Partial gland ablation with high intensity focal ultrasound impact on genito-urinary function and quality of life: our initial experience.

INTRODUCTION:   Partial gland ablation (PGA) using high intensity focal ultrasound (HIFU) is an alternative to active surveillance for low to intermediate risk localized prostate cancer.  This pilot study assessed quality of life (QoL) outcomes during the implementation of PGA-HIFU at our institution. MATERIALS AND METHODS:   We prospectively enrolled 25 men with a diagnosis of localized low/intermediate risk prostate cancer who elected to undergo PGA-HIFU in a pilot study at our institution between 2013 and 2016.  Patients underwent pre-treatment mpMRI and transrectal ultrasound-guided biopsies.  The primary endpoints were impact on patient-reported functional outcomes (erectile, urinary function, QoL) assessed at 1, 3, 6- and 12-months. RESULTS:   The median age was 64 years old (IQR 59.5-67).  Baseline median International Index of Erectile Function-15 score was 50, which decreased to 18 at 1 month (p < 0.0005), returned to baseline by 3 months and thereafter. International Prostate Symptom Score median at baseline was 8, which worsened to 12 at 1 month (p = 0.0088), and subsequently improved to baseline thereafter.  On the UCLA-Expanded Prostate Cancer Index Composite urinary function, there was a decrease in median score from 92.7 at baseline to 76.0 at 1 month (p < 0.0001), which improved to or above baseline afterwards.  QoL remained similar to baseline at each follow up period as assessed by EQ-5D and the Functional Cancer Therapy-Prostate score. CONCLUSIONS:   In this initial cohort of PGA-HIFU men at our institution, patients demonstrated a slight, but transient, deterioration in urinary and erectile function at 1 month prior to normalization.  All QoL metrics showed no impact upon 1 year of follow up post-treatment.

Role of Systematic Control Biopsies following Partial Gland Ablation with High-Intensity Focused Ultrasound for Clinically Significant Prostate Cancer.

PURPOSE: Partial gland ablation (PGA) using high-intensity focused ultrasound (HIFU) is currently under investigation for clinically significant prostate cancer (Cs-PCa). Our primary objective was to assess the role of systematic control biopsies following HIFU-PGA in a cohort of Cs-PCa patients. MATERIALS AND METHODS: We studied a single-center retrospective cohort of 77 men treated with HIFU-PGA between October 2015 and December 2019. Patients with unilateral Cs-PCa, defined as Gleason grade group (GGG) ≥2, with visible lesion on multiparametric magnetic resonance imaging (mpMRI) and prostate specific antigen (PSA) ≤15 ng/ml were included. All patients underwent mpMRI with systematic and targeted biopsies before and after HIFU-PGA. The primary outcome was the rate of Cs-PCa at control biopsy within 1 year of treatment. Logistic regression was performed to identify predictive factors of our primary outcome. RESULTS: Median age was 67 years (IQR 61-71), median PSA was 7 ng/ml (IQR 5.5-8.9). Pre-treatment biopsies revealed 48 (62.3%) GGG2 lesions, 24 (31.2%) GGG3 and 5 (6.5%) GGG4 lesions. Cs-PCa was found in 24 (31.2%) patients at systematic control biopsy post-HIFU; Cs-PCa was in the treated lobe for 18 (27%) patients. No variables were identified as significant predictors of Cs-PCa at control biopsy, including PSA kinetics and control mpMRI. Median followup time was 17 months (95% CI 15-21). Median time to any retreatment was 32 months (95% CI 23-42). CONCLUSIONS: Systematic control biopsy within a year after PGA for Cs-PCa can identify the presence of residual Cs-PCa in up to a third of patients. From our early experience, control biopsy should be systematically offered patients regardless of PSA kinetics or control mpMRI results.

Lumbar to sacral root rerouting to restore bladder function in a feline spinal cord injury model: Urodynamic and retrograde nerve tracing results from a pilot study.

