Arthur Burnett - Academia.edu (original) (raw)

Papers by Arthur Burnett

PloS one, 2015

Testosterone deficiency is associated with sickle cell disease (SCD), but its underlying mechanis... more Testosterone deficiency is associated with sickle cell disease (SCD), but its underlying mechanism is not known. We investigated the possible occurrence and mechanism of testosterone deficiency in a mouse model of human SCD. Transgenic sickle male mice (Sickle) exhibited decreased serum and intratesticular testosterone and increased luteinizing hormone (LH) levels compared with wild type (WT) mice, indicating primary hypogonadism in Sickle mice. LH-, dbcAMP-, and pregnenolone- (but not 22-hydroxycholesterol)- stimulated testosterone production by Leydig cells isolated from the Sickle mouse testis was decreased compared to that of WT mice, implying defective Leydig cell steroidogenesis. There also was reduced protein expression of steroidogenic acute regulatory protein (STAR), but not cholesterol side-chain cleavage enzyme (P450scc), in the Sickle mouse testis. These data suggest that the capacity of P450scc to support testosterone production may be limited by the supply of cholester...

The Journal of urology, Jan 9, 2015

The purpose of this guideline is to provide a clinical framework for the diagnosis and treatment ... more The purpose of this guideline is to provide a clinical framework for the diagnosis and treatment of Peyronie's disease. A systematic review of the literature using the PubMed®, EMBASE® and Cochrane databases (search dates 1/1/1965 to 1/26/15) was conducted to identify peer-reviewed publications relevant to the diagnosis and treatment of PD. The review yielded an evidence base of 303 articles after application of inclusion/exclusion criteria. The systematic review was used to create guideline statements regarding treatment of PD. When sufficient evidence existed, the body of evidence for a particular treatment was assigned a strength rating of A (high quality evidence; high certainty), B (moderate quality evidence; moderate certainty), or C (low quality evidence; low certainty). Evidence-based statements of Strong, Moderate, or Conditional Recommendation were developed based on benefits and risks/burdens to patients. Additional consensus statements related to the diagnosis of PD ...

The journal of sexual medicine, Jan 17, 2015

In 2014, the International Society for Sexual Medicine (ISSM) convened a panel of experts to deve... more In 2014, the International Society for Sexual Medicine (ISSM) convened a panel of experts to develop an evidence-based process of care for the diagnosis and management of testosterone deficiency (TD) in adult men. The panel considered the definition, epidemiology, aetiology, physiological effects, diagnosis, assessment and treatment of TD. It also considered the treatment of TD in special populations and commented on contemporary controversies about testosterone replacement therapy, cardiovascular risk and prostate cancer. The aim was to develop clearly worded, practical, evidenced-based recommendations for the diagnosis and treatment of diagnosis and management of TD for clinicians without expertise in endocrinology, such as physicians in family medicine and general urology practice. A comprehensive literature review was performed, followed by a structured, three-day panel meeting and six-month panel consultation process using electronic communication. The final guideline was compi...

Evidence-based medicine, 2009

BJU international, Jan 24, 2015

To examine the efficacy of intralesional collagenase clostridium histolyticum (CCH) in defined su... more To examine the efficacy of intralesional collagenase clostridium histolyticum (CCH) in defined subgroups of subjects with Peyronie's disease (PD). The efficacy of CCH compared with placebo from baseline to week 52 was examined in subgroups of subjects from the Investigation for Maximal Peyronie's Reduction Efficacy and Safety Studies (IMPRESS) I and II, defined by: severity of penile curvature deformity at baseline (30°-60° [n=492] and 61°-90° [n=120]); PD duration (1 to ≤2 [n=201], >2 to ≤4 [n=212], and >4 years [n=199]); degree of plaque calcification (no calcification [n=447], noncontiguous stippling [n=103], and contiguous calcification that did not interfere with the injection [n=62]); and baseline erectile function (International Index of Erectile Function [IIEF] 1-5 [n=22], 6-16 [n=106], and ≥17 [n=480]). Reductions in penile curvature deformity and PD symptom bother were observed in all subgroups. Penile curvature deformity reductions were significantly greater...

Blood, 2015

Priapism is a disorder of persistent penile erection unrelated to sexual interest or desire. This... more Priapism is a disorder of persistent penile erection unrelated to sexual interest or desire. This pathologic condition, specifically the ischemic variant, is often associated with devastating complications, notably erectile dysfunction. Because priapism demonstrates high prevalence in patients with hematological disorders, most commonly sickle cell disease (SCD), there is significant concern for its sequelae in this affected population. Thus, timely diagnosis and management are critical for the prevention or at least reduction of cavernosal tissue ischemia and potential damage consequent to each episode. Current guidelines and management strategies focus primarily on reactive treatments. However, an increasing understanding of the molecular pathophysiology of SCD-associated priapism has led to the identification of new potential therapeutic targets. Future agents are being developed and explored for use in the prevention of priapism.

American Journal of Medicine, 2007

PurposeTo assess the prevalence of erectile dysfunction and to quantify associations between puta... more PurposeTo assess the prevalence of erectile dysfunction and to quantify associations between putative risk factors and erectile dysfunction in the US adult male population.

