Edward F. Ikeguchi

Expression of senescence-associated beta-galactosidase in enlarged prostates from men with benign prostatic hyperplasia

OBJECTIVES Cellular senescence is a unique cellular response pathway thought to be closely associated with the aging process. The senescent phenotype is characterized by the loss of a cells ability to respond to proliferative and apoptotic stimuli even while normal metabolic activity and vitality is maintained. Recently, a novel biomarker, senescent-associated beta-galactosidase (SA-beta-gal), was found to identify cells with the senescent phenotype. In the present study, we examined whether human prostatic epithelial cells adopt a senescence-associated phenotype after prolonged culture and analyzed a series of human benign prostatic hyperplasia (BPH) specimens to determine whether the cellular senescence process might be a factor in the development of BPH. METHODS A primary culture of epithelial cells was established from the normal tissue of the peripheral zone of a radical prostatectomy specimen and was serially passaged until senescence. Forty-three human prostate specimens were obtained subsequent to radical prostatectomy or transrectal ultrasound-guided biopsy. The cultured cells and tissue specimens were histochemically stained to reveal the expression of SA-beta-gal, the cellular senescence biomarker. RESULTS As has been reported for other types of cultured cells, human prostatic epithelial cells demonstrated widespread expression of the cellular senescence marker, SA-beta-gal, on prolonged culture. In our survey of hypertrophied human prostate tissues, 17 specimens (40%) of the 43 analyzed demonstrated positive staining for SA-beta-gal. In these tissues, SA-beta-gal expression was noted only in the epithelial cells. No statistical correlation (P = 0.42) between the chronologic age of the patient donor and SA-beta-gal expression was found. However, a high prostate weight (greater than 55 g) was found to correlate strongly with the expression of the SA-beta-gal biomarker (P = 0. 0001). CONCLUSIONS Cultured prostatic epithelial cells expressed SA-beta-gal on reaching replicative senescence in vitro. The survey of human BPH specimens for the senescent marker showed that prostatic epithelial cells in patients with BPH with more advanced enlargement of the prostate (greater than 55 g prostate weight) expressed SA-beta-gal, and the prostates from patients with BPH that weighed less than 55 g tended to lack senescent epithelial cells. On the basis of these results, we propose that the accumulation of senescent epithelial cells may play a role in the development of the prostatic enlargement associated with BPH.

Pseudodyssynergia (Contraction of the External Sphincter During Voiding) Misdiagnosed as Chronic Nonbacterial Prostatitis and the Role of Biofeedback as a Therapeutic Option

PURPOSE Chronic lower urinary tract symptoms in young men are often attributed to misdiagnosed chronic nonbacterial prostatitis. We analyzed contraction of the external urinary sphincter during voiding (pseudodyssynergia) as an etiology of voiding dysfunction in men with misdiagnosed chronic prostatitis. MATERIALS AND METHODS The video urodynamic studies of 43 men 23 to 50 years old with chronic voiding dysfunction secondary to pseudodyssynergia performed between January 1990 and June 1996 were retrospectively analyzed. Pseudodyssynergia was diagnosed based on several criteria, including electrical activity of the external sphincter during voiding in the absence of abdominal straining, and brief and intermittent closing of the membranous urethra during voiding detected by electromyography and fluoroscopy. Patients with bacterial infection or excessive leukocytes in expressed prostatic secretions were excluded from the study. RESULTS Of the patients 39 (91%) were firstborn men. Duration of symptoms ranged from 17 to 146 months (mean 43.6). Average number of previous antibiotic days ranged from 53 to 186 (mean 67.6). In addition, empirical trials of alpha-blockers were unsuccessful. Mean American Urological Association symptom score plus or minus standard deviation was 17.5 +/- 3.7, mean maximum flow rate was 13.3 +/- 4.2 ml. per second, mean detrusor pressure at maximum flow was 46.3 +/- 13.7 cm. water and mean detrusor contraction duration was 132.8 +/- 27.7 seconds. Behavior modification and biofeedback were successful in decreasing symptoms in 35 patients (83%) at 6 months. CONCLUSIONS These results indicate that some men who are categorized as having and empirically treated for chronic nonbacterial prostatitis are misdiagnosed and, in fact, have functional bladder outlet obstruction. Urodynamics are helpful in diagnosing and predicting success with behavior modification and biofeedback in these patients.

Etiology of voiding dysfunction in men less than 50 years of age

OBJECTIVES Chronic lower urinary tract symptoms in young men are often attributed to misdiagnosed chronic nonbacterial prostatitis. The purpose of this study was to analyze etiology of chronic voiding dysfunction in men less than 50 years of age. METHODS The videourodynamic studies of 137 men 50 years of age or less with chronic voiding dysfunction, performed between January 1990 and October 1995, were retrospectively analyzed. RESULTS The distribution of urodynamic abnormalities included 74 (54%) patients with primary vesical neck obstruction, 33 (24%) with obstruction localized to membranous urethra (pseudodyssnergia), 23 (17%) with impaired bladder contractility, and the remaining 7 (5%) with an acontractile bladder. Detrusor instability was present in 67 men (49%). CONCLUSIONS Voiding dysfunction among young men is common and is often misdiagnosed. Videourodynamic evaluation is very useful in establishing the correct diagnosis and ultimately in delivery of appropriate therapy.

