KEAP1-NRF2 system regulates age-related spermatogenesis dysfunction.

Purpose: The average fatherhood age has been consistently increasing in developed countries. Aging has been identified as a risk factor for male infertility. However, its impact on various mechanisms remains unclear. This study focused on the KEAP1-NRF2 oxidative stress response system, by investigating the relationship between the KEAP1-NRF2 system and age-related changes in spermatogenesis. Methods: For examination of age-related changes, we used 10-, 30-, 60-, and 90-week-old mice to compare sperm count, sperm motility, and protein expression. For assessment of Keap1 inhibition, 85-week-old C57BL/6J mice were randomly assigned to the following groups: control and bardoxolone methyl (KEAP1 inhibitor). Whole-exome sequencing of a Japanese cohort of patients with non-obstructive azoospermia was performed for evaluating. Results: Sperm count decreased significantly with aging. Oxidative stress and KEAP1 expression in the testes were elevated. Inhibition of KEAP1 in aging mice significantly increased sperm count compared with that in the control group. In the human study, the frequency of a missense-type SNP (rs181294188) causing changes in NFE2L2 (NRF2) activity was significantly higher in patients with non-obstructive azoospermia than in healthy control group. Conclusions: The KEAP1-NRF2 system, an oxidative stress response system, is associated with age-related spermatogenesis dysfunction.

Lower Dose of 5 mL of 1% Lidocaine is More Suitable than the Conventional 10 mL for Caudal Block in Transrectal Prostate Biopsy: A Retrospective Cohort Study.

Objectives: In Japan, caudal block with 1% lidocaine is commonly used for transrectal prostate biopsy. Although 10 mL of 1% lidocaine is commonly used, the appropriate dosage of 1% lidocaine has not been studied. Our hospital routinely uses two different doses (5 or 10 mL) of 1% lidocaine for caudal block for transrectal prostate biopsy. Herein, we retrospectively evaluated the efficacy and safety of both doses of 1% lidocaine. Methods: This retrospective study included 869 patients who underwent transrectal prostate biopsy with caudal block at our hospital. The amount of 1% lidocaine was determined by the day of the week on which the biopsy was performed, and the patient voluntarily chose the day of the biopsy, unaware of the dose of 1% lidocaine used on that day. Pain, anal sphincter tonus, cancer diagnosis rate, and early complications were compared. Results: In total, 466 and 403 patients received 5 and 10 mL of 1% lidocaine for a caudal block, respectively. After propensity-score matching for patient characteristics, each group contained 395 patients. The pain score, anal sphincter tonus score, or prostate cancer diagnosis rate were not significantly different between the two groups. However, rectal bleeding was significantly more frequent and severe in the 10-mL than the 5-mL group (p=0.018 and p=0.0036, respectively). The incidence of other complications was not significantly different between the groups. Conclusions: Our results suggest that 5 mL of 1% lidocaine may be more suitable than 10 mL for caudal block during transrectal prostate biopsy.

Maintaining Serum Hemoglobin Levels Within the Physiological Range Prevented Bladder Tamponade Recurrence Due to Radiation-Induced Hemorrhagic Cystitis: A Case Report.

Radiation-induced hemorrhagic cystitis is a refractory disease that can cause severe hematuria and bladder tamponade. Bladder tamponade due to radiation-induced hemorrhagic cystitis can often recur repeatedly and markedly reduce the quality of life. However, no blood test parameter has been studied yet regarding the prevention of bladder tamponade recurrence. An 84-year-old patient with a history of radiation therapy for cervical cancer was repeatedly hospitalized for bladder tamponade due to radiation-induced hemorrhagic cystitis. At each hospitalization, blood transfusions were performed to treat severe anemia as the first treatment, resulting in hematuria improvement, and the patient was discharged without invasive treatments such as transurethral coagulation. However, anemia developed gradually after each discharge. The anemia progression was obviously unrelated to macrohematuria because macrohematuria did not appear during that period. When the serum hemoglobin level decreased below the physiological range, bladder tamponade recurred. Based on these findings, we posited that the monitoring of the serum hemoglobin level could be useful to predict the occurrence of bladder tamponade. We hypothesized that if the serum hemoglobin level did not fall below the physiological range, bladder tamponade would not occur. We treated chronic anemia after determining its cause and kept serum hemoglobin levels within the physiological range. Since the treatment was initiated, bladder tamponade has not recurred in over 27 months. In this case, the monitoring of the serum hemoglobin level was useful to predict the occurrence of bladder tamponade due to radiation-induced hemorrhagic cystitis. By maintaining serum hemoglobin levels within the physiological range, we successfully prevented the recurrence of bladder tamponade due to radiation-induced hemorrhagic cystitis.