AIMS: Lumbar to sacral rerouting surgery can potentially allow voiding via a skin-central nervous system-bladder reflex pathway. Here, we assessed if this surgery was effective in treating neurogenic bladder dysfunction/sphincter in felines. METHODS: Eight cats underwent spinal cord transection (SCT) at thoracic level 10/11. Unilateral L7 to S1 ventral root anastomosis was performed 1 month later in six cats. Two cats served as transection-only controls. Electrical and manual stimulation of L6-S1 dermatomes, and urodynamics were performed at 3, 5, 7, and 9/10 months post transection. At 9/10 months, cats were also evaluated by direct electrophysiological testing of anastomosed roots with urodynamics, then tissue collection and examination of the root anastomosis site and lumbosacral cord ventral horns for cells retrogradely labeled from tracer dye injected 2 weeks earlier into the bladder wall. RESULTS: At 9/10 months, four of six rerouted cats exhibited increased detrusor pressure provoked by cutaneous stimulation, one cat bilaterally. Two cats presented with a voiding stream after ipsilateral cutaneous stimulation at 7 and 9 months. All six rerouted animals showed regrowth of axons from the L7 ventral horn to the bladder, although some aberrant axonal regrowth was also observed. CONCLUSION: L7 to S1 ventral root rerouting below the level of SCT showed successful axonal regrowth to the bladder from the L7 spinal cord segment in all rerouted animals, and induced increased detrusor pressure response to cutaneous stimulation in a subset. This feasibility study paves the way for future animal studies for bladder reinnervation.

A combination of hemostatic agents may safely replace deep medullary suture during laparoscopic partial nephrectomy in a pig model.

PURPOSE: We assessed whether a combination of the fibrin tissue adhesive Tisseel® (human fibrinogen and thrombin) plus the hemostatic matrix FloSeal® (bovine derived gelatin matrix/human thrombin) could safely replace the conventional deep medullary suture without compromising outcomes. MATERIALS AND METHODS: Laparoscopic mid pole and one-third partial nephrectomy was performed on the right kidney of 12 female pigs. The only difference between the 2 groups of 6 pigs each was the use of a fibrin tissue adhesive plus hemostatic matrix combination in group 2 instead of the deep medullary running suture in control group 1. Renal scans and angiograms were performed at baseline and before sacrifice at 5-week followup. Retrograde in vivo pyelogram was also done. RESULTS: No significant difference was seen in operative parameters or postoperative course between the groups. Renal scans revealed a statistically insignificant trend toward greater uptake loss in group 1 and angiograms showed 3 major vessel occlusions in that group. No active bleeding was detected. Those 3 kidneys had significantly poorer postoperative uptake on renal scan than that of other kidneys (18.6% vs 39.4%, p = 0.013). Only 1 small asymptomatic pseudoaneurysm was noted in group 1. No urine leakage was found in either group. No major vessel occlusion, pseudoaneurysm or urinary complications developed in group 2. CONCLUSIONS: Even after deep one-third partial nephrectomy FloSeal with concurrent Tisseel appeared sufficient to control major medullary vascular injuries and replace the deep medullary conventional suture without compromising operative outcomes. The potential advantages seen during functional and vascular examinations by decreasing the risk of unnecessary segmental vessel occlusion need further clinical evaluation.

What do we know and not know about mirabegron, a novel ß3 agonist, in the treatment of overactive bladder?

INTRODUCTION AND HYPOTHESIS: Mirabegron is a novel ß3-adrenoceptor agonist recently approved by Japanese, American, and European authorities for overactive bladder (OAB) therapy. Here we review existing knowledge on this new class of medication, analyze existing literature on the topic, and make recommendations regarding its administration and necessary future studies. METHODS: We reviewed the current literature and analyzed mirabegron efficacy, safety, and suitability for treating OAB symptoms. We performed a systematic search of Medline/PubMed, and Embase. Studies exploring mechanisms involved in the effects of mirabegron were included. Searches were limited to the English language. RESULTS: Two phase II and two large-scale phase III multinational randomized controlled trials have supported mirabegron efficacy and tolerability with up to 12 weeks of therapy in OAB patients. The reported frequency and severity of treatment-emergent and serious adverse events were similar to antimuscarinics but with more than threefold lower incidence of dry mouth than with tolterodine. However, effects on the cardiovascular system, cognitive functions, pharmacokinetic interactions with other drugs, and long-term adverse events have not yet been fully investigated. CONCLUSION: Anticholinergic drugs should remain the first-line pharmacologic treatment for OAB until head-to-head comparative study eventually shows that mirabegron has equivalent or superior efficacy. However, it seems logical to use mirabegron as second-line treatment of OAB in patients who are poor responders or intolerant to anticholinergics.