The Incidence of Multifocal Renal Cell Carcinoma in Patients Who are Candidates for Partial Nephrectomy

PURPOSE A prospective study was performed to determine the incidence of multifocal renal cell carcinoma in patients who are candidates for partial nephrectomy. MATERIALS AND METHODS Preoperative imaging studies and surgical specimens in 44 patients suitable for partial nephrectomy but undergoing radical nephrectomy were prospectively reviewed. RESULTS Of 44 renal cell cancers 11 (25%) demonstrated pathological multifocality, while 10 of 11 multifocal tumors (91%) occurred in the face of a primary tumor 5 cm. or smaller. Tumor multifocality was independent of the size of the primary renal tumor but occurred with a slightly higher frequency in tumors of stage T3A or greater even if the primary tumor was small. CONCLUSIONS Partial nephrectomy in patients with unilateral renal cancer should be approached with caution and should not be performed simply because it is technically feasible.

URETERAL TISSUE EXPANSION FOR BLADDER AUGMENTATION

PURPOSE Ureteral augmentation is an effective method of bladder reconstruction using the native urothelium of a megaureter. Clinically this procedure is contingent on the presence of an enlarged ureter. We have iatrogenically produced a segmental megaureter, while preserving renal function in a pig model. The urothelium of the enlarged ureter was then used for augmentation cystoplasty. MATERIALS AND METHODS A tissue expander suitable for insertion into the lumen of the ureter was constructed. The tissue expander was passed antegrade through a flank incision of 8 pigs, and a separate nephrostomy tube was left in place. During the ensuing 1 to 4 weeks the pigs underwent daily dilation of the tissue expander without anesthesia. After dilation the pigs underwent ureteral augmentation of the bladder. The segment of expanded ureter was isolated from the native ureter, opened and anastomosed to the bladder. The continuity of the left ureter was restored by primary ureteroureterostomy. The animals underwent cystograms at 1 and 4 weeks and were sacrificed 4 weeks after augmentation. Tissue was harvested for gross and microscopic histology. RESULTS Of the 8 pigs starting the protocol 5 underwent successful ureteral tissue expansion followed by bladder augmentation. Tissue expansion was performed from 1 to 4 weeks, and volumes of 150 to 1,000 cc were obtained. Two to 3 weeks of dilation was optimal to achieve ease of dilation, and no animal showed evidence of discomfort or failure to thrive. All 5 animals underwent successful ureteral augmentation with primary ureteroureterostomy. Tissue expansion volumes of approximately 250 cc were optimal for tissue management and ease of augmentation. Cystograms of all augmented animals showed increased bladder capacity with filling of the ureteral segment. Histological examination of the ureteral augmentation revealed preservation and regeneration of the urothelial mucosa. CONCLUSIONS The use of a tissue expander in the lumen of the ureter is a novel method of generating urothelium for use in bladder augmentation. It may provide an alternative to bowel in patients who require bladder augmentation. Long-term studies are currently under way.

PROSPECTIVE ANALYSIS OF 373 CONSECUTIVE WOMEN WITH STRESS URINARY INCONTINENCE TREATED WITH A VAGINAL WALL SLING: THE COLUMBIA-CORNELL UNIVERSITY EXPERIENCE

PURPOSE We compare the efficacy and morbidity of 373 consecutive women who underwent a vaginal wall sling for stress urinary incontinence due either to anatomical incontinence or intrinsic sphincter deficiency. To our knowledge this series is the largest prospective database on surgical management of stress urinary incontinence in the urological literature. MATERIALS AND METHODS Preoperative evaluation included history, voiding diary, physical examination, cystoscopy, pad count and video urodynamic study. Outcome measures included postoperative presence of incontinence secondary to either stress and/or detrusor instability, number of pads used, complications, operating time, length of suprapubic catheterization, length of hospitalization and loss of work days. RESULTS A total of 373 consecutive women 18 to 85 years old (mean age 55.7) were followed for a mean of 39.8 months. Of these patients 183 (49%) presented with anatomical incontinence and the remaining 190 (51%) had intrinsic sphincter deficiency. Preoperative detrusor instability was present in 60 (33%) patients with anatomical incontinence and 68 (36%) with intrinsic sphincter deficiency. Postoperatively, 14 patients (4%) had recurrent stress urinary incontinence. De novo detrusor instability and urge incontinence were noted in 30 women (8%), and was persistent in 22 (6%). There was no correlation between the diagnosis of anatomical incontinence or intrinsic sphincter deficiency and persistent stress urinary incontinence or detrusor instability. Daily pad use was decreased from 4.3 to 0.5 and from 4.6 to 0.4, respectively, for patients with anatomical incontinence and intrinsic sphincter deficiency. Operating time, catheter duration, length of hospital stay and days lost from work for patients with anatomical incontinence (33.3 +/- 14.3 minutes, 4.7 +/- 1.1 days, 0.9 +/- 0.7 days and 11.3 +/- 2.9 days, respectively) were similar to patients with intrinsic sphincter deficiency (38.4 +/- 17.8, 4.6 +/- 0.9, 1.1 +/- 0.7, 12.4 +/- 4.7). The most common complications were urinary tract infection (3%), wound infection (4%) and pelvic organ prolapse (7%). CONCLUSIONS The results of this large database suggest that the vaginal wall sling is effective for the management of stress urinary incontinence. Efficacy, morbidity and reduced hospitalization time were similar for patients with either anatomical incontinence or intrinsic sphincter deficiency and independent of surgeon experience.

