Is intralesional interferon alpha2b a safe and effective minimally invasive treatment for Peyronie's disease?
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Biomedical subjects
Arnold Melman
Publications and source records attributed to Arnold Melman.
Diabetes-induced changes in the alternative splicing of the slo gene in corporal tissue.
OBJECTIVES: Erectile dysfunction is a common diabetic complication. Preclinical studies have documented that the Slo gene (encoding the BK or Maxi-K channel alpha-subunit) plays a critical role in erectile function. Therefore, we determined whether diabetes induces changes in the splicing of the Slo gene relevant to erectile function. METHODS: Reverse transcriptase-polymerase chain reaction was used to compare Slo splice variant expression in corporal tissue excised from control and streptozotocin (STZ)-induced diabetic Fischer F-344 rats. Splice variants were sequenced, characterized by patch clamping, and fused to green fluorescent protein to determine cellular localization. The impact of altered Slo expression on erectile function was further evaluated in vivo. RESULTS: A novel Slo splice variant (SVcyt, with a cytoplasmic location) was predominantly expressed in corporal tissue from control rats. STZ-diabetes caused upregulation of a channel-forming transcript SV0. Preliminary results suggest that SV0 was also more prevalent in the corporal tissue of human diabetic compared with nondiabetic patients. The change in isoform expression in STZ-treated rats was partially reversed by insulin treatment. Intracorporal injection of a plasmid expressing the SV0 transcript, but not SVcyt, restored erectile function in STZ-diabetic rats. CONCLUSIONS: Alternative splicing of the Slo transcript may represent an important compensatory mechanism to increase the ease with which relaxation of corporal tissue may be triggered as a result of a diabetes-related decline in erectile capacity.
Alternative Splicing↗
Sialorphin (the mature peptide product of Vcsa1) relaxes corporal smooth muscle tissue and increases erectile function in the ageing rat.
OBJECTIVE: To determine if the mature peptide product of the Vcsa1 gene, sialorphin, could restore erectile function in ageing rats, and whether these effects are mediated through relaxation of corporal smooth muscle tissue, as we recently reported that Vcsa1 is one of the most down-regulated genes in the corpora of rats in three distinct models of erectile dysfunction, and gene transfer of plasmids expressing Vcsa1 into the corpora of ageing rats restored erectile function. MATERIALS AND METHODS: Sialorphin was injected intracorporeally into retired breeder rats, and the effect on the physiology of corporal tissue was analysed by intracorporal/blood pressure (ICP/BP) measurement at different times after injection. In organ-bath studies, the ability of sialorphin (1 microg/mL) to enhance C-type natriuretic peptide (CNP) relaxation of corporal smooth muscle tissue strips was investigated after pre-contraction with 1 microm phenylephrine. RESULTS: Intracorporal injection of 100 microg sialorphin into retired breeder rats resulted in a time-dependent increase in the ICP/BP response to electrostimulation of the cavernosal nerve. After 55-65 min the ICP/BP ratio increased to approximately 0.6, a value associated with normal erectile function. In organ-bath studies after pre-contraction with 1 microm phenylephrine, 1 microm CNP significantly (67%) increased the relaxation rate of corporal tissue. This rate of relaxation was increased by 2.5-fold after incubation with sialorphin (1 microg/mL) compared with carrier alone. CONCLUSION: These results show that sialorphin has a role in erectile function, probably through a mechanism that involves relaxation of corporal smooth muscle tissue.
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Comparison of operative and functional outcomes of laparoscopic radical prostatectomy and radical retropubic prostatectomy: single surgeon experience.
