Apoptosis, a genetically controlled process of cell death, plays a central role in metazoan development and homeostasis (61,74). The apoptotic program is highly conserved during evolution, and striking similarities have been observed in the cell death programs of rodents, mammalian cells, Drosophila melanogaster, and Caenorhabditis elegans (28,81,85,91). In normally proliferating cells, the apoptotic program is actively suppressed or inactivated; however, withdrawal or inhibition of the apoptosis suppressor mechanisms triggers apoptotic pathways (16,37,86). One mechanism by which apoptotic gene products may be prevented from executing their effect may involve direct interaction with specific proteins that act to attenuate the function of the apoptotic activators or effectors. The interaction between antiapoptotic protein Bcl-2 and proapoptotic protein Bax illustrates this point: whether a cell undergoes apoptosis or not is dependent upon the relative levels of these two proteins; an excess of Bax will trigger apoptosis, whereas an excess of Bcl-2 will prevent apoptosis (38,66,68,89,90). Identification of other such antiapoptotic and proapoptotic protein pairs that dictate the survival of cells should enhance our understanding of the apoptosis process.Apoptosis is characterized by cell membrane blebbing, chromatin condensation, changes in nuclear architecture, and oligonucleosome-length DNA fragmentation (87, 88). The process of apoptotic cell death is triggered by diverse stimuli such as cytokines, withdrawal of growth factors, DNA damage, expression of oncogenes or immediate-early genes, and fluctuations in the levels of Bcl-2 family members (3,13,16,37,47,48,54,71,78,86,89). Certain apoptotic stimuli can sequentially activate the basal cell death machinery composed of initiator, amplifier, and effector proteases belonging to the interleukin-1-converting enzyme (ICE) subfamily or an ICE-related family (9,17,21,41,46,91). Downstream targets of these proteases include the ICE subfamily proteases themselves; nuclear enzymes poly(ADP-ribose) polymerase and DNA-dependent protein kinase, which are involved in DNA repair; the nuclear protein U1 ribonucleoprotein and nuclear lamins; and cytoplasmic components such as protein kinase C␦ and cytoskeleton components such as actin (cited in reference 21). However, it is unclear whether any of these cellular components are directly linked to the morphological changes associated with apoptosis.Prostate tissue, which is composed of androgen-dependent and -independent cells (8, 58), provides an excellent model system for studying apoptosis. Androgen ablation in animals leads to an elevation of intracellular calcium that subsequently results in apoptosis of the androgen-dependent but not of the androgen-independent prostatic cells (11,(42)(43)(44). However, apoptosis can be induced in androgen-independent cell cultures by artificially upregulating intracellular calcium with calcium ionophores (53, 69) or with thapsigargin (TG) (22), an

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Study Type – Therapy (case series)Level of Evidence 4What's known on the subject? and What does the study add?Female urethral stricture disease has been described for almost 200 years. The symptoms of female stricture disease may range from clinically insignificant to severe and debilitating with the exact aetiology being unclear. No strict criteria for diagnosis have been established with the diagnosis often relying on a combination of presenting symptoms and objective findings. Initial therapy for female urethral stricture disease has often rested on urethral dilatations and self‐intermittent catheterisation with surgery reserved for patients that failed conservative measures. Female urethroplasty currently is a topic of increasing attention with multiple surgical approaches described including use of both grafts (vaginal wall, buccal mucosal membrane, lingual mucosa, and labia minus) and flaps (vaginal vestibule, anterior vagina, and lateral vagina).We describe our approach to female urethroplasty using a suprameatal (dorsal) approach (described by Tsivian and Sidi) with an autologous vaginal epithelium inlay graft. The technique and modern approaches to female urethroplasty are contrasted and discussed. The success of the approach including continence rates and lack of need for long‐term self‐intermittent catheterisation is noted.OBJECTIVE To review the technique and outcomes of using a dorsal vaginal graft to perform urethroplasty for the treatment of urethral strictures in women. PATIENTS AND METHODS This is a retrospective chart review of 11 women who were treated with a dorsal vaginal graft urethroplasty by one surgeon. All women underwent preoperative evaluation that included history, physical examination, fluoro‐urodynamics and urethral calibration. After surgery interviews, physical examinations, and urinary flow and postvoid residual urine volumes (PVRs) were obtained. RESULTS In all, 11 women who had undergone dorsal vaginal graft urethroplasty were identified for review. The mean (range) age was 60.6 (39–75) years. The mean (range) follow‐up was 22.7 (6–46) months. There were no cases of new onset stress urinary incontinence. The mean PVRs before and after surgery were 187.1 mL and 75.8 mL, respectively (P= 0.003). The mean urinary flows before and after surgery were 7.3 mL/s and 21.8 mL/s, respectively (P= 0.001). No patient has required repeat surgery. Self‐reporting satisfaction scores using the Patient Global Impression of Improvement showed that four patients scored 1 (very much better), three scored 2 (much better), two patients scored 3 (a little better), and one scored 4 (no change). Only one patient scored a 5 (worse). CONCLUSION Dorsal graft urethroplasty with vaginal mucosa may be considered as a first‐line option for definitive management of female urethral stricture disease. No consensus exists for the surgical treatment of female urethral stricture disease.

Background. Thirty percent of patients with clinically localized prostate cancer and a negative bone scan will experience relapse with recurrent disease despite treatment of the primary tumor. This may be due to the presence of metastatic prostate cancer cells at the time of treatment undetected by conventional methods, radionu‐cleotide bone scan, and serum prostatic specific antigen blood test. Methods. The authors used polymerase chain reaction (PCR) amplification of the prostate‐specific antigen (PSA) mRNA sequence reverse‐transcriptase PCR (RTPCR) and immunohistochemistry using a PSA antibody to identify metastatic prostate cancer cells in the bone marrow of patients with prostate cancer. Results. Micrometastases were found in the bone marrow of 29 of the 55 patients (51%) with prostate cancer and in 0 of the 5 patients with benign prostatic hyperplasia. Samples from five of the seven patients with lymph node metastases and from all five patients with bony metastases contained micrometastases. Of the samples taken from 43 patients undergoing radical prostatectomy and with no evidence of metastatic disease, 19(44%) had micrometastases. Four of the 20 samples (20%) from patients with pathologically localized disease and 15 of the 23 samples (65%) from patients with extraprostatic disease had micrometastases (P = 0.003). Bone marrow slides were available on 24 of the 29 patients who were positive for micrometastases by RTPCR. Immunohisto‐chemistry using the PSA antibody identified metastatic cells in 19 of these 24 patients. Conclusions. Reverse‐transcriptase polymerase chain reaction of bone marrow samples from patients with clinically localized prostate cancer may improve the accuracy of prostate cancer staging and identify patients at high risk for metastatic disease.

Adenovirus hemorrhagic cystitis following bone marrow transplantation occurs in 2 to 16% of the patients. While usually self-limiting, this disease can cause significant morbidity and even mortality in the immunocompromised patient. Risk factors include graft versus host disease and pre-transplant seropositivity to adenovirus. Standard treatment of this disorder consists of hydration, diuresis and analgesics. Failure of these measures leads to multiple blood transfusions, severe patient morbidity and possible death. When conservative therapy is unsuccessful, there is no proved standard of care. We recently used ribavirin, a broad-spectrum antiviral agent against adenovirus infection in vitro, to treat refractory adenovirus hemorrhagic cystitis after bone marrow transplantation. The hematuria and urinary symptomatology resolved without demonstrable side effects. We present ribavirin as a therapeutic alternative when conservative treatment for adenovirus hemorrhagic cystitis fails.