Efficacy and safety of transdermal oxybutynin in patients with urge and mixed urinary incontinence

PURPOSE: We evaluated the efficacy and safety of an oxybutynin transdermal delivery system (TDS) in a general population of patients with overactive bladder and urge or mixed urinary incontinence. MATERIALS AND METHODS: Following symptom stabilization or treatment withdrawal 520 adult patients were randomized to 12 weeks of double-blind daily treatment with 1.3, 2.6 or 3.9 mg. oxybutynin TDS or placebo administered twice weekly, followed by a 12-week open-label, dose titration period to assess efficacy and safety further. Evaluations included patient urinary diaries, incontinence specific quality of life and safety. RESULTS: A dose of 3.9 mg. daily oxybutynin TDS significantly reduced the number of weekly incontinence episodes (median change -19.0 versus -14.5, p = 0.0165), reduced average daily urinary frequency (mean change -2.3 versus -1.7, p = 0.0457), increased average voided volume (median change 24 versus 6 ml., p = 0.0063) and significantly improved quality of life (Incontinence Impact Questionnaire total score, p = 0.0327) compared with placebo. Average voided volume increased in the daily 2.6 mg. group (19 ml., p = 0.0157) but there were no other significant differences between 1.3 and 2.6 mg. oxybutynin TDS and placebo. The most common adverse event was application site pruritus (oxybutynin TDS 10.8% to 16.8%, placebo 6.1%). Dry mouth incidence was similar in both groups (7.0% versus 8.3%, p not significant). In the open-label period a sustained reduction of nearly 3 incontinence episodes per day was reported for all groups. CONCLUSIONS: Doses of 2.6 and 3.9 mg. oxybutynin TDS daily improve overactive bladder symptoms and quality of life, and are well tolerated. Transdermal oxybutynin is an innovative new treatment for overactive bladder.     

Quantitation of viral DNA in renal allograft tissue from patients with BK virus nephropathy

BACKGROUND: BK virus (BKV) allograft nephropathy (BKVAN) is a complication in renal transplantation recipients. Histopathology is the gold standard for diagnosis. Quantitative polymerase chain reaction (PCR) assay for renal biopsy has not been evaluated as a diagnostic test. Determination of renal BKV load may identify patients at risk for disease before histologic nephropathy. METHODS: Quantitative PCR assay for BKV DNA was performed in 28 biopsies of patients with BKVAN; 50 biopsies were performed before a diagnosis of BKVAN, and 126 control biopsies were from patients without a history of BKVAN. RESULTS: BKV DNA was present in 19 of 50 (38%) biopsies performed 1 to 164 weeks before diagnosis of BKVAN. The viral load (mean 216 copies/cell) was lower than in biopsies of patients with BKVAN (mean 6063 viral copies/cell, <0.05). In 10 of 127 (7.8%) control biopsies, a low level of BKV DNA (mean 3.8 copies/cell) was found in three biopsies from chronic allograft nephropathy patients; two biopsies with acute rejection; four biopsies with borderline change; and one biopsy with cytomegalovirus nephritis. CONCLUSION: BKV load exceeding 59 copies per cell identified all cases of BKVAN. The diagnostic sensitivity, specificity, positive predictive value, and negative predictive value of quantitative PCR were 100%, 92.1%, 73.6%, and 100%, respectively. Lower levels of BKV DNA were identified in biopsies performed before viral nephropathy development. Future research will determine if earlier recognition of at-risk patients allows application of antiviral strategies to improve graft outcome.     

Characteristics of polymeric lambda-IgA binding to leukocytes in IgA nephropathy

IgA nephropathy (IgAN) is characterized by predominant mesangial polymeric IgA1 (pIgA1) deposits, with increased plasma IgA1 levels. Plasma IgA levels are determined by the rate of IgA production, uptake by leukocytes, and removal by hepatocytes. Fc(alpha) receptor 1 (Fc(alpha)R1) is a candidate molecule for the regulation of IgA levels, but reports of its expression in leukocytes in IgAN are conflicting. Increased binding of endogenous IgA to circulating granulocytes and monocytes in IgAN was demonstrated in this study. Fc(alpha)R1 expression on leukocytes was increased, independently of plasma IgA levels. Fc(alpha)R1 was not saturated in leukocytes, because of internalization of IgA after uptake. Further binding of exogenous IgA isolated from individual subjects was observed with leukocytes from the same subjects. Compared with cells from control subjects, granulocytes but not monocytes from patients with IgAN exhibited a greater binding capacity for exogenous IgA, predominantly pIgA. To circumvent the possibility that endogenous IgA might alter Fc(alpha)R1 expression, granulocytes or monocytes derived from the HL-60 or U937 cell lines were used to explore the nature of IgA binding. A higher affinity for pIgA was demonstrated. Inhibition studies using unlabeled IgA, other serum proteins, or a specific Fc(alpha)R1-blocking antibody suggested binding mechanisms other than Fc(alpha)R1 for pIgA uptake by leukocytes. This study also suggested the migration and/or sequestration of "activated" leukocytes with predominant lambda-IgA in the mononuclear phagocytic system or inflammatory tissues, after the initial binding of lambda-pIgA. These immunologic abnormalities might contribute to the glomerulointerstitial injury in IgAN, in the presence of leukocytic infiltration.     