The Journal of Sexual Medicine, 2015

Erectile dysfunction is a major complication of radical prostatectomy, commonly associated with p... more Erectile dysfunction is a major complication of radical prostatectomy, commonly associated with penile neuropathy. In animal models of peripheral nerve injury, glial growth factor-2 (GGF2), a member of the neuregulin family of growth factors, has neuroprotective and neurorestorative properties, but this potential has not been established after cavernous nerve (CN) injury. The effectiveness of GGF2 in preserving axonal integrity and recovering erectile function in a rat model of radical prostatectomy-associated CN injury. Adult male Sprague-Dawley rats underwent bilateral CN crush injury (BCNI) or sham surgery. Rats were administered GGF2 (0.5, 5, or 15 mg/kg) or vehicle subcutaneously 24 hour pre and 24-hour post-BCNI, and once weekly for 5 weeks. Erectile function was assessed in response to electrical stimulation of the CN. CN survival was assessed by fluorogold retrograde axonal tracing in major pelvic ganglia (MPG). Unmyelinated axons in the CNs were quantitated by electron microscopy. Erectile function recovery, CN survival, and unmyelinated CN axon preservation in response to GGF2 treatment following BCNI. Erectile function was decreased (P < 0.05) after BCNI, and it was improved (P < 0.05) by all doses of GGF2. The number of fluorogold-labeled cells in the MPG was reduced (P < 0.05) by BCNI and was increased (P < 0.05) by GGF2 (0.5 and 5 mg/kg). The percentage of denervated Schwann cells in the BCNI group was higher (P < 0.05) than that in the sham-treated group and was decreased (P < 0.05) in the GGF2-treated (5 mg/kg) BCNI group. In the BCNI + GGF2 (5 mg/kg) group, the unmyelinated fiber histogram demonstrated a rightward shift, indicating an increased number of unmyelinated axons per Schwann cell compared with the BCNI group. GGF2 promotes erectile function recovery following CN injury in conjunction with preserving unmyelinated CN fibers. Our findings suggest the clinical opportunity to develop GGF2 as a neuroprotective therapy for radical prostatectomy. Burnett AL, Sezen SF, Hoke A, Caggiano AO, Iaci J, Lagoda G, Musicki B, and Bella AJ. GGF2 is neuroprotective in a rat model of cavernous nerve injury-induced erectile dysfunction. J Sex Med **;**:**-**.

Heat shock protein 72 (HSP72) is a stress-inducible protein capable of protecting a variety of ce... more Heat shock protein 72 (HSP72) is a stress-inducible protein capable of protecting a variety of cells from toxins, thermal stress, and ischemic injury. The cytoprotective role and mechanism of action of HSP72 in renal cell ischemic injury remain unclear. To study this, HSP72 was introduced (liposomal transfer) or induced (thermal stress, 43°C1 hour) in renal tubular cells (LLC-PK1) with Western

Urology, 2013

To characterize transforming growth factor beta 1 (TGFβ1) and related signaling pathway proteins ... more To characterize transforming growth factor beta 1 (TGFβ1) and related signaling pathway proteins in a large cohort of human penile tissue (HPT) samples. HPT was collected from patients undergoing penile prosthesis implantation for erectile dysfunction (ED) and divided into the following 2 groups: postradical prostatectomy ED (RP-ED; n = 57) and organic ED (O-ED; n = 30). HPT from patients undergoing partial penectomy without ED was used as controls (CON; n = 6). Western blot analysis was performed to investigate the protein expressions of TGFβ1, thrombospondin 1 (TSP1; an activator of TGFβ1), fibronectin (an extracellular matrix glycoprotein induced by TGFβ1), and a family of transcriptional factors activated by TGFβ1 (Smad2, phospho-Smad2-serine-465/467 [pSmad2], Smad3, phospho-Smad3-serine-423/425 [pSmad3]). Expressions of TGFβ1 and TSP1 were significantly higher in RP-ED (P <.05) and O-ED (P <.05) groups compared with that of the CON group and were not different between either ED groups. Expressions of Smad2, pSmad2, Smad3, pSmad3, and fibronectin were similar among all groups. Within the RP-ED group, a subgroup analysis showed that time from RP to penile prosthesis implantation was related to increased expression of pSmad2 (P <.05), and previous history of intracavernosal injection was related to increased expression of TGFβ1 (P <.05). Our results demonstrate that TSP1- and TGFβ1-dependent fibrotic changes occur in penile tissue in patients with ED regardless of etiology. The unchanged expression of the Smad transcriptional factors may be reconciled by a Smad-independent downstream signaling pathway transmitting TGFβ1 signals.

