial cells (EC) transduced with empty vector (control) or iNOS were grown in culture and transplanted into the corpus cavernosum of severe combined immunodeficient mice. Endothelial NOS expression was compared in control and iNOS-transduced cells grown in the presence or absence of a selective iNOS inhibitor, L-N6- (1-iminoethyl) lysine hydrochloride (L-NIL). At 3-5 days after cell transplantation, we recorded intracorporal pressure (ICP) responses to cavernosal nerve stimulation and measured cavernosal total NO and eNOS protein expression. In this study, EC transduced with iNOS produced significantly more NO than controls but exhibited a twofold downregulation of eNOS protein and mRNA. This effect was reversed by L-NIL. In vivo, the cell-based gene transfer of iNOS led to significantly increased ICP responses, compared to mice transplanted with control ECs. Consistent with the in vitro data, cavernosal lysates had significantly reduced eNOS expression. In conclusion, EC gene transfer of iNOS downregulates EC expression of eNOS by an NOS-dependent mechanism. In the cavernosum of mice transplanted with Inos-transduced EC, nerve-stimulated erectile responses were augmented by the short-term gene transfer. However, our findings suggest that iNOS gene transfer may have deleterious effects on endothelial function if used as a treatment for erectile dysfunction.

Melanocortinergic control of penile erection.

Melanocortin receptors in the forebrain and spinal cord can be activated by endogenous or synthetic ligands to induce penile erection in rats and human subjects. To better understand how melanocortin circuits play a role in sex behavior, we review the contribution of melanocortin receptors and/or neurons in the hypothalamus, hindbrain, spinal cord and peripheral nerves to erectile function. New information regarding neuropeptides that mediate penile erection has extended our understanding of the central control of sex behavior, and melanocortin agonists may provide alternatives to existing treatment for highly prevalent problems including erectile dysfunction.

Ac-Nle-c[Asp-His-DPhe-Arg-Trp-Lys]-NH2 induces penile erection via brain and spinal melanocortin receptors.

Penile erection induced by alpha-melanocyte-stimulating hormone and melanocortin receptors (MC-R) in areas of the spinal cord and periphery has not been demonstrated. To elucidate sites of the proerectile action of melanocortin peptides, in awake male rats we administered the MC-R agonist Ac-Nle-c[Asp-His-DPhe-Arg-Trp-Lys]-NH(2) (MT-II) i.c.v., intrathecal (i.th.) and i.v. and scored penile erection and yawning. Injection of the MC-R antagonist Ac-Nle-c[Asp-His-DNal(2')-Arg-Trp-Lys]-NH(2) (SHU-9119) i.c.v. or i.th. in combination with i.th. MT-II differentiated spinal from supraspinal effects. To exclude a site of action in the penis, we recorded intracavernous pressure responses to intracavernosal injection of MT-II in the anesthetized rat.I.c.v., i.th., and i.v. MT-II induced penile erections in a dose-dependent fashion. Yawning was observed with i.c.v. and i.v. MT-II, while spinal injection did not produce this behavior. Intrathecal delivery of MT-II to the lumbosacral spinal cord was more efficacious in inducing erections than i.c.v. or i.v. administration; SHU-9119 blocked the erectile responses to i.th. MT-II when injected i.th. but not i.c.v. Intracavernosal MT-II neither increased intracavernous pressure nor augmented neurostimulated erectile responses. We confirmed the central proerectile activity of MT-II and demonstrated that in addition to a site of action in the brain, the distal spinal cord contains melanocortin receptors that can initiate penile erection independent of higher centers. These results provide new insight into the central melanocortinergic pathways that mediate penile erection and may allow for more efficacious melanotropin-based therapy for erectile dysfunction.

Melanocortin receptor agonists, penile erection, and sexual motivation: human studies with Melanotan II.

We review our experience with Melanotan II, a non-selective melanocortin receptor agonist, in human subjects with erectile dysfunction (ED). Melanotan II was administered to 20 men with psychogenic and organic ED using a double-blind placebo-controlled crossover design. Penile rigidity was monitored for 6 h using RigiScan. Level of sexual desire and side effects were reported with a questionnaire. In the absence of sexual stimulation, Melanotan II led to penile erection in 17 of 20 men. Subjects experienced a mean of 41 min Rigiscan tip rigidity>80%. Increased sexual desire was reported after 13/19 (68%) doses of Melanotan II vs 4/21 (19%) of placebo (P<0.01). Nausea and yawning were frequently reported side effects due to Melanotan II; at a dose of 0.025 mg/kg, 12.9% of subjects had severe nausea. We conclude that Melanotan II is a potent initiator of penile erection in men with erectile dysfunction. Our findings warrant further investigation of melanocortin agonists and antagonists on penile erection. International Journal of Impotence Research (2000) 12, Suppl 4, S74-S79.

Men with diabetes may require more aggressive treatment for erectile dysfunction.