OBJECTIVES: To compare radical retropubic prostatectomy (RRP) and laparoscopic radical prostatectomy (LRP) outcomes in a contemporary series. METHODS: A total of 70 LRP patients operated on between 2001 and 2002 with at least 18 months of follow-up were selected. These patients were compared with a matched cohort of 70 patients who had undergone RRP by the same surgeon from 1999 to 2001. The baseline patient characteristics, perioperative and histologic parameters, recovery time, complications, and 18-month functional data were compared. RESULTS: No significant differences were found in the preoperative characteristics. The mean operative time was 181.8 +/- 18.7 minutes for RRP and 246.4 +/- 46.1 minutes for LRP (P <0.0001). The mean estimated blood loss was 563.2 mL for RRP and 275.8 mL for LRP (P <0.0001). The positive margin rate was 20% and 15.7% for the RRP and LRP groups, respectively (P = NS). The mean pain score on postoperative day 1 was 4.5 in the LRP group and 7.8 in the RRP group on an analog pain score of 0 to 10 (P = 0.02). Full recovery was achieved at 33 +/- 17 days and 45 +/- 20 days for the LRP and RRP groups, respectively (P <0.001). The total perioperative complication rate for LRP and RRP was comparable at 18.5% and 15.7%, respectively. The diurnal continence rate (no pads) for the LRP and RRP groups was 70%, 90%, and 92.8% and 71.4%, 87.6%, and 92% at 6, 12, and 18 months, respectively (P = NS). The potency rate after bilateral neurovascular preservation with or without sildenafil for the LRP and RRP group was 55%, 72.6%, and 79.5% and 43%, 58%, and 72.4% at 6, 12, and 18 months, respectively (P = NS). CONCLUSIONS: LRP is well tolerated and provides short-term oncologic and functional results comparable to those of RRP.
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Renal obstruction caused by herniation of renal pelvis and ureteropelvic junction through superior lumbar triangle hernia (Grynfeltt hernia).
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Ion channel gene therapy for smooth muscle disorders: relaxing smooth muscles to treat erectile dysfunction.
The promise of gene therapy to treat diseases remains largely unfulfilled. Past setbacks and the complexity of the delivery systems used, in terms of both targeting the appropriate cells and inducing expression of products at therapeutic levels, thus far have prevented significant success for gene therapy. Smooth muscle disorders represent a unique target for gene therapy. In many cases, smooth muscle is readily accessible and, to induce a therapeutic effect, will not require very high levels of gene product expression. This allows a lower efficiency of gene transfer to be successful. With these important features in mind, we believe that naked DNA transfer of potassium ion channels represents a novel and successful way to treat smooth muscle disorders. Herein, we present a rationale for treating erectile dysfunction, a smooth muscle disorder of the cavernosal bodies of the penis, with naked DNA gene transfer therapy. By inserting the hSlo gene, which codes for Maxipotassium channels, into smooth muscle cells, we can improve smooth muscle relaxation in the corporal bodies and thus improve erectile function. This method of gene transfer has proven to be safe and effective for erectile dysfunction, and human trials are ongoing.
Base Sequence↗
hMaxi-K gene transfer in males with erectile dysfunction: results of the first human trial.
Eleven patients with moderate to severe erectile dysfunction (ED) were given a single-dose corpus cavernosum injection of hMaxi-K, a "naked" DNA plasmid carrying the human cDNA encoding hSlo (for human slow-poke), the gene for the alpha, or pore-forming, subunit of the human smooth muscle Maxi-K channel. Three patients each were given 500, 1000, and 5000 microg, and two patients were given 7500 microg, of hMaxi-K and monitored for 24 weeks. The primary objectives of this phase I study were safety and tolerability of escalating hMaxi-K doses as assessed by clinical evaluations and laboratory tests. Secondary efficacy objectives were measured primarily by use of the International Index of Erectile Function (IIEF) scale. Patient responses were validated by partner responses. There were no serious adverse events and no dose-related adverse events attributed to gene transfer for any patient at any dose or study visit. No clinically significant changes from baseline were seen in physical evaluations (general and genitourinary), hematology, chemistry, and hormone analyses, or in cardiac events evaluated by repeated electrocardiograms. Importantly, no plasmid was detected in the semen of patients at any time after the injections. Patients given the two highest doses of hMaxi-K had apparent sustained improvements in erectile function (EF) as indicated by improved IIEF-EF domain scores over the length of the study. One patient given 5000 microg and one given 7500 microg reported EF category improvements that were highly clinically significant and were also maintained through the 24 weeks of study. Efficacy conclusions cannot be drawn from results of a phase I trial with no control group. However, the promising primary safety outcomes of the study and preliminary indications of effectiveness provide evidence that hMaxi-K gene transfer is a viable approach to the treatment of ED and that further studies investigating the efficacy of hMaxi-K in patients with ED should be performed.
Adult↗
Effects of streptozotocin-induced diabetes on bladder and erectile (dys)function in the same rat in vivo.