Therapeutic efficacy and safety of a free-standing motorized ejaculation aid for patients with intravaginal ejaculatory dysfunction.

Purpose: There are no approved drugs or devices for the treatment of intravaginal ejaculation disorders, and treatment is often difficult. This study aimed to evaluate the efficacy and safety of the A10 Cyclone SA + PLUS® ejaculation aid (Rends Co., Ltd., Chiba, Japan), which allows the user to adjust the intensity of stimulation, for intravaginal ejaculation disorders. Methods: Each participant was instructed to perform practice masturbation with the A10 Cyclone SA + PLUS to simulate vaginal ejaculation. After 8 weeks of training, the participants were asked about their intravaginal ejaculation status. Sexual function was also evaluated before and after the training using several specific questionnaires, including the numerical rating scale for ejaculatory satisfaction. Results: Among the 10 participants (41.5 ± 3.21 years) who completed the training and questionnaire evaluation, four (40%) became capable of intravaginal ejaculation. The questionnaire evaluation showed predominant improvement after training in the ejaculation-capable group according to the numerical rating scale, which expresses satisfaction with ejaculation. The participants experienced no significant adverse events. Conclusion: As no effective treatment currently exists for intravaginal ejaculation disorders, we conclude that the A10 Cyclone SA + PLUS may be one treatment tool for intravaginal ejaculation disorders with good efficacy and no adverse events.

Evaluation of the efficacy of creatine chemical exchange saturation transfer imaging in assessing testicular maturity.

Purpose: Microscopic testicular sperm extraction is the most effective treatment for NOA, but the sperm retrieval rate is low and depends on testicular maturity. However, there are limited useful tests to assess testicular maturity. Chemical exchange saturation transfer (CEST) imaging is a new magnetic resonance imaging (MRI) technique that can image the distribution of trace substances in vivo. We focused on the potential role of creatine (Cr) in testes and hypothesized that Cr-CEST could indicate intratesticular spermatogenesis. Methods: We performed Cr-CEST by using 7T MRI on wild-type C57B6/J mice and several types of male infertility models such as Sertoli-cell only (SCO) (Kitw/Kitwv), maturation arrest (MA) (Zfp541 knockout mouse and Kctd19 knockout mouse), and teratozoospermia (Tbc1d21 knockout mouse). After performing Cr-CEST, histological analysis was performed. Results: The SCO and MA models showed decreased CEST signal intensity (p < 0.05), while no reduction was observed in the teratozoospermia model (p = 1.0). CEST signal intensity increased as the spermatogenesis stage progressed from the SCO model to the MA and teratozoospermia models. Furthermore, CEST signal intensity was reduced in 4-week-old wild-type mice with immature testes (p < 0.05). Conclusions: This study suggests that Cr-CEST evaluates intratesticular spermatogenesis noninvasively and provides a new therapeutic strategy for treating male infertility.

Localization and potential role of prostate microbiota.

Introduction: We aimed to clarify the presence and localization of the prostate microbiota and examine its association with benign prostate enlargement (BPE). Methods: The microbiota of prostate tissues and catheterized urine from 15 patients were analyzed by 16S metagenomic analysis and compared to show that the prostate microbiota was not a contaminant of the urinary microbiota. Fluorescence in situ hybridization (FISH) and in situ hybridization (ISH) using the specific probe for eubacteria was performed on prostate tissue to show the localization of bacteria in the prostate. The BPE group was defined as prostate volume ≥30 mL, and the non-BPE group as prostate volume <30 mL. The microbiota of the two groups were compared to clarify the association between prostate microbiota and BPE. Results: Faith's phylogenetic diversity index of prostate tissue was significantly higher than that of urine (42.3±3.8 vs 25.5±5.6, P=0.01). Principal coordinate analysis showed a significant difference between the microbiota of prostate tissue and catheterized urine (P<0.01). FISH and ISH showed the presence of bacteria in the prostatic duct. Comparison of prostate microbiota between the BPE and non-BPE groups showed that the Chao1 index of the BPE group was significantly lower than that of the latter [142 (50-316) vs 169 (97-665), P=0.047] and the abundance of Burkholderia was significantly higher in the BPE group than in the latter. Conclusions: We demonstrated that the prostate microbiota was located in the prostatic duct and reduced diversity of prostate microbiota was associated with BPE, suggesting that prostate microbiota plays a role in BPE.

[A Case of Panperitonitis Due to Bladder Rupture Caused by Spinal Metastasis of Colorectal Cancer].

