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Biomedical subjects

K T McVary

Publications and source records attributed to K T McVary.

At least 19 recordsLinked to original sources
PubMed2001

Analysis of NOS isoform changes in a post radical prostatectomy model of erectile dysfunction.

Optimal treatment of erectile dysfunction (ED) following radical prostatectomy remains a subject of much controversy and is a significant concern for prostate cancer patients requiring surgical intervention. Neural stimulation involving nitric oxide synthase (NOS) is a crucial aspect of the normal erection process. In this study NOS isoform interaction was evaluated to improve our understanding of molecular changes pertaining to erection post radical prostatectomy. Bilateral cavernous nerve (CN) resected and control adult male Sprague-Dawley rats were killed 7, 14 and 21 days after injury. RT-PCR, in situ hybridization, Western blot and immunohistochemical analysis were used to evaluate changes in NOS isoform expression and distribution. NOS-I protein was dramatically decreased after CN injury while NOS-III and NOS-II remained unchanged. A profound decrease in smooth muscle and endothelium was observed in the corpora. To our knowledge this is the first report of differential altered NOS isoform protein abundance under conditions which mimic radical prostatectomy. These results show the importance of maintaining at least partial innervation of the penis after surgical intervention and that endothelial and smooth muscle changes resulting from loss of innervation may account for the ED observed in prostatectomy patients.

Actins↗
PubMed2001

Characterization and localization of nitric oxide synthase isoforms in the BB/WOR diabetic rat.

PURPOSE: Erectile dysfunction is a common pathological development in individuals with diabetes mellitus. Nitric oxide synthase (NOS) is essential for regulation of normal penile erection and NOS protein activity has been shown to be altered with diabetes. Several different isoforms and subtypes of NOS exist. However, little is known about how the distribution and abundance of these isoforms are altered with diabetes. We characterized the distribution and abundance of NOS isoforms and explored how they are altered with diabetes and result in erectile failure. MATERIALS AND METHODS: In situ hybridization and quantitative reverse transcriptase-polymerase chain reaction were done to measure the abundance and distribution of NOS-Ia, NOS-Ib, NOS-Ic, NOS-II and NOS-III in control and diabetic (BB/WOR) rats. Protein was localized by immunohistochemical analysis and alterations in protein abundance with diabetes were examined by Western blot analysis. RESULTS: NOS-I, NOS-II and NOS-III were observed in the endothelium lining the cavernous spaces and in the epithelium of the urethra. NOS-I protein was also present in the nerves of control and diabetic penes. We observed an increase in NOS-II expression around the dorsal nerves of diabetic penes, a decrease in NOS-III expression in diabetic pelvic ganglia and a decrease in NOS-Ib expression in the diabetic penis. NOS-I protein abundance was significantly decreased in diabetic pelvic ganglia. CONCLUSIONS: To our knowledge this is the first report of regional differences in the distribution of NOS-III in the urethra and altered NOS-Ib gene expression with diabetes.

Animals↗
PubMed2001

Smoking and erectile dysfunction: evidence based analysis.

PURPOSE: We examined available evidence concerning the role of smoking in the development of erectile dysfunction. This task involved a complete review of the smoking literature as it pertained to erectile dysfunction and select endothelial diseases. MATERIALS AND METHODS: We comprehensively reviewed the literature, including PubMed and recent abstract proceedings from national meetings relevant to smoking, erectile dysfunction and endothelial diseases. The quality of the evidence was assessed by methods used to develop clinical practice guidelines. Our review involved an objective evaluation of the basic science literature and clinical studies. When necessary, we examined studies of endothelial diseases other than erectile dysfunction because of obvious gaps in the literature. RESULTS: There are strong parallels and shared risks among smoking, coronary artery disease, atherosclerosis and erectile dysfunction. Clinical and basic science studies provide strong indirect evidence that smoking may affect penile erection by the impairment of endothelium dependent smooth muscle relaxation. The association of erectile dysfunction with risk factors such as coronary artery disease and hypertension appears to be amplified by cigarette smoking. Smoking may increase the likelihood of moderate or complete erectile dysfunction 2-fold. The prevalence of erectile dysfunction in former smokers was no different from that in individuals who had never smoked, implying that smoking cessation may decrease the risk of erectile dysfunction. Case studies and retrospective series have shown an association of smoking with erectile dysfunction. CONCLUSIONS: Available evidence on the association of smoking with erectile dysfunction is not complete insofar as association linking factors are concerned. However, the evidence of such an association is likely due to the consistency of the relationship of smoking and endothelial disease, and the strength of the association of erectile dysfunction with other endothelial diseases.