Urology, 1999

Objectives. To develop Patient and Partner versions of a psychometrically sound questionnaire, th... more Objectives. To develop Patient and Partner versions of a psychometrically sound questionnaire, the EDITS (Erectile Dysfunction Inventory of Treatment Satisfaction), to assess satisfaction with medical treatments for erectile dysfunction. Methods. Treatment satisfaction differs from treatment efficacy as it focuses on a person's subjective evaluation of treatment received. Twenty-nine items representing the domain of treatment satisfaction for men and 20 representing partner satisfaction were generated. Two independent samples of 28 and 29 couples completed all items at two points in time. Spearman rank-order correlations were derived to assess test-retest reliability and couple coefficients of validity. Internal consistency coefficients were calculated for both Patient and Partner versions and a content validity panel was used to analyze content validity. Results. Only items that met all the following criteria were selected to comprise the final questionnaires: (a) range of response four or more out of five; (b) test-retest reliability greater than 0.70; (c) ratings by at least 70% of the content validity panel as belonging in and being important for the domain; and (d) significant correlation between the subjects' and partners' responses. Eleven patient items met criteria and formed the Patient EDITS; five partner items met criteria and formed the Partner EDITS. Scores on the two inventories were normally distributed with internal consistencies of 0.90 and 0.76, respectively. Test-retest reliability for the Patient EDITS was 0.98; for the Partner EDITS, it was 0.83. Conclusions. Reliability and validity were well established, enabling the EDITSs to be used to assess satisfaction with treatment modalities for erectile dysfunction and to explore the impact of patient and partner satisfaction on treatment continuation. UROLOGY 53: [793][794][795][796][797][798][799] 1999. © 1999, Elsevier Science Inc. All rights reserved.

Urology, 2000

After radical prostatectomy, the rates for recovery of urinary continence and sexual function rep... more After radical prostatectomy, the rates for recovery of urinary continence and sexual function reported by experienced surgeons are much higher than the patient-reported outcomes from other centers. It is uncertain whether this represents differences in surgical technique or in the collection of data. This study was performed to determine patient-reported rates of continence and potency after radical prostatectomy performed by an experienced surgeon at a high-volume referral center for the treatment of localized prostate cancer. Sixty-four men with localized prostate cancer who were potent preoperatively and who had sexual partners underwent anatomic radical prostatectomy between March 1997 and January 1998. A validated disease-targeted quality-of-life survey that assesses function and bother in two organ systems (urinary and sexual) was administered preoperatively and at 3, 6, 12, and 18 months postoperatively. Urinary continence, which was defined as wearing no pads, gradually improved during the first 12 months after surgery, and at 1 2 and 18 months, 93% of the patients were dry. Throughout the study, 93% to 98% of the patients characterized their urinary bother as none or small. Potency, defined as the ability to have unassisted intercourse with or without the use of sildenafil, improved gradually, and by 18 months, 86% of patients were potent and 84% considered sexual bother as none or small. Although one third of patients at 18 months were using sildenafil intermittently, only 2 patients were not able to have intercourse without its use. Patient-reported rates of continence and potency after radical prostatectomy performed by an experienced surgeon are high.

Urology, 2008

To demonstrate the use of optical coherence tomography (OCT) for imaging of the cavernous nerve (... more To demonstrate the use of optical coherence tomography (OCT) for imaging of the cavernous nerve (CN) and periprostatic tissues. The rates of nerve preservation and postoperative potency after radical prostatectomy might improve with better identification of the CN using emerging intraoperative imaging modalities. OCT is an imaging modality that allows for real-time, high-resolution, cross-sectional imaging of tissues. Seven male Sprague-Dawley rats underwent surgery using a midline celiotomy to expose the bladder, prostate, and seminal vesicles. The CNs and major pelvic ganglion were identified. Visual identification of the CN was further confirmed by electrical stimulation with simultaneous intracorporeal pressure measurements. OCT images of the CN, major pelvic ganglion, bladder, prostate, and seminal vesicles were acquired and correlated directly with the histologic findings. Once a baseline technique for the scanning and interpretation of the acquired images was established using the rat model, OCT was used to image ex vivo human prostatectomy specimens. OCT provided unique imaging characteristics, differentiating the CN from the bladder, prostate, seminal vesicles, and periprostatic fat. OCT images of the CN and prostate correlated well with the histologic findings. OCT of ex vivo human prostatectomy specimens revealed findings similar to those with the rat experiments, with, however, less dramatic architecture visualized in part because of the thicker capsule and more dense stroma of human prostates. The results of our study have shown that OCT provides real-time, high-resolution imaging of the CN in the rat model with excellent correlation to the histologic findings. This study provides a basis for the intraoperative use of this emerging technology during nerve-sparing prostatectomy.

Urology, 2008

To evaluate the effect of the fibrin sealant, Evicel, on the neuroregulatory control of penile er... more To evaluate the effect of the fibrin sealant, Evicel, on the neuroregulatory control of penile erections in an experimental rat model. Two groups of rats were used: sham-operated rats with exposure of the bilateral cavernous nerves (CNs) and application of saline vehicle (500 microL), and rats treated with direct application of Evicel (500 microL) bilaterally to the CNs. At 14 and 45 days after application of Evicel to the CNs, the CNs were stimulated to measure the in vivo erectile responses. Additionally, we evaluated the neuronal nitric oxide synthase immunoreactivity in the dorsal CNs of the penis and changes in the smooth muscle and collagen deposition in the penis using a trichrome stain. Evicel application to the CNs did not have any detrimental effect on the neurogenic erectile responses in vivo at 14 or 45 days after application. The neuronal nitric oxide synthase expression in the dorsal CNs of the penis was unchanged after Evicel application at all points studied, and we saw no change in the histomorphometric analysis findings of smooth muscle and collagen deposition in the penis. These data suggest that the hemostatic agent, Evicel, is safe in an experimental rat model of erection physiology, with no detrimental effects on neuroregulatory control of erection.

