Pathophysiology of Overactive Bladder and Pharmacologic Treatments Including β3-Adrenoceptor Agonists -Basic Research Perspectives- / 대한배뇨장애요실금학회지

Overactive bladder (OAB) is a symptom-based syndrome defined by urinary urgency, frequency, and nocturia with or without urge incontinence. The causative pathology is diverse; including bladder outlet obstruction (BOO), bladder ischemia, aging, metabolic syndrome, psychological stress, affective disorder, urinary microbiome, localized and systemic inflammatory responses, etc. Several hypotheses have been suggested as mechanisms of OAB generation; among them, neurogenic, myogenic, and urothelial mechanisms are well-known hypotheses. Also, a series of local signals called autonomous myogenic contraction, micromotion, or afferent noises, which can occur during bladder filling, may be induced by the leak of acetylcholine (ACh) or urothelial release of adenosine triphosphate (ATP). They can be transmitted to the central nervous system through afferent fibers to trigger coordinated urgency-related detrusor contractions. Antimuscarinics, commonly known to induce smooth muscle relaxation by competitive blockage of muscarinic receptors in the parasympathetic postganglionic nerve, have a minimal effect on detrusor contraction within therapeutic doses. In fact, they have a predominant role in preventing signals in the afferent nerve transmission process. β3-adrenergic receptor (AR) agonists inhibit afferent signals by predominant inhibition of mechanosensitive Aδ-fibers in the normal bladder. However, in pathologic conditions such as spinal cord injury, it seems to inhibit capsaicin-sensitive C-fibers. Particularly, mirabegron, a β3-agonist, prevents ACh release in the BOO-induced detrusor overactivity model by parasympathetic prejunctional mechanisms. A recent study also revealed that vibegron may have 2 mechanisms of action: inhibition of ACh from cholinergic efferent nerves in the detrusor and afferent inhibition via urothelial β3-AR.

High Prevalence of Dysplastic Development of Sacral Vertebral Arches in Pediatric Enuresis / 대한배뇨장애요실금학회지

Purpose@#This is the first report to compare 3-dimensional computed tomography (3D-CT) images between pediatric patients with enuresis and children without lower urinary tract symptoms who underwent pelvic CT for other reasons. @*Methods@#Forty-seven children (33 boys and 14 girls) with primary enuresis underwent 3D-CT of sacrococcygeal bones. The control group consisted of 138 children (78 boys and 60 girls) who underwent pelvic CT for other reasons. First, we determined the presence or absence of unfused sacral arches at the L4-S3 levels in both cohorts. Subsequently, we compared the fusion of sacral arches in age- and sex-matched children from these 2 groups. @*Results@#Dysplastic sacral arches, characterized by lack of fusion at 1 or more levels of the S1–3 arches, were observed in nearly all patients in the enuresis group. In the control group (n=138), 54 of 79 children over 10 years old (68%) exhibited fused sacral arches at 3 S1–3 levels. All 11 control children under 4 years old displayed at least 2 unfused sacral arches at the S1–3 levels. In a comparative study of age- and sex-matched patients with enuresis and control children aged 5 to 13 years (n=32 for each group, with 21 boys and 11 girls; mean age, 8.0±2.2 years [range, 5–13 years]), only 1 patient (3%) in the enuresis group exhibited fusion of all S1–3 arches. In contrast, 20 of 32 control group participants (63%) had 3 fused sacral arches (P<0.0001). @*Conclusions@#Sacral vertebral arches typically fuse by the age of 10 years. However, in this study, children with enuresis exhibited a significantly elevated prevalence of unfused sacral arches, suggesting that dysplastic development of sacral vertebral arches may play a pathological role in enuresis.