Animals↗
PubMed2000

Testosterone supplementation for erectile dysfunction: results of a meta-analysis.

PURPOSE: To our knowledge a causal relationship between altered levels of androgens and erectile dysfunction has not yet been established. We reviewed the literature to assess the usefulness of androgen replacement for erectile dysfunction. MATERIALS AND METHODS: Meta-analysis was chosen as the method of evaluating the literature. Study inclusion criteria were testosterone given as the only therapy for erectile dysfunction and a clearly stated definition of response for evaluating treatment success or failure. RESULTS: We evaluated 73 articles obtained by a MEDLINE search of 1966 to 1998 and included 16 in our study. The overall response rate was 57%. In the 9 series with response rate by etiology patients with primary versus secondary testicular failure had a response rate of 64% versus 44% (p <0.001). Intramuscular and oral methods of delivery were equivalent with a response rate of 51.3% and 53.2%, respectively. However, the response to transdermal therapy was significantly different from that of intramuscular and oral treatment (80.9% versus 51.3% and 53.2%, respectively, p <0.001). The mean confidence level response for testosterone treatment was 16. 7% in the placebo and 65.4% in the treated group (p <0.0001). CONCLUSIONS: Our meta-analysis of the usefulness of androgen replacement therapy for erectile dysfunction indicates that the response rate for a primary etiology was improved over that for a secondary etiology, transdermal testosterone therapy was more effective than intramuscular or oral treatment, and intramuscular and oral treatments were equivalent. In addition, there was a statistically significant difference in favor of testosterone over placebo, implying a role for supplementation in select groups.

Administration, Oral↗
PubMed1999

Sildenafil causes a dose- and time-dependent downregulation of phosphodiesterase type 6 expression in the rat retina.

OBJECTIVES: Some authors have advocated the daily use of sildenafil for prophylaxis against, or treatment of, erectile dysfunction. However, no information has been published to support such a dosage regimen. The safety profile of uninterrupted use of sildenafil has not been evaluated as it pertains to alteration of PDE type 6 in the retina. In the present study we investigated whether short- or long-term exposure to a variety of sildenafil doses affect the expression of an enzyme important in the normal phototransduction cascade. METHODS: Sustained-release sildenafil pellets were implanted in 120-day-old male rats with concentrations from 1-200mg. Rat retinal tissue was harvested 7, 14, and 29 days after implantation. Quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) using GAPDH as an endogenous internal standard was used to quantitate PDE type 6 gene expression. RESULTS: Expression of PDE type 6 was upregulated after 7 days with dosages < or =5 mg (P<0.02). Significant downregulation of PDE type 6 expression was first noted with high dose sildenafil 14 days after implantation (P<0.02). Expression of PDE type 6 was significantly and profoundly downregulated 29 days after implantation for all pellet formulations > or =10 mg (P<0.01). CONCLUSIONS: Sildenafil downregulates PDE type 6 expression in a dose- and time-dependent fashion. These findings support the explanation that PDE type 6 inhibition causes the dose-dependent clinical effects of visual disturbance in men taking sildenafil. Implications for long-term, daily use of sildenafil in men are not clear.

Animals↗
PubMed1999

Topical prostaglandin E1 SEPA gel for the treatment of erectile dysfunction.