Urologic Oncology: Seminars and Original Investigations, 2014

Infection by high-risk human papillomavirus (HR-HPV) plays an important role in the pathogenesis ... more Infection by high-risk human papillomavirus (HR-HPV) plays an important role in the pathogenesis of penile cancer in approximately 50% of the patients. The gold standard for human papillomavirus (HPV) detection is the polymerase chain reaction (PCR) assay. However, technical requirements and associated costs preclude the worldwide use of PCR assays on a routine basis. Herein, we evaluated the predictive abilities of tumor morphology, immunohistochemistry for p16(INK4a) expression, and in situ hybridization (ISH) for HR-HPV detection in defining HPV status, as established by PCR. Tissue samples from 48 patients with HPV-positive penile squamous cell carcinoma (SCC) were included in 4 tissue microarrays (TMA). Sensitivities and specificities were as follows: tumor morphology, 70% and 68%; p16(INK4a) immunohistochemistry, 65% and 90%; HR-HPV ISH, 47% and 100%. Regarding combinations of the predictors, the best performance was seen when HR-HPV ISH and p16(INK4a) immunohistochemistry were combined, regardless of the tumor morphology: sensitivity, 88%; specificity, 64%; area under the receiver-operating characteristic (AUC) curve, 0.83. Combinations of tumor morphology with p16(INK4a) immunohistochemistry or with HR-HPV ISH performed similarly well. In penile SCC, both p16(INK4a) immunohistochemistry and ISH for HR-HPV increase the predictive ability of routine morphology in defining HPV status. These tests can be interpreted differentially, depending on the necessity of a higher sensitivity or a higher specificity. For research/screening studies, we recommend combining tumor morphology, p16(INK4a) immunohistochemistry, and HR-HPV ISH. To increase sensitivity, positivity in any of these predictors should be considered as indicative of HPV infection. For routine diagnosis of clinical cases, criteria should be more stringent, and, to achieve the highest specificity in classifying a case as HPV-related, all predictors should be consistently positive. The data generated in the present study could be used in algorithms for defining HPV status in penile carcinomas.

Proceedings of the National Academy of Sciences, 2002

In the penis, nitric oxide (NO) can be formed by both neuronal NO synthase and endothelial NOS (e... more In the penis, nitric oxide (NO) can be formed by both neuronal NO synthase and endothelial NOS (eNOS). eNOS is activated by viscous drag/shear stress in blood vessels to produce NO continuously, a process mediated by the phosphatidylinositol 3-kinase (PI3kinase)/Akt pathway. Here we show that PI3-kinase/Akt physiologically mediates erection. Both electrical stimulation of the cavernous nerve and direct intracavernosal injection of the vasorelaxant drug papaverine cause rapid increases in phosphorylated (activated) Akt and eNOS. Phosphorylation is diminished by wortmannin and LY294002, inhibitors of PI3-kinase, the upstream activator of Akt. The two drugs also reduce erection. Penile erection elicited by papaverine is reduced profoundly in mice with targeted deletion of eNOS. Our findings support a model in which rapid, brief activation of neuronal NOS initiates the erectile process, whereas PI3-kinase/Akt-dependent phosphorylation and activation of eNOS leads to sustained NO production and maximal erection.

Nature Medicine, 1997

Idiopathic voiding disorders affect up to 10-15% of men and women. We describe bladder abnormalit... more Idiopathic voiding disorders affect up to 10-15% of men and women. We describe bladder abnormalities in mice with targeted deletion of the gene for neuronal nitric oxide synthase which model the clinical disorders. The mice possess hypertrophic dilated bladders and dysfunctional urinary outlets which do not relax in response to electrical field stimulation or L-arginine. The mice also display increased urinary frequency.

Nature, 2002

Subcellular localization of nitric oxide (NO) synthases with effector molecules is an important r... more Subcellular localization of nitric oxide (NO) synthases with effector molecules is an important regulatory mechanism for NO signalling. In the heart, NO inhibits L-type Ca2+ channels but stimulates sarcoplasmic reticulum (SR) Ca2+ release, leading to variable effects on myocardial contractility. Here we show that spatial confinement of specific NO synthase isoforms regulates this process. Endothelial NO synthase (NOS3) localizes to caveolae, where compartmentalization with beta-adrenergic receptors and L-type Ca2+ channels allows NO to inhibit beta-adrenergic-induced inotropy. Neuronal NO synthase (NOS1), however, is targeted to cardiac SR. NO stimulation of SR Ca2+ release via the ryanodine receptor (RyR) in vitro, suggests that NOS1 has an opposite, facilitative effect on contractility. We demonstrate that NOS1-deficient mice have suppressed inotropic response, whereas NOS3-deficient mice have enhanced contractility, owing to corresponding changes in SR Ca2+ release. Both NOS1-/- and NOS3-/- mice develop age-related hypertrophy, although only NOS3-/- mice are hypertensive. NOS1/3-/- double knockout mice have suppressed beta-adrenergic responses and an additive phenotype of marked ventricular remodelling. Thus, NOS1 and NOS3 mediate independent, and in some cases opposite, effects on cardiac structure and function.