Microbial cancer immunotherapy reprograms hematopoietic stem cells to enhance anti-tumor immunity.

Mycobacterium bovis BCG is the vaccine against tuberculosis and an immunotherapy for bladder cancer. When administered intravenously, BCG reprograms bone marrow hematopoietic stem and progenitor cells (HSPCs), leading to heterologous protection against infections. Whether HSPC-reprogramming contributes to the anti-tumor effects of BCG administered into the bladder is unknown. We demonstrate that BCG administered in the bladder in both mice and humans reprograms HSPCs to amplify myelopoiesis and functionally enhance myeloid cell antigen presentation pathways. Reconstitution of naive mice with HSPCs from bladder BCG-treated mice enhances anti-tumor immunity and tumor control, increases intratumor dendritic cell infiltration, reprograms pro-tumorigenic neutrophils, and synergizes with checkpoint blockade. We conclude that bladder BCG acts systemically, reprogramming HSPC-encoded innate immunity, highlighting the broad potential of modulating HSPC phenotypes to improve tumor immunity.

Effect of the anticonvulsant medications pregabalin and lamotrigine on urodynamic parameters in an animal model of neurogenic detrusor overactivity.

AIMS: To assess the effects of different doses and treatment durations of pregabalin and lamotrigine on the urodynamic parameters of an animal model of neurogenic detrusor overactivity (NDO). MATERIALS AND METHODS: Ninety rats were used; six as normal controls and the remaining 84 were divided as follows: Six "paraplegic controls," 6 "paraplegic-vehicle controls," and the remaining 72 divided into two equal groups. Group 1 was divided into six subgroups; pregabalin was given in doses of 10 mg/kg, 20 mg/kg, or 30 mg/kg for 1 or 2 weeks. Group 2 was similarly subdivided; lamotrigine was given in doses of 1.5 mg/kg, 3 mg/kg, or 6 mg/kg for 1 or 2 weeks. RESULTS: All paraplegic controls developed NDO within 3 weeks from spinalization. Their baseline bladder pressure (BBP) 19 ± 4.4 cmH(2) O, detrusor pressure at maximum capacity (DPMaxC) 47.6 ± 4.3 cmH(2) O, bladder capacity (BC) 0.45 ± 0.1 ml, and frequency of detrusor overactivity (FDO) 3.7 ± 0.9/min. Both pregabalin and lamotrigine produced significant improvement. Urodynamic values in those treated with 20 mg pregabalin for 1 or 2 weeks were: BBP 11.7 ± 1.3 and 9 ± 0.2 cmH(2) O, BC 0.6 ± 0.1 and 0.7 ± 0.01 ml, DPMaxC 17.3 ± 4.0 and 23 ± 2.6 cmH(2) O, FDO 2.1 ± 0.2/min and 1.7 ± 0.1/min. Urodynamic values in those treated with 3 mg/kg lamotrigine for 1 or 2 weeks were: BBP 9.7 ± 2.2 and 8.6 ± 1.9 cmH(2) O, DPMaxC 17.2 ± 1.8 and 29 ± 1.2 cmH(2) O, BC 0.7 ± 0.1 and 0.8 ± 0.1 ml, FDO 1.9 ± 0.2/min and 1.9 ± 0.2/min (P < 0.001). CONCLUSIONS: Pregabalin and lamotrigine may represent novel alternative treatments of NDO. Clinical trials remain to be performed.

Bone marrow mesenchymal stromal cell therapy for external urethral sphincter restoration in a rat model of stress urinary incontinence.