PURPOSE: We compare the systemic effects, local tolerance and effectiveness of topical gel formulations on the penis containing alprostadil (prostaglandin E1) plus 5% SEPA versus SEPA alone (placebo) in men with erectile dysfunction. MATERIALS AND METHODS: Erectile response, skin discomfort and erythema were measured in 48 men with erectile dysfunction secondary to vascular, neurogenic, psychogenic or mixed etiologies in this single-blind, placebo controlled trial. RESULTS: Application of prostaglandin E1 gel correlated positively with erectile response as 67 to 75% of patients had an erection compared to 17% of controls (p<0.001). Blood pressure and heart rate varied minimally. No serious adverse effects were observed in the 48 patients, although the majority had skin discomfort. CONCLUSIONS: Topical prostaglandin E1 gel applied to the penis appears to be safe, and facilitates audiovisual and tactile stimulation resulting in an erection when given in a clinic setting. Consequences to the female partner remain unknown.

Adjuvants, Pharmaceutic↗
PubMed1998

Transurethral alprostadil as therapy for patients who withdrew from or failed prior intracavernous injection therapy.

OBJECTIVES: Patients experiencing erectile dysfunction who fail intracavernous injection (ICI) therapy are commonly believed to have exhausted pharmacologic options. We evaluated the efficacy and safety of transurethral alprostadil (MUSE) in patients experiencing erectile dysfunction who underwent prior ICI therapy (alprostadil, papaverine, phentolamine, or a combination of these). METHODS: Of the 1511 patients enrolled in a multicenter trial of transurethral alprostadil, 452 (30%) reported prior ICI therapy and its effects. These patients tested up to four dose levels of transurethral alprostadil in the clinic, and those who achieved an erection satisfactory for intercourse were treated at home in a double-blind, placebo-controlled trial. RESULTS: Prior ICI therapy was reported to be "not effective" by 95 of 452 patients (21%), "sometimes effective" by 119 of 452 (26%), and "effective" by 238 of 452 (53%). In patients reporting ICI therapy as "not effective," 58% achieved an erection sufficient for intercourse following transurethral alprostadil therapy in the clinic; 47% of these responsive patients reported successful sexual intercourse after transurethral alprostadil therapy during home treatment. For patients reporting ICI therapy as "sometimes effective" or "effective," 68% achieved an erection sufficient for intercourse following transurethral alprostadil therapy in the clinic setting and 67% of these responsive patients reported successful intercourse following transurethral alprostadil therapy at home. Few adverse effects were encountered. The most common adverse effect was penile pain, which occurred with 7.8% of administrations. CONCLUSIONS: Transurethral alprostadil therapy is an effective therapeutic option for patients with erectile dysfunction and may even "rescue" some patients who have failed prior intracavernous injection therapy.

Administration, Topical↗
PubMed1998

Comparison of tunica albuginea substitutes for the treatment of Peyronie's disease.

PURPOSE: Peyronie's disease is a connective tissue disorder resulting in fibrotic plaque formation on the tunica albuginea of the penis. One approach to repair consists of plaque excision and patching with one of many potential patch materials. Because the optimal patch material for covering the resultant defect has not been determined, this study compares histological and cavernosometric changes in the penis as a result of the placement of three different types of patch grafts used in surgery for Peyronie's disease. MATERIALS AND METHODS: Eleven mongrel dogs were divided into three groups, each receiving a different patch material (superficial dorsal penile vein, silicone fabric, and dermabraded preputial flap). Each dog had dynamic infusion cavernosometry (DIC) performed prior to placement of the patch over a 6 x 3 mm. defect surgically created in the tunica albuginea. Three months later, DIC was repeated prior to sacrifice. Histology of the penis was examined using Masson's trichrome, and hematoxylin and eosin stains. RESULTS: The only difference among the cavernosometric parameters (preop versus postop) was a higher initial pressure in the dermabraded preputial flap group postoperatively. The dogs undergoing vein patch had moderate fibrosis with apparent reformation of the tunica albuginea over the patch site. The normal venous architecture of the graft was no longer recognizable. Those dogs receiving a silicone patch had moderate fibrosis with a fibrous sheath of compressed histiocytes and fibroblasts enveloping the graft site. Finally, the dermabraded preputial flap patch group had mild-moderate fibrosis with focal loss of the cavernosal space underlying the flap. CONCLUSIONS: We feel that continued use of the vein patch for repair of Peyronie's disease is warranted.

Animals↗
PubMed1998

Prostate innervation.