PloS one, 2015

Testosterone deficiency is associated with sickle cell disease (SCD), but its underlying mechanis... more Testosterone deficiency is associated with sickle cell disease (SCD), but its underlying mechanism is not known. We investigated the possible occurrence and mechanism of testosterone deficiency in a mouse model of human SCD. Transgenic sickle male mice (Sickle) exhibited decreased serum and intratesticular testosterone and increased luteinizing hormone (LH) levels compared with wild type (WT) mice, indicating primary hypogonadism in Sickle mice. LH-, dbcAMP-, and pregnenolone- (but not 22-hydroxycholesterol)- stimulated testosterone production by Leydig cells isolated from the Sickle mouse testis was decreased compared to that of WT mice, implying defective Leydig cell steroidogenesis. There also was reduced protein expression of steroidogenic acute regulatory protein (STAR), but not cholesterol side-chain cleavage enzyme (P450scc), in the Sickle mouse testis. These data suggest that the capacity of P450scc to support testosterone production may be limited by the supply of cholester...

The Journal of urology, Jan 9, 2015

The purpose of this guideline is to provide a clinical framework for the diagnosis and treatment ... more The purpose of this guideline is to provide a clinical framework for the diagnosis and treatment of Peyronie's disease. A systematic review of the literature using the PubMed®, EMBASE® and Cochrane databases (search dates 1/1/1965 to 1/26/15) was conducted to identify peer-reviewed publications relevant to the diagnosis and treatment of PD. The review yielded an evidence base of 303 articles after application of inclusion/exclusion criteria. The systematic review was used to create guideline statements regarding treatment of PD. When sufficient evidence existed, the body of evidence for a particular treatment was assigned a strength rating of A (high quality evidence; high certainty), B (moderate quality evidence; moderate certainty), or C (low quality evidence; low certainty). Evidence-based statements of Strong, Moderate, or Conditional Recommendation were developed based on benefits and risks/burdens to patients. Additional consensus statements related to the diagnosis of PD ...

The journal of sexual medicine, Jan 17, 2015

In 2014, the International Society for Sexual Medicine (ISSM) convened a panel of experts to deve... more In 2014, the International Society for Sexual Medicine (ISSM) convened a panel of experts to develop an evidence-based process of care for the diagnosis and management of testosterone deficiency (TD) in adult men. The panel considered the definition, epidemiology, aetiology, physiological effects, diagnosis, assessment and treatment of TD. It also considered the treatment of TD in special populations and commented on contemporary controversies about testosterone replacement therapy, cardiovascular risk and prostate cancer. The aim was to develop clearly worded, practical, evidenced-based recommendations for the diagnosis and treatment of diagnosis and management of TD for clinicians without expertise in endocrinology, such as physicians in family medicine and general urology practice. A comprehensive literature review was performed, followed by a structured, three-day panel meeting and six-month panel consultation process using electronic communication. The final guideline was compi...

Evidence-based medicine, 2009

BJU international, Jan 24, 2015

To examine the efficacy of intralesional collagenase clostridium histolyticum (CCH) in defined su... more To examine the efficacy of intralesional collagenase clostridium histolyticum (CCH) in defined subgroups of subjects with Peyronie's disease (PD). The efficacy of CCH compared with placebo from baseline to week 52 was examined in subgroups of subjects from the Investigation for Maximal Peyronie's Reduction Efficacy and Safety Studies (IMPRESS) I and II, defined by: severity of penile curvature deformity at baseline (30°-60° [n=492] and 61°-90° [n=120]); PD duration (1 to ≤2 [n=201], >2 to ≤4 [n=212], and >4 years [n=199]); degree of plaque calcification (no calcification [n=447], noncontiguous stippling [n=103], and contiguous calcification that did not interfere with the injection [n=62]); and baseline erectile function (International Index of Erectile Function [IIEF] 1-5 [n=22], 6-16 [n=106], and ≥17 [n=480]). Reductions in penile curvature deformity and PD symptom bother were observed in all subgroups. Penile curvature deformity reductions were significantly greater...

Blood, 2015

Priapism is a disorder of persistent penile erection unrelated to sexual interest or desire. This... more Priapism is a disorder of persistent penile erection unrelated to sexual interest or desire. This pathologic condition, specifically the ischemic variant, is often associated with devastating complications, notably erectile dysfunction. Because priapism demonstrates high prevalence in patients with hematological disorders, most commonly sickle cell disease (SCD), there is significant concern for its sequelae in this affected population. Thus, timely diagnosis and management are critical for the prevention or at least reduction of cavernosal tissue ischemia and potential damage consequent to each episode. Current guidelines and management strategies focus primarily on reactive treatments. However, an increasing understanding of the molecular pathophysiology of SCD-associated priapism has led to the identification of new potential therapeutic targets. Future agents are being developed and explored for use in the prevention of priapism.

American Journal of Medicine, 2007

PurposeTo assess the prevalence of erectile dysfunction and to quantify associations between puta... more PurposeTo assess the prevalence of erectile dysfunction and to quantify associations between putative risk factors and erectile dysfunction in the US adult male population.