Reduction of Bladder Capacity Under Anesthesia Following Multiple Recurrences and Repeated Surgeries of Hunner Lesions in Patients With Interstitial Cystitis / 대한배뇨장애요실금학회지

Purpose@#To investigate the influence of multiple recurrences and repeated surgeries of Hunner lesions on bladder capacity under general anesthesia in patients with interstitial cystitis (IC). @*Methods@#We retrospectively reviewed the clinical records of Hunner-type IC (HIC) patients who underwent transurethral fulguration or resection of Hunner lesions combined with hydrodistension by a single surgeon between 2011 and 2020. Recurrence was defined as reappearance of uncontrolled urinary symptoms in association with new Hunner lesions identified by cystoscopy. Recurrent Hunner lesions were then treated by transurethral surgeries. The recurrence-free rate, potential predictive factors of recurrence, and changes in bladder capacity under anesthesia were examined at each surgical procedure. @*Results@#A total of 92 surgeries were performed in 47 HIC patients, 23 (49%) of whom required multiple procedures (range, 1–5 times). The mean recurrence-free time after the first surgery was 21.7 months. The recurrence-free rate was 53% at 24 months, and decreased to 32% at 48 months. There were no significant differences in age, sex, bladder capacity under anesthesia at the first surgery, duration from symptom onset to the first surgery, O’Leary-Sant questionnaire including symptom and problem indexes, visual analogue scale pain score, and the number of comorbidities between the cases with or without recurrence. Bladder capacity under anesthesia was gradually decreased as the number of surgeries was increased, and bladder capacity at the fourth procedure was significantly decreased to 80% of the capacity at the first surgery. @*Conclusions@#These results suggest that multiple recurrences and repeated surgeries of Hunner lesions result in a reduction of bladder capacity under anesthesia in HIC patients although no predictive factors for recurrence of Hunner lesions were detected.

Current Understanding and Future Perspectives of Interstitial Cystitis/Bladder Pain Syndrome / 대한배뇨장애요실금학회지

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic disease characterized by suprapubic pain and lower urinary tract symptoms. Perhaps because of the heterogeneous nature of this disease and its multifactorial etiology, clinical trials in allinclusive populations of IC/BPS patients without phenotyping in the last decade have mainly failed to discover new therapeutic modalities of IC/BPS. Thus, phenotyping IC/BPS, aimed at identifying bladder-centric and/or bladder-beyond pathologies, including cystoscopic observation of Hunner or non-Hunner lesions of the bladder mucosa, is particularly important for the future of IC/BPS management. Based on recent discussions at international conferences, including the International Consultation on IC, Japan, it has been proposed that Hunner-lesion IC should be separated from other non-Hunner IC/BPS because of its distinct inflammatory profiles and epithelial denudation compared with non-Hunner IC/BPS. However, there are still no standard criteria for the diagnosis of Hunner lesions other than typical lesions, while conventional cystoscopic observations may miss atypical or small Hunner lesions. Furthermore, diagnosis of the bladder-centric phenotype of IC/BPS requires confirmation that identified mucosal lesions are truly a cause of bladder pain in IC/BPS patients. This review article discusses the current status of IC/BPS pathophysiology and diagnosis, as well as future directions of the proper diagnosis of bladder-centric IC/BPS, in which pathophysiological mechanisms other than those in inflammatory pathways, such as angiogenic and immunogenic abnormalities, could also be involved in both Hunner-lesion IC and non-Hunner IC/BPS. It is hoped that this new paradigm in the pathophysiological evaluation and diagnosis of IC/BPS could lead to pathology-based phenotyping and new treatments for this heterogeneous disease.

Current Understanding and Future Perspectives of Interstitial Cystitis/Bladder Pain Syndrome / 대한배뇨장애요실금학회지

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic disease characterized by suprapubic pain and lower urinary tract symptoms. Perhaps because of the heterogeneous nature of this disease and its multifactorial etiology, clinical trials in allinclusive populations of IC/BPS patients without phenotyping in the last decade have mainly failed to discover new therapeutic modalities of IC/BPS. Thus, phenotyping IC/BPS, aimed at identifying bladder-centric and/or bladder-beyond pathologies, including cystoscopic observation of Hunner or non-Hunner lesions of the bladder mucosa, is particularly important for the future of IC/BPS management. Based on recent discussions at international conferences, including the International Consultation on IC, Japan, it has been proposed that Hunner-lesion IC should be separated from other non-Hunner IC/BPS because of its distinct inflammatory profiles and epithelial denudation compared with non-Hunner IC/BPS. However, there are still no standard criteria for the diagnosis of Hunner lesions other than typical lesions, while conventional cystoscopic observations may miss atypical or small Hunner lesions. Furthermore, diagnosis of the bladder-centric phenotype of IC/BPS requires confirmation that identified mucosal lesions are truly a cause of bladder pain in IC/BPS patients. This review article discusses the current status of IC/BPS pathophysiology and diagnosis, as well as future directions of the proper diagnosis of bladder-centric IC/BPS, in which pathophysiological mechanisms other than those in inflammatory pathways, such as angiogenic and immunogenic abnormalities, could also be involved in both Hunner-lesion IC and non-Hunner IC/BPS. It is hoped that this new paradigm in the pathophysiological evaluation and diagnosis of IC/BPS could lead to pathology-based phenotyping and new treatments for this heterogeneous disease.