The growth of the prostate gland has been considered to be controlled exclusively by endocrine means. The abundance of alpha adrenergic and muscarinic receptors and nerve fibers suggests that the autonomic nervous system may in fact play a role in the growth maturation and secretory functions of the prostate. The predominant adrenergic input to the prostate is from short adrenergic neurons, while cholinergic nerves are closely related to the glandular epithelium, presumably affecting a secretory function. The prostate has a high density of alpha-1 and beta-2 adrenergic receptors, and the presence of these receptors, as well as their regulation by androgens, suggests and supports the direct mitogenic effect of catecholamines on prostate growth. The activated signal transduction pathways in these neural systems also appear to modulate prostatic function and growth. Denervation of the prostate results in a loss of functional and structural integrity of the gland. The effects of sympathectomy and parasympathectomy support the conclusion that the dichotomy of function in prostatic autonomic innervation has a fundamental regulatory purpose. The majority of the afferent innervation to the ventral prostate is localized to sensory nerves from the L5 and L6 segments. There is some smaller degree of innervation from T13-L2. There is evidence of extensive bilateral innervation of pelvic viscera. Despite the importance of afferent sensory feedback in regulating the control of prostate growth, its effect is of a smaller magnitude than that observed with androgens. Regardless of the specific control mechanisms suggested by neural involvement in the growth differentiation and secretory function of the prostate, the presence of innervation appears to be consistent and reproducible, and holds great potential for increasing our understanding of pathologic influences in prostate disease.

Animals↗
PubMed1998

The usefulness of touch preparation cytological evaluation and prostatic capsule involvement in prediction of prostate cancer recurrence.

PURPOSE: Touch preparation cytology has been used in oncology as a technique to assist in predicting local tumor recurrence. We prospectively investigated the relationship between this cytological evaluation and the standard histological method of assessing specimens, measuring the distance from the tumor to the various anatomical boundaries and disease recurrence in radical retropubic prostatectomy patients. MATERIALS AND METHODS: In a prospective study of 91 consecutive clinical stages T1c and T2 cancer cases radical retropubic prostatectomy touch preparation cytology was performed intraoperatively in an anatomical fashion (apex, posterior, lateral right and left, and base). A single blinded cytopathologist reviewed all prostate touch preparation specimens and categorized them as malignant, benign or atypical cells. Benign or atypical cells were classified as negative cytology. Detailed histological margin analysis of the surgical specimens was also done in which distances between the tumor front, and prostate capsule (inner and outer edge) and surgical margins (apex, posterior, right and left lateral, and base) were measured. All specimens were re-staged by the same pathologist. Median followup was 38 months. Disease recurrence was determined biochemically (prostate specific antigen), and with bone scans, prostatic fossa biopsies and digital rectal examinations. RESULTS: Of the 91 specimens 25 were excluded from study because distance measurements could not be made for technical reasons. Multivariate analysis was performed on the remaining 66 patients based on the variables of stage, age, cytology status, distance from tumor to the inner prostatic capsule, distance from tumor to the surgical margin and postoperative Gleason sum. The only variable with independent prognostic value was postoperative Gleason sum (p = 0.04). Cytology status was not statistically significant (p = 0.07) nor were distance data to the inner capsule (p >0.05) and surgical margin (p >0.05). CONCLUSIONS: Although touch preparation cytology does not enhance prognostic information already provided by Gleason sum, it does correlate highly with postoperative Gleason sum. Other gross macroscopic variables, that is pathological stage, margin status and distance measurements, although lacking in independent predictive value, correlated with postoperative Gleason sum. The constancy of Gleason sum leads us to believe that the key to predicting prostatic cancer behavior lies not on the macroscopic but on the molecular or cellular level. Of the various factors analyzed in this study postoperative Gleason sum remains the most powerful predictor of recurrence risk.

Aged↗
PubMed1997

Sexual dysfunction in the diabetic BB/WOR rat: a role of central neuropathy.