The Journal of Sexual Medicine, 2015

Erectile dysfunction is a major complication of radical prostatectomy, commonly associated with p... more Erectile dysfunction is a major complication of radical prostatectomy, commonly associated with penile neuropathy. In animal models of peripheral nerve injury, glial growth factor-2 (GGF2), a member of the neuregulin family of growth factors, has neuroprotective and neurorestorative properties, but this potential has not been established after cavernous nerve (CN) injury. The effectiveness of GGF2 in preserving axonal integrity and recovering erectile function in a rat model of radical prostatectomy-associated CN injury. Adult male Sprague-Dawley rats underwent bilateral CN crush injury (BCNI) or sham surgery. Rats were administered GGF2 (0.5, 5, or 15 mg/kg) or vehicle subcutaneously 24 hour pre and 24-hour post-BCNI, and once weekly for 5 weeks. Erectile function was assessed in response to electrical stimulation of the CN. CN survival was assessed by fluorogold retrograde axonal tracing in major pelvic ganglia (MPG). Unmyelinated axons in the CNs were quantitated by electron microscopy. Erectile function recovery, CN survival, and unmyelinated CN axon preservation in response to GGF2 treatment following BCNI. Erectile function was decreased (P < 0.05) after BCNI, and it was improved (P < 0.05) by all doses of GGF2. The number of fluorogold-labeled cells in the MPG was reduced (P < 0.05) by BCNI and was increased (P < 0.05) by GGF2 (0.5 and 5 mg/kg). The percentage of denervated Schwann cells in the BCNI group was higher (P < 0.05) than that in the sham-treated group and was decreased (P < 0.05) in the GGF2-treated (5 mg/kg) BCNI group. In the BCNI + GGF2 (5 mg/kg) group, the unmyelinated fiber histogram demonstrated a rightward shift, indicating an increased number of unmyelinated axons per Schwann cell compared with the BCNI group. GGF2 promotes erectile function recovery following CN injury in conjunction with preserving unmyelinated CN fibers. Our findings suggest the clinical opportunity to develop GGF2 as a neuroprotective therapy for radical prostatectomy. Burnett AL, Sezen SF, Hoke A, Caggiano AO, Iaci J, Lagoda G, Musicki B, and Bella AJ. GGF2 is neuroprotective in a rat model of cavernous nerve injury-induced erectile dysfunction. J Sex Med **;**:**-**.

Heat shock protein 72 (HSP72) is a stress-inducible protein capable of protecting a variety of ce... more Heat shock protein 72 (HSP72) is a stress-inducible protein capable of protecting a variety of cells from toxins, thermal stress, and ischemic injury. The cytoprotective role and mechanism of action of HSP72 in renal cell ischemic injury remain unclear. To study this, HSP72 was introduced (liposomal transfer) or induced (thermal stress, 43°C1 hour) in renal tubular cells (LLC-PK1) with Western

Urology, 2013

To characterize transforming growth factor beta 1 (TGFβ1) and related signaling pathway proteins ... more To characterize transforming growth factor beta 1 (TGFβ1) and related signaling pathway proteins in a large cohort of human penile tissue (HPT) samples. HPT was collected from patients undergoing penile prosthesis implantation for erectile dysfunction (ED) and divided into the following 2 groups: postradical prostatectomy ED (RP-ED; n = 57) and organic ED (O-ED; n = 30). HPT from patients undergoing partial penectomy without ED was used as controls (CON; n = 6). Western blot analysis was performed to investigate the protein expressions of TGFβ1, thrombospondin 1 (TSP1; an activator of TGFβ1), fibronectin (an extracellular matrix glycoprotein induced by TGFβ1), and a family of transcriptional factors activated by TGFβ1 (Smad2, phospho-Smad2-serine-465/467 [pSmad2], Smad3, phospho-Smad3-serine-423/425 [pSmad3]). Expressions of TGFβ1 and TSP1 were significantly higher in RP-ED (P <.05) and O-ED (P <.05) groups compared with that of the CON group and were not different between either ED groups. Expressions of Smad2, pSmad2, Smad3, pSmad3, and fibronectin were similar among all groups. Within the RP-ED group, a subgroup analysis showed that time from RP to penile prosthesis implantation was related to increased expression of pSmad2 (P <.05), and previous history of intracavernosal injection was related to increased expression of TGFβ1 (P <.05). Our results demonstrate that TSP1- and TGFβ1-dependent fibrotic changes occur in penile tissue in patients with ED regardless of etiology. The unchanged expression of the Smad transcriptional factors may be reconciled by a Smad-independent downstream signaling pathway transmitting TGFβ1 signals.

