Resistance to apoptosis and up regulation of Bcl-2 in benign prostatic hyperplasia after androgen deprivation.

PURPOSE: Benign prostatic hyperplasia (BPH) is related to advancing age and the presence of androgens and occurs in virtually all older men. BPH causes morbidity, most often by urinary obstruction, in a substantial fraction of men over sixty. Both finasteride and androgen ablation induce partial diminution in BPH that occurs over weeks to months. This is in contrast to the often rapid involution seen in both normal prostatic epithelium and prostatic carcinoma in response to androgen withdrawal. This study was performed to analyze the response of prostatic cells, and in particular BPH, to acute androgen ablation. MATERIALS AND METHODS: We subjected a cohort of 26 men to androgen ablation with goserelin, a gonadotrophin releasing hormone agonist, for 3-4 weeks prior to radical prostatectomy for prostate cancer. Preablation biopsy specimens and prostatectomy specimens were immunohistochemically stained for apoptotic cells and for expression of apoptosis regulatory proteins Bcl-2, Bax, Bcl-x, and Bak. RESULTS: Normal prostatic epithelial cells and prostate cancer responded to hormone deprivation by undergoing apoptosis, but in 19/26 specimens prostatic hyperplasia had a total absence of apoptosis. In all 26 specimens, benign prostatic hyperplasia demonstrated increased expression of the Bcl-2 protein, but no change in the expression of Bax, Bcl-x, and Bak. In contrast, adjacent normal and malignant prostatic epithelium showed positive staining for apoptosis and did not alter Bcl-2 expression in response to androgen ablation. CONCLUSIONS: BPH demonstrated increased staining for Bcl-2 after androgen deprivation that may render hyperplastic epithelium relatively resistant to apoptosis induced acutely by androgen withdrawal.

Differential effects of ethanol on two synaptic membrane Ca2+ transport systems.

The Na+-Ca2+ exchange activity in synaptic plasma membranes is inhibited by very low concentrations of ethanol (less than 25 mM). The high affinity Mg2+- and ATP-dependent Ca2+ transport in highly purified synaptic membranes is much less sensitive to inhibition by ethanol, with no statistically significant inhibition observed until an ethanol concentration of nearly 800 mM was used. Manipulations of the lipid environment designed to increase membrane fluidity enhanced the activity of the Na+-Ca2+ exchange system but inhibited the ATP-dependent Ca2+ pump. The differential responses of the two synaptic plasma membrane Ca2+ transporting systems to such modifications of membrane structure suggest that these two ion transport processes differ in the extent to which their activity is dependent on the lipid microenvironment in which they reside. Thus, the effects of ethanol on the Na+-Ca2+ antiporter may represent a fairly selective inhibitory process.

Alcohol effects on synaptic membrane calcium ion fluxes.

The effects of ethanol on Na+-dependent CA2+ fluxes have been examined in resealed synaptic membrane vesicles assayed at 3 different temperatures. Sodium chloride-loaded vesicles were preincubated with various concentrations of ethanol for 120 sec prior to being diluted into a 45CaCl2-containing medium in the presence or absence of an outward-directed Na+ gradient. The effect of ethanol on Na+-dependent Ca2+ transport measured at 23 degrees C was biphasic. However, when the assay was conducted either at 16 degrees C or at 35 degrees C, all ethanol concentrations tested (10-300 mM) produced only inhibition of Ca2+ influx. The role of membrane fluidization in the ethanol-induced inhibition was explored by determining the effects of incorporating various fatty acids into the membranes. Membrane fluidizing agents such as cis-vaccenic acid stimulated Ca2+ influx whereas trans-vaccenic and saturated fatty acids had little effect. The fluidizing effect of incorporating cis-vaccenic acid into the membranes was confirmed with electron paramagnetic resonance (EPR) spectroscopy. The data obtained from these studies suggest that the inhibition of Ca2+ fluxes produced by alcohol and local anesthetics is not the result of a general increase in bulk phase synaptic membrane fluidity.

Complications associated with surgical repair of urethrovaginal fistula.

We present 4 patients seen in the last five years with urethrovaginal fistulas involving the mid or proximal urethra. Our experience in the transvaginal repair of these fistulas has been disappointing. The best chance for the development of a functioning continent urethra is by suprapubic bladder flap technique or bladder tube replacement with suprapubic urinary diversion. We suggest that no urethral catheter be placed. Complications following surgical repair have been fistula recurrence, urethral shortening and retraction, persistent reflux, bladder calculi, and bladder cancer.