OBJECTIVE: To assess the effect of intra-sphincteric injections of bone marrow mesenchymal stromal cells (MSCs) on Valsalva leak point pressure (VLPP) changes in an animal model of stress urinary incontinence (SUI). MATERIALS AND METHODS: Twenty-four female Sprague-Dawley rats underwent bilateral pudendal nerve section to induce SUI. Six rats were SUI controls, 6 received periurethral injection of Plasma-Lyte (SUI placebo control) and 12 were given periurethral injection of PKH26-labeled MSCs. Four weeks after injection, conscious cystometry was undertaken in animals and VLPP recorded. All groups were sacrificed, and frozen urethra sections were submitted to pathology and immunohistochemistry assessment. RESULTS: Rat MSCs were positive for the cell surface antigens CD44, CD73, CD90, and RT1A, and negative for CD31, CD45, and RT1B, confirming their stem cell phenotype. In vitro, differentiated MSCs expressed α-smooth muscle actin (SMA) and desmin, markers of smooth and striated muscles in vivo. Immunohistochemistry of rat urethras revealed PKH26-labeled MSCs in situ and at the injection site. LPP was significantly improved in animals injected with MSCs. Mean LPP was 24.28 ± 1.47 cmH(2) O in rats implanted with MSCs and 16.21 ± 1.26 cmH(2) O in SUI controls (P<0.001). Atrophic urethras with implanted MSCs were positively stained for myosin heavy chain and desmin. CONCLUSION: Rat MSCs have the ability to differentiate and skew their phenotype towards smooth and striated muscles, as demonstrated by SMA up-regulation and desmin expression. Periurethral injection of MSCs in an animal model of SUI restored the damaged external urethral sphincter and significantly improved VLPP.

The role of bladder urine transforming growth factor-beta1 concentrations in diagnosis and management of unilateral prenatal hydronephrosis.

PURPOSE: We evaluated the relationship between bladder urine transforming growth factor-beta1 concentration and severity of hydronephrosis in newborns with unilateral prenatal hydronephrosis. MATERIALS AND METHODS: We prospectively studied all newborns presenting with unilateral prenatal hydronephrosis between January 2005 and 2007. Patients with associated anomalies, vesicoureteral reflux, contralateral pathology or ipsilateral ureteral dilatation were excluded from study. Postnatal evaluation included voiding cystourethrography, renal ultrasonography and determination of bladder urine transforming growth factor-beta1 concentration. Diuretic renal scans were performed in patients with initial grade 3 or 4 hydronephrosis or increasing hydronephrosis during followup. Pyeloplasty was performed when a well tempered renogram showed an obstructive drainage curve with a half-time greater than 20 minutes and/or an obstructive washout curve pattern during the diuretic phase. Patients were analyzed in observational and surgical groups. We studied the longitudinal changes in bladder urine transforming growth factor-beta1 in each group and compared concentration levels in the first 3 months of life in both groups. RESULTS: A total of 42 newborns were included. The observational group consisted of 31 patients followed for a mean of 14 +/- 6 months. During the first 3 months, from 3 to 12 months and in the second year of life mean ultrasound grade and bladder urine transforming growth factor-beta1 decreased from 2.3 to 1.7 to 1.2 (p <0.05) and from 11.5 to 8.6 to 6.1 pg/mmol creatinine (p <0.05), respectively. Pyeloplasty was performed in 11 patients at a mean age of 6 +/- 5 months. Mean followup was 7 +/- 5 months. In the first 3 months, preoperatively and at 3 to 12 months postoperatively mean ultrasound grade and bladder urine transforming growth factor-beta1 were 3.5, 4 and 3 (p >0.05), and 23, 29 (p >0.05) and 8 pg/mmol creatinine (p <0.003), respectively. Mean bladder urine transforming growth factor-beta1 levels in the first 3 months of life were 23 +/- 14 and 11.5 +/- 8 pg/mmol creatinine in the surgical and observational groups, respectively (p <0.001). Limiting comparison to the 23 patients with initial grades 3 and 4 hydronephrosis revealed levels of 23 +/- 14 and 13 +/- 9 pg/mmol creatinine in the surgical and observational groups, respectively (p <0.02). At a cutoff of 17 pg/mmol creatinine bladder urine transforming growth factor-beta1 in the first 3 months of life was 82% sensitive and 86% specific in predicting surgery. CONCLUSIONS: Bladder urine transforming growth factor-beta1 changes through time are associated with similar changes in hydronephrosis grade. Bladder urine transforming growth factor-beta1 in the first 3 months of life can predict the need for surgery in newborns with prenatal hydronephrosis.

Montreal electronic artificial urinary sphincters: Our futuristic alternatives to the AMS800™.