Urology, 1999

Objectives. To develop Patient and Partner versions of a psychometrically sound questionnaire, th... more Objectives. To develop Patient and Partner versions of a psychometrically sound questionnaire, the EDITS (Erectile Dysfunction Inventory of Treatment Satisfaction), to assess satisfaction with medical treatments for erectile dysfunction. Methods. Treatment satisfaction differs from treatment efficacy as it focuses on a person's subjective evaluation of treatment received. Twenty-nine items representing the domain of treatment satisfaction for men and 20 representing partner satisfaction were generated. Two independent samples of 28 and 29 couples completed all items at two points in time. Spearman rank-order correlations were derived to assess test-retest reliability and couple coefficients of validity. Internal consistency coefficients were calculated for both Patient and Partner versions and a content validity panel was used to analyze content validity. Results. Only items that met all the following criteria were selected to comprise the final questionnaires: (a) range of response four or more out of five; (b) test-retest reliability greater than 0.70; (c) ratings by at least 70% of the content validity panel as belonging in and being important for the domain; and (d) significant correlation between the subjects' and partners' responses. Eleven patient items met criteria and formed the Patient EDITS; five partner items met criteria and formed the Partner EDITS. Scores on the two inventories were normally distributed with internal consistencies of 0.90 and 0.76, respectively. Test-retest reliability for the Patient EDITS was 0.98; for the Partner EDITS, it was 0.83. Conclusions. Reliability and validity were well established, enabling the EDITSs to be used to assess satisfaction with treatment modalities for erectile dysfunction and to explore the impact of patient and partner satisfaction on treatment continuation. UROLOGY 53: [793][794][795][796][797][798][799] 1999. © 1999, Elsevier Science Inc. All rights reserved.

Urology, 2000

After radical prostatectomy, the rates for recovery of urinary continence and sexual function rep... more After radical prostatectomy, the rates for recovery of urinary continence and sexual function reported by experienced surgeons are much higher than the patient-reported outcomes from other centers. It is uncertain whether this represents differences in surgical technique or in the collection of data. This study was performed to determine patient-reported rates of continence and potency after radical prostatectomy performed by an experienced surgeon at a high-volume referral center for the treatment of localized prostate cancer. Sixty-four men with localized prostate cancer who were potent preoperatively and who had sexual partners underwent anatomic radical prostatectomy between March 1997 and January 1998. A validated disease-targeted quality-of-life survey that assesses function and bother in two organ systems (urinary and sexual) was administered preoperatively and at 3, 6, 12, and 18 months postoperatively. Urinary continence, which was defined as wearing no pads, gradually improved during the first 12 months after surgery, and at 1 2 and 18 months, 93% of the patients were dry. Throughout the study, 93% to 98% of the patients characterized their urinary bother as none or small. Potency, defined as the ability to have unassisted intercourse with or without the use of sildenafil, improved gradually, and by 18 months, 86% of patients were potent and 84% considered sexual bother as none or small. Although one third of patients at 18 months were using sildenafil intermittently, only 2 patients were not able to have intercourse without its use. Patient-reported rates of continence and potency after radical prostatectomy performed by an experienced surgeon are high.

Urology, 2008

To demonstrate the use of optical coherence tomography (OCT) for imaging of the cavernous nerve (... more To demonstrate the use of optical coherence tomography (OCT) for imaging of the cavernous nerve (CN) and periprostatic tissues. The rates of nerve preservation and postoperative potency after radical prostatectomy might improve with better identification of the CN using emerging intraoperative imaging modalities. OCT is an imaging modality that allows for real-time, high-resolution, cross-sectional imaging of tissues. Seven male Sprague-Dawley rats underwent surgery using a midline celiotomy to expose the bladder, prostate, and seminal vesicles. The CNs and major pelvic ganglion were identified. Visual identification of the CN was further confirmed by electrical stimulation with simultaneous intracorporeal pressure measurements. OCT images of the CN, major pelvic ganglion, bladder, prostate, and seminal vesicles were acquired and correlated directly with the histologic findings. Once a baseline technique for the scanning and interpretation of the acquired images was established using the rat model, OCT was used to image ex vivo human prostatectomy specimens. OCT provided unique imaging characteristics, differentiating the CN from the bladder, prostate, seminal vesicles, and periprostatic fat. OCT images of the CN and prostate correlated well with the histologic findings. OCT of ex vivo human prostatectomy specimens revealed findings similar to those with the rat experiments, with, however, less dramatic architecture visualized in part because of the thicker capsule and more dense stroma of human prostates. The results of our study have shown that OCT provides real-time, high-resolution imaging of the CN in the rat model with excellent correlation to the histologic findings. This study provides a basis for the intraoperative use of this emerging technology during nerve-sparing prostatectomy.

Urology, 2008

To evaluate the effect of the fibrin sealant, Evicel, on the neuroregulatory control of penile er... more To evaluate the effect of the fibrin sealant, Evicel, on the neuroregulatory control of penile erections in an experimental rat model. Two groups of rats were used: sham-operated rats with exposure of the bilateral cavernous nerves (CNs) and application of saline vehicle (500 microL), and rats treated with direct application of Evicel (500 microL) bilaterally to the CNs. At 14 and 45 days after application of Evicel to the CNs, the CNs were stimulated to measure the in vivo erectile responses. Additionally, we evaluated the neuronal nitric oxide synthase immunoreactivity in the dorsal CNs of the penis and changes in the smooth muscle and collagen deposition in the penis using a trichrome stain. Evicel application to the CNs did not have any detrimental effect on the neurogenic erectile responses in vivo at 14 or 45 days after application. The neuronal nitric oxide synthase expression in the dorsal CNs of the penis was unchanged after Evicel application at all points studied, and we saw no change in the histomorphometric analysis findings of smooth muscle and collagen deposition in the penis. These data suggest that the hemostatic agent, Evicel, is safe in an experimental rat model of erection physiology, with no detrimental effects on neuroregulatory control of erection.