Diabetes mellitus (DM) and erectile dysfunction (ED) are common health problems that markedly increase in prevalence and incidence with advancing age. DM is a known risk factor for developing ED; however, among men with ED it is unknown if DM alters the need for more invasive therapies. We sought to determine whether DM is associated with increased ED severity, reduced effectiveness of first-line (oral) therapies, and therefore higher utilization of second- and third-line therapies. The Inovus I3 database was queried to identify men with ED. Claims were followed for 48 months. Men with incomplete follow-up data and those diagnosed with DM after ED diagnosis were excluded from analysis. Rates of second-line (penile suppositories or injectables) and third-line (penile prostheses) ED therapies were compared between men with and without preexisting DM. Risk of progressing to second- and third-line therapies associated with DM was assessed with logistic regression and Kaplan-Meier analysis. From 1 January 2002 to 31 December 2006, 136 306 men were identified with prevalent and incident ED. Among this group, 19 236 men had DM that preceded their ED diagnosis. Men with DM were more than 50% more likely to be prescribed secondary ED treatments over the 2-year observation period, and more than twice as likely to undergo penile prosthesis surgery. Among a large population-based cohort of men with ED, those with DM are more likely to require more aggressive treatments. These data suggest that ED among men with diabetes may be less responsive to first-line treatments (oral agents), worsen more rapidly, or both.

Female sexual dysfunction.

The overall prevalence of sexual dysfunction is actually higher among women than among men. For women, as for men, sexual dysfunction can be a source of considerable psychological distress. Yet very few women with sexual dysfunction seek treatment. Physicians should therefore be alert to this problem, especially in postmenopausal patients. New therapies are likely to become available for treating female sexual dysfunction in the near future, and physicians will need a good working knowledge of normal female sexual response and female sexual dysfunction in order to provide the best possible treatment for patients who have this common problem.

Genital skin loss: unified reconstructive approach to a heterogeneous entity.

Genital skin loss results from a heterogeneous group of traumatic and infectious processes. Removal of all devitalized tissue is necessary prior to reconstructive surgery; hyperbaric oxygen may help in the management of necrotizing infections. Defect coverage depends more on the remaining genital skin than on the etiology of the loss.

Comparison of open and endoscopic treatment of posttraumatic posterior urethral strictures.

The purpose of this study was to compare the invasiveness, morbidity, and outcomes of open versus endoscopic treatment of posttraumatic posterior urethral strictures. We compared two groups of men with strictures of the posterior urethra after pelvic fracture: Group I (n = 6) underwent cut-to-the-light procedures before 1995, and group II (n = 9) underwent perineal anastomotic urethroplasty after 1995. The operating time and blood loss were lower in the endoscopic group, but no other significant differences in morbidity or invasiveness were found. All six patients in group I required multiple secondary procedures: Three reached a stable voiding pattern after a mean of three interventions, two required subsequent urethroplasty, and one was lost to long-term follow-up. Normal voiding was achieved in all group II patients, although two (22%) required single internal urethrotomy within 3 months after surgery. The data show the comparable morbidity of open urethroplasty and cut-to-the-light procedures and support an aggressive surgical approach for the delayed treatment of posttraumatic posterior urethral strictures. Other than a reduced operating time, endoscopic procedures offered no compelling advantage over surgical reconstruction.

Circular penile fasciocutaneous flap reconstruction of urethral strictures: technical considerations and results in 40 patients.

The reconstruction of complex anterior urethral strictures has evolved from free graft urethroplasty to the use of vascularized skin flaps. The circular penile fasciocutaneous flap is based on Buck's fascia, is hairless, and reliably provides 15 cm of skin. We have used this technique in 40 patients with urethral strictures from the fossa navicularis to the veru montanum. Indications include severe spongiofibrosis, penile urethral location, inflammatory or ischemic etiology, and need for complete tube replacement. A successful result was obtained in 85% of patients. Complete tube replacement is less successful than onlay type procedures (77% vs. 96%) and we make every effort to preserve the urethral plate. This technique is the mainstay of our armamentarium for the repair of urethral strictures and also allows an excellent cosmetic result.

Effect of colon injury on the management of simultaneous renal trauma.

PURPOSE: We determined the effect of simultaneous colon injury on the management of renal trauma. MATERIALS AND METHODS: A retrospective review was done of 62 cases of colon and renal injuries from 1977 to 1994, representing 2.5% of 2,596 renal trauma cases. RESULTS: Renal trauma management was consistent with the grade of renal injury. Renal exploration was performed in 58% of the cases, with nephrectomy performed in 16% of the explorations and only for severely injured kidneys. Urological complications occurred in 16% of the cases but they resulted in loss of only 1 renal unit. CONCLUSIONS: Renal injury and reconstruction should not be treated differently in the face of colon injury, including gross fecal contamination.

Use of free grafts in urethral stricture reconstruction.