INTRODUCTION: We aimed to present three novel remotely controlled hydromechanical artificial urinary sphincters (AUSs) and report their in-vitro and ex-vivo results. METHODS: We successively developed three distinct hydromechanical AUSs on the basis of the existing AMS800™ device by incorporating an electronic pump. No changes were made to the cuff and balloon. The AUS#1 was designed as an electromagnetically controlled device. The AUS#2 and AUS#3 were conceived as Bluetooth 2.1 remotely controlled and Bluetooth 4.0 remotely-controlled, adaptive devices, respectively. In-vitro experiments profiled occlusive cuff pressure (OCP) during a complete device cycle, with different predetermined OCP. Ex-vivo experiments were performed on a fresh pig bladder with 4 cm cuff placed around the urethra. Leak point pressure with different predetermined OCP values was successively measured during cystometry via a catheter at the bladder dome. RESULTS: Our in-vitro and ex-vivo experiments demonstrated that these three novel AUSs provided stable and predetermined OCP - within the physiological range - and completely deflated the cuff, when required, in a limited time compatible with physiological voiding cycles. CONCLUSIONS: Our three novel, remotely controlled AUSs showed promising results that should be confirmed by in-vivo experiments focusing on efficacy and safety.

Elastic modulus for long-term evaluation of the tensile properties of polypropylene meshes in an in vivo rat model.

PURPOSE: Mid-urethral slings have become the gold standard treatment of stress urinary incontinence in women. Their tensile properties should be evaluated in order to measure how they wear off with time. Our objective was a long-term assessment of the tensile properties of 2 synthetic tapes (TVT-O and I-STOP) after in vivo implantation in rats in terms of elastic modulus. METHODS: Strips from both meshes were implanted in the abdominal wall of 30 rats, which were sacrificed at 5 time intervals. Their fibers were untangled to single components. Ultimate tensile strength (UTS), strain at UTS and the elastic modulus of each fiber type were measured. RESULTS: I-STOP maintained UTS and strain over time, while TVT-O UTS and strain were significantly reduced. However, the elastic modulus of both tapes remained constant. CONCLUSIONS: Both meshes maintained their stiffness and elasticity with time. Elastic modulus could be an appropriate factor to predict long-term implantation outcomes. The clinical significance of such findings remains to be demonstrated by long-term analysis.

Structural differences and architectural features of two different polypropylene slings (TVT-O and I-STOP) have no impact on biocompatibility and tissue reactions.

INTRODUCTION: To evaluate the impact of design features of the synthetic mid-urethral slings on tissue integrity and inflammatory responses. MATERIAL AND METHODS: In total 30 female Sprague-Dawley rats were implanted with type I monofilamentous, macroporous polypropylene meshes: Gynecare TVT-Obturator tape® (Ethicon Inc., Johnson & Johnson, Somerville, NJ, USA) and I-STOP® (CL Medical Inc., Lyon, France). All animal groups were sacrificed at set time intervals - 6 weeks, 3 months, 6 months, 9 months and 12 months - and the abdominal wall was harvested with mesh strips for histological evaluation. RESULTS: All mesh strips appeared to be well incorporated into the abdominal wall, and no signs of shrinkage was noticed. All specimens showed a thin/delicate, loose, fibrous interface between the synthetic graft plate and abdominal wall, along with mild inflammatory reactions from 6 weeks to 12 months. CONCLUSIONS: Both mesh brands induced comparable, minimal foreign body reactions and integrated well into the host tissues despite differences in architectural features. TVT-O® and I-STOP® evoked similar low-grade inflammatory responses up to 12 months in this animal model. Structural differences and architectural features of polypropylene slings used in this study have had no impact on tissue integrity and inflammatory responses.

Bladder tissue engineering: a literature review.

PURPOSE OF REVIEW: In bladder cancer and neuro-bladder, reconstruction of the bladder requires bowel segment grafting for augmentation cystoplasty or neo-bladder creation. However, even if currently considered as the gold standard, it is associated with potentially severe short- and long-term adverse effects. Thus, bladder tissue engineering is a promising approach to bladder reconstruction. RECENT FINDINGS: In the last few years, progress has been made with the development of new biomaterials for bladder tissue replacement and in deciphering the role of stem cells as well as their contribution to bladder scaffold integration and tissue regeneration. SUMMARY: This review of recently published articles allows us to forecast the characteristics of efficient and safe bladder biomaterials. However, several factors, such as native bladder traits, the specific involvement of urine, and bladder tissue replacement indications, have to be assessed with caution before including bladder tissue engineering in clinical trials. Many authors agree that these challenging techniques could deliver significant benefits with clinical application, reducing morbidity and global long-term costs.