WORLDWIDE VARIATIONS IN SPERM COUNTS

OBJECTIVES Based on the premise that various human disease processes manifest differently depending on geography, we set out to determine whether sperm counts vary from different nations and different regions within the United States. METHODS We reviewed the literature of all significant population-based studies that evaluated sperm counts from fertile or presumably fertile men from 1930 to the present. RESULTS We found that sperm counts did, in fact, vary greatly. Throughout the United States, average sperm counts ranged from a low of 48 million/cc in lowa to a high of 134 million/cc in New York, with multiple values in-between from Texas, Minnesota, Washington State, and California. Internationally, average sperm counts ranged from a low of 52.9 million/cc in Thailand to a high of 102.9 million/cc in France. CONCLUSIONS We conclude that sperm counts are subject to a wide range of variation among geographic locations.

URETERAL TISSUE EXPANSION FOR BLADDER AUGMENTATION: A LONG-TERM PROSPECTIVE CONTROLLED TRIAL IN A PORCINE MODEL

PURPOSE We recently described a technique that iatrogenically produces segmental megaureter while preserving renal function. In our initial report in 5 of 8 pigs that underwent this procedure bladder augmentation with the expanded ureter was successful. Throughout the expansion and reconstructive process renal function was preserved and all 5 animals that underwent augmentation had increased bladder capacity at sacrifice 1 month postoperatively. In the present study we evaluated the long-term durability and performance of the ureteral segment used for augmentation. MATERIALS AND METHODS We performed a prospective, controlled, double armed study in 8 pigs, including 4 control animals that underwent subtotal cystectomy only (group 1) and 4 animals that underwent subtotal cystectomy followed by bladder augmentation using the expanded ureteral segment (group 2). End point measurements included cystography, and measurement of bladder capacity, serum creatinine and random bladder residual urine volumes. All cystograms were performed using passive filling conditions at a standard filling pressure of 32 cm. water. RESULTS Bladder capacity throughout the study revealed consistently higher volumes in group 2 than in group 1. In 3 of the 4 group 1 subjects vesicoureteral reflux developed compared to no reflux in group 2. Creatinine levels were elevated at sacrifice in 50% of the animals in group 1 compared to none in group 2. Random bladder residual urine was less than 150 cc in 3 of the 4 group 2 subjects. CONCLUSIONS Serial cystograms in pigs after ureteral augmentation suggest that the tissue does not contract with time. Animals that underwent ureteral augmentation had significantly greater bladder capacity than controls. Random bladder residual urine volume remained low throughout the study period. Ureteral tissue expansion for bladder augmentation appears to be feasible and durable in this animal model. In addition, it may be protective against the deleterious effects associated with small capacity bladders.

Bladder Outlet Obstruction in Males

Bladder outlet obstruction in males may be a complex syndrome of either dynamic functional or fixed anatomic forces resulting in resistance to the flow of urine. Particularly in males, bladder outlet obstruction is a frequently encountered finding. From a diagnostic standpoint, the evaluation of bladder outlet obstruction relies heavily upon traditional methods. While the most common etiology of bladder outlet obstruction in males relates to prostatic obstruction, an accurate history and physical exam may alert the clinician that other causes may be at hand. Newer technologies have, however, proven to be particularly helpful to the clinician in ascertaining the correct diagnosis and etiology of bladder outlet obstruction prior to the institution of therapy. Urologists have also seen the treatment of bladder outlet obstruction change dramatically over the past decade. While transurethral prostate resection was the most commonly performed procedure by urologists of yesteryear, it now competes with multiple alternative surgical and medical therapies. Finally, in addressing bladder outlet obstruction in males, more attention has been given to functional voiding disorders commonly seen in younger male populations. Herein, an overview of the evaluation and treatment of bladder outlet obstruction in males will be presented, addressing the most commonly utilized therapies for the most commonly seen etiologies.