OBJECTIVE: To establish the methods, feasibility and utility of evaluating the impact of diabetes on bladder and erectile function in the same rat, as more than half of diabetic patients have bladder dysfunction, and half of diabetic men have erectile dysfunction, but the severity of coincident disease has not been rigorously assessed. MATERIALS AND METHODS: In all, 16 F-344 rats had diabetes induced by streptozotocin (STZ), and were divided into insulin-treated (five) and untreated (11), and compared with age-matched controls (10), all assessed in parallel. All STZ rats were diabetic for 8-11 weeks. Cystometric studies were conducted on all rats, with cavernosometric studies conducted on a subset of rats. RESULTS: There were insulin-reversible increases in the following cystometric variables; bladder weight, bladder capacity, micturition volume, residual volume, micturition pressure and spontaneous activity (P < 0.05, in all, one-way analysis of variance, anova). Cavernosometry showed a diabetes-related, insulin-reversible decline in the cavernosal nerve-stimulated intracavernosal pressure (ICP) response at all levels of current stimulation (P < 0.05, in all one-way anova). Plotting erectile capacity (i.e. ICP) against bladder capacity showed no correlation between the extent of the decline in erectile capacity and the magnitude of the increase in bladder capacity. CONCLUSIONS: These studies extend previous work to indicate that the extent of diabetes-related bladder and erectile dysfunction can vary in the same rat. As such, these findings highlight the importance of evaluating the impact of diabetes on multiple organ systems in the lower urinary tract. Future studies using this model system should lead to a better understanding of the initiation, development, progression and coincidence of these common diabetic complications.
Animals↗
Variable coding sequence protein A1 as a marker for erectile dysfunction.
OBJECTIVE: To investigate whether variable coding sequence protein A1 (Vcsa1) is down-regulated in rat models of diabetes and ageing, and to investigate the role of Vcsa1 in erectile function, as Vcsa1 is the most down-regulated gene in the corpora of a rat model of neurogenic erectile dysfunction (ED). MATERIALS AND METHODS: Quantitative reverse-transcriptase polymerase-chain reaction was used to determine Vcsa1 expression in the corpora of rats in three models of ED, i.e. streptozotocin-induced diabetes, retired breeder (old), and neurogenic (bilaterally ligated cavernosal nerves), and in control rats. To confirm a physiological role of Vcsa1 in erectile function, we carried out gene transfer studies using a plasmid in which Vcsa1 was expressed from a cytomegalovirus promoter (pVAX-Vcsa1). This plasmid was injected intracorporally into old rats, and the effect on physiology of corporal tissue was analysed by intracorporal/blood pressure (ICP/BP) measurement and histological analysis, and compared with the effects of a positive control plasmid (pVAX-hSlo, which we previously reported to restore erectile function in diabetic and ageing rats) and a negative control plasmid (pVAX). RESULTS: In each rat model of ED there was a significant down-regulation of the Vcsa1 transcript of at least 10-fold in corporal tissue. Remarkably, intracorporal injection with 80 microg pVAX-Vcsa1 caused priapism, as indicated by visible prolonged erection, histological appearance, and elevated resting ICP/BP. Lower doses of pVAX-Vcsa1 (5 and 25 microg) increased ICP/BP over that in untreated controls. CONCLUSION: These results show that Vcsa1 has a role in erectile function and might be a molecular marker for organic ED. The role of Vcsa1 in erectile function suggests that it could represent a novel therapeutic target for treating ED.
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Genital sensation and sexual function in women bicyclists and runners: are your feet safer than your seat?
INTRODUCTION: Bicycling is associated with neurological impairment and impotence in men. Similar deficits have not been confirmed in women. AIM: To evaluate the effects of bicycling on genital sensation and sexual function in women. METHODS: Healthy, premenopausal, competitive women bicyclists and runners (controls) were compared. MAIN OUTCOME MEASURES: (1) Genital vibratory thresholds (VTs) were determined using the Medoc Vibratory Sensation Analyzer 3000. (2) Sexual function and sexually related distress were assessed by the Dennerstein Personal Experience Questionnaire (SPEQ) and the Female Sexual Distress Scale (FSDS). RESULTS: Forty-eight bicyclists and 22 controls were enrolled. The median age was 33 years. The bicyclists were older, had higher body mass indices (BMIs), were more diverse in their sexual orientation, and were more likely to have a current partner. Bicyclists rode an average of 28.3 +/- 19.7 miles/day (range 4-100), 3.8 +/- 1.5 days/week, for an average of 2.1 +/- 1.8 hours/ride. The mean number of years riding was 7.9 +/- 7.1 years (range 0.5-30). Controls ran an average of 4.65 +/- 2.1 miles/day (range 1.5-8) and 5.0 +/- 1.2 days/week. On bivariate analysis, bicyclists had significantly higher VTs than runners, indicating worse neurological function at all sites (P < 0.05). Multivariate analysis found significant correlations between higher VTs and bicycling at the left and right perineum, posterior vagina, left and right labia. Increasing VTs at the clitoris, anterior vagina, and urethra were associated with age. In bicyclists, there were no correlations between VTs and miles biked per week, duration of riding, or BMI. Composite SPEQ scores indicated normal sexual function in all sexually active subjects. Neither group suffered from sexually related distress. CONCLUSION: There is an association between bicycling and decreased genital sensation in competitive women bicyclists. Negative effects on sexual function and quality of life were not apparent in our young, healthy premenopausal cohort.