Tissue engineering of rat bladder using marrow-derived mesenchymal stem cells and bladder acellular matrix.

Bladder replacement or augmentation is required in congenital malformations or following trauma or cancer. The current surgical solution involves enterocystoplasty but is associated with high complication rates. Strategies for bladder tissue engineering are thus actively sought to address this unmet clinical need. Because of the poor efficacy of synthetic polymers, the use of bladder acellular matrix (BAM) has been proposed. Indeed when cellular components are removed from xenogenic or allogeneic bladders, the extracellular matrix scaffold thus obtained can be used alone or in combination with stem cells. In this study, we propose the use of BAM seeded with marrow-derived mesenchymal stem cells (MSCs) for bladder tissue engineering. We optimized a protocol for decellularization of bladder tissue from different species including rat, rabbit and swine. We demonstrate the use of non-ionic detergents followed by nuclease digestion results in efficient decellularization while preserving the extracellular matrix. When MSCs were seeded on acellular matrix scaffold, they remained viable and proliferative while adopting a cellular phenotype consistent with their microenvironment. Upon transplantation in rats after partial cystectomy, MSC-seeded BAM proved superior to unseeded BAM with animals recovering nearly 100% normal bladder capacity for up to six months. Histological analyses also demonstrated increased muscle regeneration.

Protective role of hypothermia on ischemia of prepubertal rodent testicle.

OBJECTIVES: To assess the role of hypothermia in testicular ischemic injury in a prepubertal rat model. METHODS: The study included 24 male, prepubertal Sprague-Dawley rats. Of the 24 rats, 20 were subjected to right testicular ischemia with and without hypothermia for 30 and 60 minutes, 5 in each group. The remaining 4 rats underwent sham operation and were used as controls. A vascular clamp was used to clamp the spermatic cord for the specified time. Hypothermic treatment consisted of placing the testicle in ice slush. At 8 weeks postoperatively, both testicles were harvested. The left testicle was used as the control. A pathologist, who was unaware of the groups, examined all the slides. The mean seminiferous tubular diameter (STD) and mean number of germinal cell layers (GCLs) were obtained. RESULTS: When the contralateral testicle was used as the control, the mean GCL and STD in the ipsilateral operated sides were significantly worse in all ischemic groups. When the sham-operated testicles were used as the control, no significant differences were found between the cold ischemia groups and the sham group. In the warm ischemia groups, the mean GCL and STD were significantly worse than those in the sham group. We compared the operated sides among the groups. At 30 minutes, the mean GCL and STD showed a trend toward preservation with cold ischemia, although the difference was insignificant. At 60 minutes, the mean GCL and STD were significantly worse with warm than with cold ischemia. CONCLUSIONS: The results of our study have shown that permanent ipsilateral ischemic testicular damage occurred as early as 30 minutes in prepubertal rats. The damage might be reduced with hypothermia.

PAX2 is reactivated in urinary tract obstruction and partially protects collecting duct cells from programmed cell death.

Obstruction of the urinary tract activates apoptotic pathways in collecting duct cells and leads to loss of renal parenchyma before surgical intervention. It has been suggested that developmental pathways may be reactivated to offset acute organ damage. One such molecule, PAX2, is expressed throughout the fetal collecting duct and was recently shown to suppress apoptosis during kidney development. We hypothesized that acute unilateral urinary tract obstruction (UUO) reactivates PAX2 expression in the mature kidney and partially suppresses apoptosis. If so, animals with PAX2 mutations should have increased susceptibility to parenchymal damage. Wild-type and heterozygous Pax2 mutant (C3H/Pax2(1Neu)) mice underwent unilateral ureteric ligation or sham operation at 6 wk of age; kidneys were examined after 5, 10, and 15 days. Whereas PAX2 protein levels fell to low levels in the first weeks of life, it was sharply reactivated by day 10 in collecting duct cells of wild-type but not in Pax2(1Neu) mutant mice with UUO. Wild-type mice with UUO had marked TUNEL and cleaved spectrin staining in tubular cells and reduced kidney weight after 10-15 days. Mutant mice had exaggerated increases in markers of apoptosis and exaggerated loss of renal parenchymal loss in the obstructed kidney. These observations suggest that PAX2 is rapidly reactivated in UUO and that mice with genetically limited PAX2 expression have heightened susceptibility to apoptosis.