Urologic Oncology: Seminars and Original Investigations, 2014

Infection by high-risk human papillomavirus (HR-HPV) plays an important role in the pathogenesis ... more Infection by high-risk human papillomavirus (HR-HPV) plays an important role in the pathogenesis of penile cancer in approximately 50% of the patients. The gold standard for human papillomavirus (HPV) detection is the polymerase chain reaction (PCR) assay. However, technical requirements and associated costs preclude the worldwide use of PCR assays on a routine basis. Herein, we evaluated the predictive abilities of tumor morphology, immunohistochemistry for p16(INK4a) expression, and in situ hybridization (ISH) for HR-HPV detection in defining HPV status, as established by PCR. Tissue samples from 48 patients with HPV-positive penile squamous cell carcinoma (SCC) were included in 4 tissue microarrays (TMA). Sensitivities and specificities were as follows: tumor morphology, 70% and 68%; p16(INK4a) immunohistochemistry, 65% and 90%; HR-HPV ISH, 47% and 100%. Regarding combinations of the predictors, the best performance was seen when HR-HPV ISH and p16(INK4a) immunohistochemistry were combined, regardless of the tumor morphology: sensitivity, 88%; specificity, 64%; area under the receiver-operating characteristic (AUC) curve, 0.83. Combinations of tumor morphology with p16(INK4a) immunohistochemistry or with HR-HPV ISH performed similarly well. In penile SCC, both p16(INK4a) immunohistochemistry and ISH for HR-HPV increase the predictive ability of routine morphology in defining HPV status. These tests can be interpreted differentially, depending on the necessity of a higher sensitivity or a higher specificity. For research/screening studies, we recommend combining tumor morphology, p16(INK4a) immunohistochemistry, and HR-HPV ISH. To increase sensitivity, positivity in any of these predictors should be considered as indicative of HPV infection. For routine diagnosis of clinical cases, criteria should be more stringent, and, to achieve the highest specificity in classifying a case as HPV-related, all predictors should be consistently positive. The data generated in the present study could be used in algorithms for defining HPV status in penile carcinomas.

Proceedings of the National Academy of Sciences, 2002

In the penis, nitric oxide (NO) can be formed by both neuronal NO synthase and endothelial NOS (e... more In the penis, nitric oxide (NO) can be formed by both neuronal NO synthase and endothelial NOS (eNOS). eNOS is activated by viscous drag/shear stress in blood vessels to produce NO continuously, a process mediated by the phosphatidylinositol 3-kinase (PI3kinase)/Akt pathway. Here we show that PI3-kinase/Akt physiologically mediates erection. Both electrical stimulation of the cavernous nerve and direct intracavernosal injection of the vasorelaxant drug papaverine cause rapid increases in phosphorylated (activated) Akt and eNOS. Phosphorylation is diminished by wortmannin and LY294002, inhibitors of PI3-kinase, the upstream activator of Akt. The two drugs also reduce erection. Penile erection elicited by papaverine is reduced profoundly in mice with targeted deletion of eNOS. Our findings support a model in which rapid, brief activation of neuronal NOS initiates the erectile process, whereas PI3-kinase/Akt-dependent phosphorylation and activation of eNOS leads to sustained NO production and maximal erection.

Nature Medicine, 1997

Idiopathic voiding disorders affect up to 10-15% of men and women. We describe bladder abnormalit... more Idiopathic voiding disorders affect up to 10-15% of men and women. We describe bladder abnormalities in mice with targeted deletion of the gene for neuronal nitric oxide synthase which model the clinical disorders. The mice possess hypertrophic dilated bladders and dysfunctional urinary outlets which do not relax in response to electrical field stimulation or L-arginine. The mice also display increased urinary frequency.

Nature, 2002

Subcellular localization of nitric oxide (NO) synthases with effector molecules is an important r... more Subcellular localization of nitric oxide (NO) synthases with effector molecules is an important regulatory mechanism for NO signalling. In the heart, NO inhibits L-type Ca2+ channels but stimulates sarcoplasmic reticulum (SR) Ca2+ release, leading to variable effects on myocardial contractility. Here we show that spatial confinement of specific NO synthase isoforms regulates this process. Endothelial NO synthase (NOS3) localizes to caveolae, where compartmentalization with beta-adrenergic receptors and L-type Ca2+ channels allows NO to inhibit beta-adrenergic-induced inotropy. Neuronal NO synthase (NOS1), however, is targeted to cardiac SR. NO stimulation of SR Ca2+ release via the ryanodine receptor (RyR) in vitro, suggests that NOS1 has an opposite, facilitative effect on contractility. We demonstrate that NOS1-deficient mice have suppressed inotropic response, whereas NOS3-deficient mice have enhanced contractility, owing to corresponding changes in SR Ca2+ release. Both NOS1-/- and NOS3-/- mice develop age-related hypertrophy, although only NOS3-/- mice are hypertensive. NOS1/3-/- double knockout mice have suppressed beta-adrenergic responses and an additive phenotype of marked ventricular remodelling. Thus, NOS1 and NOS3 mediate independent, and in some cases opposite, effects on cardiac structure and function.