Time-Dependent Changes of Urethral Function in Diabetes Mellitus: A Review / 대한배뇨장애요실금학회지

This article reviewed the current knowledge on time-course manifestation of diabetic urethral dysfunction (DUD), and explored an early intervention target to prevent the contribution of DUD to the progression of diabetes-induced impairment of the lower urinary tract (LUT). In the literature search through PubMed, key words used included “diabetes mellitus,” “diabetic urethral dysfunction,” and “diabetic urethropathy.” Polyuria and hyperglycemia induced by diabetes mellitus (DM) can cause the time-dependent changes in functional and morphological manifestations of DUD. In the early stage, it promotes urethral dysfunction characterized by increased urethral pressure during micturition. However, the detrusor muscle of the bladder tries to compensate for inducing complete voiding by increasing the duration and amplitude of bladder contractions. As the disease progresses, it can induce an impairment of coordinated micturition due to dyssynergic activity of external urethra sphincter, leading to detrusor-sphincter dyssynergia. The impairment of relaxation mechanisms of urethral smooth muscles (USMs) may additionally be attributable to decreased responsiveness to nitric oxide, as well as increased USM responsiveness to α1-adrenergic receptor stimulation. In the late stage, diabetic neuropathy may play an important role in inducing LUT dysfunction, showing that the decompensation of the bladder and urethra, which can cause the decrease of voiding efficiency and the reduced thickness of the urothelium and the atrophy of striated muscle bundles, possibly leading to the vicious cycle of the LUT dysfunction. Further studies to increase our understandings of the functional and molecular mechanisms of DUD are warranted to explore potential targets for therapeutic intervention of DM-induced LUT dysfunction.

Predicting outcomes to optimize disease management in inflammatory bowel disease in Japan: their differences and similarities to Western countries

Inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), is a chronic inflammatory disease of the gastrointestinal tract, with increasing prevalence worldwide. IBD Ahead is an international educational program that aims to explore questions commonly raised by clinicians about various areas of IBD care and to consolidate available published evidence and expert opinion into a consensus for the optimization of IBD management. Given differences in the epidemiology, clinical and genetic characteristics, management, and prognosis of IBD between patients in Japan and the rest of the world, this statement was formulated as the result of literature reviews and discussions among Japanese experts as part of the IBD Ahead program to consolidate statements of factors for disease prognosis in IBD. Evidence levels were assigned to summary statements in the following categories: disease progression in CD and UC; surgery, hospitalization, intestinal failure, and permanent stoma in CD; acute severe UC; colectomy in UC; and colorectal carcinoma and dysplasia in IBD. The goal is that this statement can aid in the optimization of the treatment strategy for Japanese patients with IBD and help identify high-risk patients that require early intervention, to provide a better long-term prognosis in these patients.

A Surgical Case of Right Coronary Ostial Stenosis, Aortic Regurgitation, and Annuloaortic Ectasia Associated with Syphilitic Aortitis / 日本心臓血管外科学会雑誌