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The first human trial for gene transfer therapy for the treatment of erectile dysfunction: preliminary results.
OBJECTIVE: To test the safety of a single intracavernous injection of a plasmid vector (hMaxi-K) that expresses the hSlo gene, that encodes the alpha-subunit of the Maxi-K channel, for the treatment of erectile dysfunction (ED). METHODS: Six men, thus far have fulfilled the entry criteria of the protocol and had gene transfer with hMaxi-K. Three received a dose of 500 microg and three received a dose 1000 microg of the gene product, injected intracavernously as naked DNA. Dosing at 5000 microg and higher is planned. RESULTS: The primary end point of the phase I trial is safety. No drug-related adverse events or significant laboratory changes have occurred after the gene transfer. Moreover, there is no evidence of the gene in semen at the one copy per mug total DNA in any of the participants. CONCLUSION: Preliminary results indicate that, in a single dose escalation study, ion channel gene transfer with hMaxi-K can be administered safely to men with ED without adverse events.
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Effect of neonatal circumcision on penile neurologic sensation.
OBJECTIVES: To evaluate penile sensory thresholds in neonatally circumcised and uncircumcised men. METHODS: We evaluated 125 patients, 62 uncircumcised men and 63 neonatally circumcised men. All patients completed the Erectile Function domain of the International Index of Erectile Function questionnaire. Of the 125 patients, 29 (International Index of Erectile Function score of between 25 and 30) were placed in the functional group, and 96 in the dysfunctional group. The patients were tested on the dorsal midline glans of the penis (foreskin retracted). Quantitative somatosensory testing was performed and included vibration, pressure, spatial perception, and warm and cold thermal thresholds. RESULTS: In the functional group, t-test analysis demonstrated a significant (P <0.001) difference, with worse vibration and better pressure sensation for uncircumcised men. When controlling for age, hypertension, and diabetes, all t-test significance was lost. In the dysfunctional group, circumcised men (49 +/- 16 years) were significantly younger (P <0.01) than uncircumcised men (56 +/- 13 years). For the dysfunctional group, t-test analysis also demonstrated worse vibration sensation for uncircumcised men (P <0.01). Again, when controlling for age, hypertension, and diabetes, all t-test significance was lost. CONCLUSIONS: We present a comparative analysis of uncircumcised and circumcised men using a battery of quantitative somatosensory tests that evaluate the spectrum of small to large axon nerve fiber function. Our study controlled for factors, including age, erectile function status, diabetes, and hypertension, that have been shown to alter neurologic testing. In our study of neonatally circumcised men, we demonstrated that circumcision status does not significantly alter the quantitative somatosensory testing results at the glans penis.
Adult↗
Images in clinical urology. Late complication after penile elongation.
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Adult↗
Evaluation of two techniques of partial urethral obstruction in the male rat model of bladder outlet obstruction.
OBJECTIVES: To perform a comparison to determine which of two methods of partial urethral ligation produces the most consistent outcome and fewest side effects. Such a study has not been previously reported. Partial urethral ligation is a means of causing reproducible bladder outlet obstruction. In the male rat model, partial urethral obstruction can be performed either by perineal incision and bulbous urethral ligation or retropubic incision and midprostatic obstruction. METHODS: Fifteen male Sprague-Dawley rats were studied. Five were selected for bulbous urethral obstruction through a perineal incision, five for midprostatic obstruction using a retropubic approach, and five for a sham operation through a perineal incision. RESULTS: The operative time was shorter and morbidity lower with the perineal approach compared with the retropubic approach. Inflammation or infection, or both, were seen in the prostate, bladder, proximal urethra, ureters, and kidneys in the rats in which a midprostatic obstruction was performed. The proximal urethra and prostate were mildly inflamed in those rats that underwent bulbous obstruction. Sham-operated rats exhibited mild prostatitis only. CONCLUSIONS: The perineal approach to the bulbous urethra is the method of choice for creating a partial urethral obstruction model of bladder outlet obstruction in the male rat.