A 74-year-old patient was undergoing treatment for ascending colon cancer (cT4aN2M1a) in the Department of Surgery at our hospital. During treatment for increased lymph node metastasis and spinal metastasis, she complained of numbness in her dorsal thigh. Magnetic resonance imaging showed spinal canal stenosis due to L4 bone metastasis. Immediately after starting radiation therapy for L4 bone metastasis, bladder rupture occurred and led to generalized peritonitis. We performed emergency laparotomy and drainage. Later, the patient's general condition improved, but irreversible neurological symptoms remained, and activities of daily living decreased markedly. This was thought to be caused by weakening of the bladder wall due to chronic cystitis, and hyperextension of the bladder due to neurogenic bladder. Bacteriuria leaked into the abdominal cavity, resulting in generalized peritonitis.

Assessment of bone health in patients with prostate cancer using cancer staging computed tomography.

PURPOSE: To evaluate the utility of vertebral Hounsfield unit (HU) values from computed tomography (CT) in cancer staging as a supplementary screening tool for bone health among prostate cancer (PCa) patients. METHODS: T-scores of bone mineral density (BMD) in each lumbar vertebra (L1-L4) and hip for newly diagnosed PCa patients (N = 139) were measured using dual-energy X-ray absorptiometry (DXA). The degenerative changes in each lumbar vertebra were assessed, and the HU values of trabecular bone in axial CT images of each vertebral body (vertebral CT-HU value) were measured using staging CT. RESULTS: 556 vertebrae were analyzed. 326 of 556 (59%) lumbar vertebrae had degenerative changes. The vertebral CT-HU value was positively correlated with the lumbar BMD T-score, with higher correlation coefficients observed in vertebrae without degenerative changes (r = 0.655, N = 230) when compared to vertebrae with degenerative changes (r = 0.575, N = 326). The thresholds matching BMD T-scores of - 2.0 and - 1.5 set by cancer treatment-induced bone loss guidelines were 95 HU and 105 HU, respectively. Based on the intervention threshold (lumbar BMD T-score < - 1.5), 15.1% of PCa patients required osteoporosis treatment; and, this value increased to 30.9% when L1-L4 CT-HU thresholds that corresponded to BMD T-score < - 1.5 were used. CONCLUSION: Lumbar BMD values from DXA may not reflect true bone health in PCa patients who often have lumbar degenerative diseases. Thresholds based on the vertebral CT-HU value can be used as a supplementary method to identify PCa patients who need anti-osteoporosis drugs.

[A Case of Adrenal Anastomosing Hemangioma].

An 83-year-old man with left lower back pain was found to have a 5 cm mass in contact with the right adrenal gland and a 12 mm left ureteral stone by abdominal plain computed tomography. An abdominal plain magnetic resonance imaging T2-weighted image revealed a heterogeneous high signal mass in the right adrenal gland. Pheochromocytoma, adrenal carcinoma, and retroperitoneal neurogenic tumor were suspected. Tumor markers and endocrine examinations were within standard values. Laparoscopic right adrenalectomy was performed. A 4×3.6 cm, 62 g solid tumor was found in contact with right adrenal gland. Histopathologically, hobnail-like vascular endothelial cells were found in the tumor, but no malignant findings such as multi-layered vascular endothelial cells and nuclear atypia were observed. This tumorwas diagnosed to be an anastomosing hemangioma.

Bladder urothelium converts bacterial lipopolysaccharide information into neural signaling via an ATP-mediated pathway to enhance the micturition reflex for rapid defense.

When bacteria enter the bladder lumen, a first-stage active defensive mechanism flushes them out. Although urinary frequency induced by bacterial cystitis is a well-known defensive response against bacteria, the underlying mechanism remains unclear. In this study, using a mouse model of acute bacterial cystitis, we demonstrate that the bladder urothelium senses luminal extracellular bacterial lipopolysaccharide (LPS) through Toll-like receptor 4 and releases the transmitter ATP. Moreover, analysis of purinergic P2X2 and P2X3 receptor-deficient mice indicated that ATP signaling plays a pivotal role in the LPS-induced activation of L6-S1 spinal neurons through the bladder afferent pathway, resulting in rapid onset of the enhanced micturition reflex. Thus, we revealed a novel defensive mechanism against bacterial infection via an epithelial-neural interaction that induces urinary frequency prior to bacterial clearance by neutrophils of the innate immune system. Our results indicate an important defense role for the bladder urothelium as a chemical-neural transducer, converting bacterial LPS information into neural signaling via an ATP-mediated pathway, with bladder urothelial cells acting as sensory receptor cells.

Secondary immune thrombocytopenic purpura with renal cell carcinoma.