The pathophysiological mechanisms of diabetic impotence remain obscure. We have presented an analysis of sexual function in a diabetic rat (BB/WOR) model characterized by diffuse neuropathic changes without a confounding vasculopathy that allows us to define the neural components of erectile failure. Copulatory behavioral testing demonstrated that diabetic males were severely impaired: the controls mounted three times more than the diabetics and had about one-half the latency to first mount. The diabetics had about one-fourth the number of intromissions and took nearly twice as long to achieve first ejaculation. The number of ejaculations was drastically reduced as well. We examined sexual reflexes in the anesthetized acutely spinalized rat. These experiments tested the integrity of spinal circuits controlling sexual function. Reflex testing demonstrated that spinal sexual reflexes were also severely impaired: the onset latency of reflexes was more than doubled, and the duration of reflexes was less than one-half. More than one-half of the diabetic rats showed no penile erections. Neural studies showed even more derangement in reflex measures in rats, without erection. Nerve conduction velocity experiments suggested a peripheral neuropathic change in hypogastric nerve and motor pudendal nerve fibers. These dysfunctional findings were seen without any androgen deficiency. These results indicate that diabetic impotence in this model reflects central and peripheral neuropathic disease processes.

Animals↗
PubMed1997

One core positive prostate biopsy is a poor predictor of cancer volume in the radical prostatectomy specimen.

PURPOSE: In view of the recent increase in patients presenting with only 1 core positive for prostate carcinoma, we examined the correlation in tumor volume between the biopsy and the subsequent radical prostatectomy specimen. MATERIALS AND METHODS: We studied a total of 169 consecutive prostate biopsies with matched radical prostatectomy specimens and selected 48 patients with only 1 positive core. RESULTS: Cancers found in the biopsy regardless of their size were associated with a wide range of cancer volume in the radical prostatectomy specimens, and the amount of cancer in the biopsy was a poor predictor of the volume of cancer in the prostatectomy specimen. Even with a cancer of 3 mm. or less in the biopsy, 57% of patients had cancer of clinically significant volume (greater than 0.5 ml.). Other modalities for the evaluation of prostate cancer such as Gleason score and clinical stage were not helpful in segregating patients with clinically significant from those with insignificant volume of cancer. However, when combined with a preoperative serum prostate-specific antigen higher than 10 ng./ml., 1 core positive biopsy could reliably predict the presence of cancer of significant volume. CONCLUSIONS: One core only positive prostate biopsy, when accompanied by an elevated serum prostate specific antigen value (greater than 10 ng./ml.), strongly suggests the presence of clinically significant cancer.

Adenocarcinoma↗
PubMed1997

Long-term results of radical retropubic prostatectomy in men with high grade carcinoma of the prostate.

PURPOSE: We sought to determine the efficacy of radical retropubic prostatectomy in men with high grade adenocarcinoma of the prostate in a population that had not been screened for prostate specific antigen (PSA). MATERIALS AND METHODS: An inception cohort of 116 men surgically treated for prostate cancer between 1980 and 1991 was created in April 1992 and prospectively followed thereafter. Median followup was 7 years (range 2.2 to 14.6). RESULTS: The major cause of death in this group of men was prostate cancer, not competing causes. Ten-year disease specific survival was 96% for organ confined (stage pT2c or less) and 78% for unconfined (stage pT3a or greater) disease. Five and 10-year PSA progression-free survival by pathological stage was 83 and 53% for organ confined disease, and 34 and 22% for unconfined disease with negative pelvic lymph node dissection (p = 0.001). Five and 10-year metastasis-free survival was 96% for organ confined disease, and 81 and 62% for unconfined disease (p = 0.011). Men with pelvic lymph node metastasis had 70 and 30% 5 and 10-year metastasis-free survival, and 75 and 55% disease specific survival, respectively. PSA progression-free survival was 33% at 5 years. A significantly decreased risk of PSA progression was observed in men with unconfined carcinoma who received adjuvant external beam radiotherapy. CONCLUSIONS: In men with high grade prostate cancer the major cause of death was prostate cancer, not competing causes. Pathologically confined carcinoma had a significantly decreased rate of metastatic progression. These observations support the bias that early detection in these men at high risk for cause specific death may favorably impact survival.

Actuarial Analysis↗