PURPOSE: The indications, contraindications and results of free graft urethroplasty are determined. MATERIALS AND METHODS: A retrospective review was done of 40 consecutive patients who underwent free graft urethroplasty with penile and preputial skin, buccal mucosa and bladder epithelium. RESULTS: Of the 35 patients in whom adequate followup data were available the outcome was successful in 30 (86%). Success was unrelated to donor site, prior intervention or cause of stricture. Failure was attributed to placement of grafts onto the penile urethra and patient age. CONCLUSIONS: For strictures in the bulbar urethra the success rate of free grafts was high. Failures occurred in patients in whom full thickness skin grafts were extended far onto the penile urethra.

Current controversies in anterior urethral stricture repair: free-graft versus pedicled skin-flap reconstruction.

Reconstruction of long anterior urethral strictures that cannot be excised and reanastomosed remains controversial. We critically reviewed the literature on free-graft and pedicled skin-flap urethroplasty to determine the optimal method of repair. Overall, free grafts were successful in 84.3% of cases and flaps, in 85.9%. Buccal mucosa grafts are the most successful method for reconstruction of bulbar urethral strictures. For strictures in the penile urethral or a compromised graft bed a distal penile skin flap is the most reliable and tested approach. Dorsal free-graft urethroplasty may be considered when penile skin deficiency prevents use of a flap. For the most complex strictures, in which a flap is not possible and the graft bed is of poor quality, a mesh graft in two stages may be the only option. Thus, for reconstruction of complex anterior urethral strictures, both free-graft and flap procedures remain indispensable.

Endothelial cell transplantation into the corpus cavernosum: moving towards cell-based gene therapy.

PURPOSE: As a first step toward a cell based gene therapy for erectile dysfunction, we transplanted fluorescently labeled autologous microvessel endothelial cells (MVEC) into the rat corpus cavernosum. MATERIALS AND METHODS: MVEC were isolated from the epididymal fat pad, labeled with the membrane intercalating dye PKH 26, and injected into the corpus cavernosum. Two to 15 days after transplantation the penises were removed, cryosectioned, and examined under epifluorescent and phase contrast microscopy. RESULTS: In 7 consecutive animals transplanted fluorescent cells were identified in the corpora cavernosa. Bilateral distribution was noted in each animal, and staining with ED1 determined that the fluorescence was not due to engulfment of the MVEC by phagocytic cells. CONCLUSION: Transplanted endothelial cells adhere and persist in the corporal sinusoids and provide a rationale for cell-based gene therapy in the penis.

Preservation of renal function after reconstruction for trauma: quantitative assessment with radionuclide scintigraphy.

PURPOSE: We quantified the degree of preservation of renal function after reconstruction of traumatic renal injuries and identified the factors that influence preservation. MATERIALS AND METHODS: We reviewed the records of 52 patients between 1977 and 1995 who underwent radionuclide scintigraphy an average of 11.4 days after renal reconstruction for trauma. Of the injuries (75% penetrating and 25% blunt) 6% were grade 2, 43% grade 3, 49% grade 4 and 2% grade 5. RESULTS: On the reconstructed side mean renal function was 39.3%. Adequate preservation was possible in 42 patients (81% overall), while 10 (19%) had less than a third function on the injured side. CONCLUSIONS: Our results provide quantitative evidence that renal reconstruction successfully preserves functioning renal tissue and is an appropriate method of treating major renal trauma. Preservation of functioning renal parenchyma is less successful in patients with renovascular trauma and severe concomitant injuries with shock and extensive blood loss.

Single stage reconstruction of complex anterior urethral strictures: combined tissue transfer techniques.

PURPOSE: Reconstruction of most urethral strictures is possible with anastomotic, graft or skin flap procedures alone. We describe the combination of tissue transfer techniques to preserve the urethral plate and reconstruct long and complex urethral strictures in 1 stage. MATERIALS AND METHODS: We reviewed the results in 25 patients who underwent anterior urethroplasty requiring more than 1 tissue transfer technique to achieve urethral reconstruction in 1 stage. RESULTS: Outcome was excellent in 22 patients (88%). Seven patients with pan-urethral strictures (mean length 19 cm.) required a fasciocutaneous flap combined with a buccal mucosa, bladder epithelium or skin graft. A total of 13 patients with focally dense strictures underwent excision of the most severe portion of the stricture with dorsal reapproximation, thereby improving the quality of the urethral plate and allowing simultaneous flap or graft onlay reconstruction. Five patients with multiple separate strictures required a distal onlay fasciocutaneous flap with excision and end-to-end anastomosis of a separate, more proximal stricture. CONCLUSIONS: A thorough knowledge of the vascular supply of the urethra allowed creative application of different tissue transfer techniques, enabling 1-stage reconstruction of complex urethral strictures. An excellent outcome was achieved by preserving or revising the urethral plate and avoiding the problems associated with hair-bearing flaps and 2-stage procedures.