INTRODUCTION: Several types of cancers are reported to induce secondary immune thrombocytopenia resembling immune thrombocytopenic purpura-like syndrome. However, renal cell carcinoma-induced immune thrombocytopenic purpura is an extremely rare phenomenon. CASE PRESENTATION: A 73-year-old male with right renal tumor and multiple enlarged lymph nodes presented severe thrombocytopenia, without bone or hepatic metastasis. Although platelet transfusion and high-dose immunoglobulin treatment were refractory, surgical resection of the tumor and lymph nodes promptly improved thrombocytopenia. After recurrence, he presented thrombocytopenia again. Tyrosine kinase inhibitor treatment was ceased due to uncontrollable hemorrhagic gastric ulcer. The patient eventually died of cancer 4 months after surgery. Flow cytometry analysis revealed the presence of integrin glycoprotein IIb/IIIa, which is a fibronectin/fibrinogen receptor on platelets and as an antigen in immune thrombocytopenic purpura. CONCLUSION: To the best of our knowledge, this is the first reported case of renal cell carcinoma-induced immune thrombocytopenic purpura that demonstrates the presence of platelet-autoantibody glycoprotein IIb/IIIa.

Intravesical ATP instillation induces urinary frequency because of activation of bladder afferent nerves without inflammatory changes in mice: A promising model for overactive bladder.

ATP in the suburothelial layer is released from the bladder urothelium by mechanical stimuli. ATP directly activates purinergic receptors that are expressed on primary bladder afferent neurons and induces the micturition reflex. Although ATP is also released to the bladder lumen from the bladder urothelium, the role of ATP in the bladder lumen is unknown. Recently, clinical studies have reported that urinary ATP levels are much higher in patients with an overactive bladder than healthy controls. These results suggest that ATP in the bladder lumen is also involved in the micturition reflex. In this study, we performed intravesical ATP instillation in the mouse bladder. We evaluated urinary function with novel reliable methods using improved cystometry and ultrasonography, which we previously established. We found that intravesical ATP instillation induced urinary frequency because of activation of bladder afferent nerves without inflammatory changes in the bladder or an increase in post-void residual urine. These results suggest that not only ATP in the suburothelial layer, but also ATP in the bladder lumen, are involved in enhancement of the micturition reflex.

[Intravesical Recurrence of Small Cell Carcinoma of the Ureter: A Case Report].

A 63-year-old man who presented with asymptomatic gross hematuria was referred to our hospital. Left ureteral tumor (cT3N0M0) was diagnosed and left nephroureterectomy was performed. Pathological examination revealed urothelial carcinoma and small cell carcinoma with local invasion (pT3). The patient was treated with three cycles of adjuvant chemotherapy with gemcitabine and cisplatin. Three months after the chemotherapy, cystoscopy showed an intravesical recurrence of the tumor. Transurethral resection was performed and histopathological examination revealed small cell carcinoma (pT1). We recommended a cystectomy and neoadjuvant chemotherapy with etoposide and carboplatin according to the standard care of small cell carcinoma of bladder. However, the patient refused to undergo cystectomy and desired to preserve his bladder. Therefore, after two cycles of chemotherapy with etoposide and carboplatin, transurethral resection was performed to examine the presence of the residual tumor instead of immediate cystectomy. Because of no residual tumor, another two cycles of chemotherapy were added instead of a cystectomy. There is no evidence of recurrence seven months after the chemotherapy.

Authentic role of ATP signaling in micturition reflex.

Adenosine triphosphate (ATP) is a signaling molecule that regulates cellular processes. Based on previous studies of bladder function over the past decade, bladder ATP signaling was thought to have an essential role in the normal micturition reflex. In this study, we performed detailed analyses of bladder function in purinergic receptor-deficient mice using the automated voided stain on paper method and video-urodynamics. Unexpectedly, a lack of P2X2 or P2X3 receptors did not affect bladder function under normal physiological conditions, indicating that bladder ATP signaling is not essential for normal micturition reflex. In contrast, we found that lipopolysaccharide (LPS) induced markedly high levels of ATP release from the urothelium. In addition, LPS-induced rapid bladder hyperactivity was attenuated in P2X2(-/-) and P2X3(-/-) mice. Contrary to the previous interpretation, our present findings indicate that bladder ATP signaling has a fundamental role in the micturition reflex, especially in bladder dysfunction, under pathological conditions. Therefore, the bladder ATP signaling pathway might be a highly promising therapeutic target for functional bladder disorders. This study newly defines an authentic role for bladder ATP signaling in the micturition reflex.

[Primary Carcinoid Tumor of the Urinary Bladder: A Case Report and Questionnaire Survey on the Reported Cases in Japan].