Role of complement in tubulointerstitial injury from proteinuria

The complement system is being increasingly implicated in the pathogenesis of progressive renal disease resulting from persistent proteinuria. It has recently been established that renal tubular cells can produce complement, activate complement, and respond to complement activation. Complement proteins that pass through the glomerular barrier along with other serum proteins in the proteinuric state may become activated at the tubular epithelial brush border, and lead to a cascade of events culminating in cell injury. Furthermore, nephrotic components in the urinary space may cause direct activation of the tubular cells to overexpress complement and contribute to local tissue injury. In this review, we will discuss the current evidence supporting a role for complement in the pathogenesis of progressive tubulointerstitial damage in the proteinuric state. The possibility of complement inhibition intervening in progressive tubulointerstitial injury due to proteinuric glomerular disease will also be considered.     

Craniofacial resection for paranasal sinus cancers

BACKGROUND: Combined anterior craniofacial resection (CFR) has been in use for more than 25 years. The advent of the free revascularized tissue transfer flap in l980 permitted safe resection of tumors that had spread beyond the confines of the paranasal sinuses with immediate reconstruction of the sino-orbital cranial defect. The purpose of this study was to examine the outcomes and morbidity of a management policy of primary CFR and postoperative radiotherapy for paranasal sinus cancers infiltrating the skull base over a 21-year period. METHODS: Seventy-three patients with paranasal sinus cancers were treated at the Prince of Wales Hospital between l975 and l996. All were newly diagnosed with the exception of one patient who had received radiotherapy elsewhere 5 years earlier. Only 22% were early lesions and 31% were advanced (more than six sites involved). There were 59 men and 14 women. The mean age was 57 years. All but two patients had a performance status of either 0 or 1. Orbital exenteration was performed in 31 patients. Since l980, all major defects were reconstructed with free tissue transfer flaps. RESULTS: The 5-year cancer-specific survival (CSS) for the 73 patients was 69%, which was unchanged at 10 years. Twenty two patients died from or with their index cancer. An additional 11 patients died from unrelated causes. The actuarial overall survival (OS) at 5 and 10 years was 61% and 48%, respectively. The 5-year recurrence-free rate was 59%. The CSS for the three dominant pathologic conditions were adenocarcinoma 70%, squamous cancer 51%, and olfactory neuroblastoma 84%. The difference was not significant; however, there was a significant difference in OS, with olfactory neuroblastoma having the best prognosis. Orbital involvement, radiologic evidence of skull base erosion, and involvement of the infratemporal fossa were not poor prognostic indicators. Patients with a performance status of 0 had improved OS. There was no operative mortality. CONCLUSIONS: An aggressive policy of combined CFR and postoperative radiotherapy with free-flap reconstruction for large defects gave survival results that were comparable to less-advanced lesions and superior to many other treatment alternatives. There was a high exenteration rate (42%). Squamous cancers were associated with the greatest morbidity and poorest OS.     

Prevalence of HIV in workforces in southern Africa, 2000-2001.

OBJECTIVES: Most data on HIV prevalence in low-risk populations in sub-Saharan Africa are drawn from sentinel surveys of pregnant women attending antenatal clinics and are not representative of formal sector workforces. We surveyed workforces in southern Africa to determine HIV prevalence among formally employed, largely male populations. METHODS: Voluntary, anonymous, unlinked seroprevalence surveys of 34 workforces with 44,000 employees were carried out in South Africa, Botswana, and Zambia in 2000-2001. Results were stratified to obtain estimates of prevalence by industrial sector, location, age, sex, and job level. RESULTS: Average HIV prevalence for the entire sample was 16.6% (95% CI: 16.3-17.0%). Country-wide prevalence was 14.5% (14.1-14.9%) in South Africa, 17.9% (17.1-18.7%) in Zambia, and 24.6% (23.6-25.7%) in Botswana. Among industrial sectors, mining (18.0%, 17.6-18.5%) and metal processing (17.3%, 15.9-18.7%) had the highest infection rates. Males, who comprised 85% of participants of known sex, were more likely (16.3%, 15.3-17.4%) to be infected than were females (10.7%, 8.7-12.7%). Contract (23%, 21.9-24.1%), unskilled (18.3%, 17.5-19.1%), and semi-skilled workers (18.7%, 18.1-19.4%) were much more likely to be infected than were skilled workers (10.5%, 9.5-11.4%) and managers (4.5%, 3.4-5.6%). Participation in the surveys averaged 63% of eligible employees. CONCLUSIONS: HIV prevalence among formally employed workers in southern Africa shows different patterns than among antenatal clinic attendees. Anonymous workplace surveys generate prevalence estimates for demographic groups that are not represented in antenatal surveys and can strengthen support for prevention and treatment interventions.