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Trypanosoma cruzi infection induced changes in the innervation, structure and function of the murine bladder.
PURPOSE: The involvement of the lower urinary tract in chronic Chagas' disease has received little attention. Therefore, we investigated pathology and functional alterations in the bladder of Trypanosoma cruzi infected mice. MATERIALS AND METHODS: CD1 mice were infected with 5 x 10 T. cruzi trypomastigotes of the Brazil strain of T. cruzi. At day 100 after infection bladder structure and function were examined by pathological evaluation, magnetic resonance imaging and cystometric studies. RESULTS: The bladder in infected mice weighed more and were large, dilated, deformed, friable and thin walled compared with control mice. Magnetic resonance imaging confirmed these observations. Inflammation, fibrosis and ganglionitis was observed. Cystometric studies revealed that baseline, threshold and micturition pressures were increased in infected mice. Bladder overactivity and decreased bladder compliance were also noted in infected mice. There were no detectable differences in bladder capacity, micturition volume or residual volume between infected and uninfected mice. CONCLUSIONS: Bladder abnormalities may be a more common clinical sequelae of T. cruzi infection than previously appreciated.
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Surgery for localized prostate cancer after renal transplantation.
OBJECTIVE: To investigate the feasibility of perineal radical prostatectomy (RP) in renal transplant recipients with localized prostate cancer. PATIENTS AND METHODS: The study comprised seven consecutive renal transplant patients who had a perineal RP between May 1991 and February 2004. All available clinicopathological data were reviewed. Results All seven patients successfully tolerated RP with no major complications. The mean (sd, range) age at surgery was 62.3 (2.5, 55-74) years and the mean interval from renal transplant to RP 86.5 (25.25, 24-192) months. There was no evidence of increased blood loss, operative duration, transfusion requirement, hospital stay or deterioration of graft function. The presence of an allograft did not alter the surgical approach or management of the patients after RP. The mean follow-up was 22 (2-130) months and all seven patients were followed. One patient had evidence of biochemical recurrence with no radiographic evidence of metastatic disease. Serum prostate-specific antigen was undetectable in the remaining patients. CONCLUSION: A perineal RP in renal transplant recipients for treating localized prostate cancer offers many advantages over other treatments.
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Radical perineal prostatectomy: a more optimal treatment approach than laparoscopic radical prostatectomy in obese patients?
In comparison with laparoscopic radical prostatectomy (LRP), the perineal approach to radical prostatectomy offers specific technical advantages related to obesity and its unique surgical challenges. Radical perineal prostatectomy (RPP) reduces operative time and its associated risk of complication, which may be more pronounced in obese men. It allows for low blood loss, low postoperative use of narcotics for pain, short hospital stays, and requires only 1 small perineal incision. With a proven history of success, RPP presents obese men with an advantageous surgical option.
Journal Article↗
Overcoming the steep learning curve of laparoscopic radical prostatectomy: single-surgeon experience.
PURPOSE: To evaluate the influence of intensive laparoscopic skills training and self-critical video review on the learning curve for laparoscopic radical prostatectomy (LRP). PATIENTS AND METHODS: The initial 40 patients who underwent a transperitoneal LRP (groups 1-4) and the subsequent 20 who underwent LRP by the extraperitoneal approach (group 5) were studied. Eight weeks prior to initiating the LRP program, intensive laparoscopic skills training at a minimally invasive surgery center was undertaken for an average of 4 hours per week. This self-training was continued for 12 weeks into the program, with self-critical review of videotapes of each procedure. The groups were compared with respect to total operative time (ORT), anastomosis time, and blood loss. RESULTS: There were significant differences in the ORT and anastomosis times between each of the first two groups and the last two groups (P <0.001). The learning curve for ORT was overcome after approximately 35 cases, as there were no significant differences in ORT between group 3 and the subsequent groups. The anastomosis took longer to master, as significant time decreases were observed up to group 4, after which, the mean reached a plateau (group 4 v 5 P = NS). The differences in blood loss were not significant. Overall, there were 7 intraoperative (12.7%) and 8 postoperative (14.5%) complications. CONCLUSIONS: The use of similar facilities and training tools can help overcome the steep learning curve of LRP. Longer follow-up is needed to assess these means of attaining better functional results after LRP.
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