An 83-year-old man presented with asymptomatic macroscopic hematuria while being treated for prostate cancer with hormonal therapy in January 2009. Cystoscopy revealed a 5 mm surface-smooth non pedunculated tumor lateral to the left ureteral orifice. Transurethral resection was carried out to examine the histology of the tumor. Histopathologic examination revealed the tumor arranged in a pseudoglandular pattern covered with erosive urothelial cells. The tumor had inconspicuous nucleoli, and abundant eosinophilic cytoplasm. An immunohistochemical study showed the tumor cells were positively stained for chromogranin A, synaptophysin, CD56, and NSE. Ki67 index of the tumor was below 2 %, indicating that the tumor was a carcinoid tumor. He showed no carcinoid syndrome, and neither recurrence nor metastasis has been detected for 66 months.

[A Case of Tubercular Prostatic Abscess Following Intravesical Bacillus Calmette-Guerin Therapy].

We report a case of tubercular prostatic abscess. A 65-year-old man had undergone intravesical Bacillus Calmette-Guerin therapy for a non-muscle invasive bladder carcinoma. One year 8 months later, the prostate-specific antigen concentration in serum was elevated (18. 58 ng/ml). Results of magnetic resonance imaging (MRI) of the pelvis led us to suspect a prostatic abscess, and transurethral resection of the prostate for drainage was performed. A culture of fluid obtained from the latter procedure revealed a tubercular prostatic abscess. We administered the antituberculous agents, isoniazid (300 mg) and rifampicin(450 mg) daily, for 6 months. One year after surgery, the patient had no urinary symptoms or evidence of recurrence.

Living-donor kidney transplant from a type a donor to a type a subgroup recipient.

Type A subgroup is rare in Japan, and kidney transplant to a type A subgroup recipient is rare worldwide. A 65-year-old man presented for living-donor kidney transplant. Blood group testing showed that his wife (kidney donor) had blood group type A. The patient (recipient) had a type A subgroup because reverse blood grouping showed a weak reaction with A1 antigen. Further testing showed that the recipient had type A subgroup between Ax and Ael because adsorption elution experiments and flow cytometry showed a few A antigens that were not detected on forward grouping, and DNA analysis was not consistent with Ael. The patient was given a milder protocol for immunosuppressive preoperative therapy than typically used for ABO-incompatible kidney transplant; mycophenolate mofetil and prednisolone were started 3 weeks and cyclosporine 2 weeks before transplant, rituximab (100 mg) was given once, and double filtration plasmapheresis and plasma exchange were not used. Follow-up at 9 months after transplant showed stable clinical status and no allograft rejection. In summary, the present case showed that when type A subgroup recipient has low level of anti-A1 antibody and is receiving a kidney transplant from a blood type A donor, milder immunosuppressive preoperative therapy appears safe.

[Complete atrioventricular block due to cardiac metastasis from bladder cancer: case report].

A 72-year-old woman was diagnosed with bladder cancer (cT3bN0M0). After 2 cycles of GC (gemcitabine，cisplatin) neoadjuvant chemotherapy, the patient underwent a cystectomy and ileal conduit construction. Pathological findings showed urothelial carcinoma, high grade, G2＞G3, pT3a, INFß, ly0, v1. Six months after the operation, metastases to the liver, lung, left adrenal gland, rib, multiple lymph nodes, and peritoneum were revealed. Under palliative care, she suffered from palpitation and general fatigue. Electrocardiogram findings showed a complete atrioventricular block, while echocardiography and computed tomography revealed cardiac metastasis. We diagnosed her with complete atrioventricular block due to cardiac metastasis from bladder cancer. She died 7 days after onset of the complete atrioventricular block without use of a pacemaker.

[Posterior reversible encephalopathy syndrome (PRES) after kidney transplantation: a case report].

A 60-year-old woman with chronic renal failure due to a polycystic kidney underwent living kidney transplantation. Initial immunosuppressive therapy consisted of tacrolimus (TAC), mycophenolate mofetil (MMF), prednisolone, and basiliximab. Furthermore, rituximab was administered, and double filtration plasmapheresis and plasma exchange were utilized because of ABO-incompatible transplantation, while intravenous immune serum globulin (IVIG) was given because donor specific antibody was positive. Four days after the renal transplantation, the patient developed visual abnormalities, a headache, and paralysis. Then, he became unconscious. Magnetic resonance imaging of the brain demonstrated bilateral posterior vasogenic edema. Our diagnosis was posterior reversible encephalopathy syndrome due to TAC neurotoxicity. After converting TAC to reduced cyclosporine and everolimus, the symptoms rapidly disappeared.