<p>We report a case of syphilitic aortitis (SA) associated with severe right coronary ostial stenosis, aortic regurgitation (AR), and annuloaortic ectasia (AAE). A 48-year-old man presented to a regional hospital with easy fatigability and nocturnal dyspnea. Echocardiography revealed Seller's grade 3 AR. A computed tomography scan showed AAE, dilatation of the ascending aorta, and calcification of both coronary ostia. Coronary angiography demonstrated that the left coronary artery was intact ; however, the right coronary artery was obscure. Active syphilis was detected on routine blood tests on admission. Therefore, the patient was started on a course of ampicillin/sulbactam (ABPC/SBT). Subsequently, he underwent the Bentall procedure and coronary artery bypass grafting with the right internal thoracic artery. The intraoperative findings showed degeneration of the aorta and severe right coronary ostial stenosis. The pathological findings of the aortic wall and aortic valve were consistent with SA. The postoperative course was uneventful. The patient continued receiving ABPC/SBT for 3 weeks postoperatively, and was then switched to oral amoxicillin.</p>

Off-Pump Coronary Artery Bypass Graft in a Patient with Congenital Factor V Deficiency and Hereditary Spherocytosis Complicated with Stage 4 Diabetic Nephropathy / 日本心臓血管外科学会雑誌

<p>A 64-year-old man with congenital factor V deficiency and hereditary spherocytosis was attending our hospital for type II diabetes and stage 4 diabetic nephropathy. Coronary angiography performed to assess chest pain revealed severe triple-vessel disease, including total occlusion of the right coronary artery. The patient required surgical coronary revascularization. In the preoperative examination, the activated partial thromboplastin time (APTT) and prothrombin time-international normalized ratio (PT-INR) were high (89.5 s and 1.95) and factor V activity was low (6% ; normal range, 70-135%). Hemodialysis was performed on the day of the operation, and 6 units of fresh frozen plasma (FFP) were administered, which reduced immediately the preoperative PT-INR to 1.33. We performed off-pump coronary artery bypass grafting (OPCAB) and perioperatively administered 6 units of FFP with 4 units of red blood cells (RBC) transfusion. The postoperative course of the patient was uneventful, and he was discharged on postoperative day 22. Here we report the case of a patient with a very rare disease of congenital factor V deficiency and hereditary spherocytosis complicated with stage 4 diabetic nephropathy who required OPCAB.</p>

Pregnancy outcome in women with inflammatory bowel disease treated with anti-tumor necrosis factor and/or thiopurine therapy: a multicenter study from Japan

BACKGROUND/AIMS: Anti-tumor necrosis factor drugs (anti-TNF) and thiopurines are important treatment options in patients with inflammatory bowel disease (IBD), including during pregnancy. However, there are limited data on the benefit/risk profile of anti-TNF and thiopurines during pregnancy in Asia. The aim of this study was to analyze pregnancy outcomes of female Japanese IBD patients treated with anti-TNF and/or thiopurines. METHODS: This cross-sectional study assessed pregnancy outcomes in 72 women with IBD. Pregnancy outcomes were compared among 31 pregnancies without exposure to infliximab (IFX), adalimumab (ADA), or thiopurines; 24 pregnancies with exposure to anti-TNF treatment (23 IFX, 1 ADA); 7 pregnancies with exposure to thiopurines alone; and 10 pregnancies with exposure to both IFX and thiopurines. RESULTS: Thirty-five of the 41 pregnancies (85.3%) that were exposed to anti-TNF treatment and/or thiopurines resulted in live births after a median gestational period of 38 weeks. Of the 35 live births, 3 involved premature deliveries; 7, low birth weight; and 1, a congenital abnormality. There were 6 spontaneous abortions in pregnancies that were exposed to anti-TNF treatment (17.7%). Pregnancy outcomes among the 4 groups were similar, except for the rate of spontaneous abortions (P =0.037). CONCLUSIONS: Exposure to anti-TNF treatment or thiopurines during pregnancy was not related to a higher incidence of adverse pregnancy outcomes in Japanese IBD patients except for spontaneous abortion.

Neural Mechanisms Underlying Lower Urinary Tract Dysfunction

This article summarizes anatomical, neurophysiological, and pharmacological studies in humans and animals to provide insights into the neural circuitry and neurotransmitter mechanisms controlling the lower urinary tract and alterations in these mechanisms in lower urinary tract dysfunction. The functions of the lower urinary tract, to store and periodically release urine, are dependent on the activity of smooth and striated muscles in the bladder, urethra, and external urethral sphincter. During urine storage, the outlet is closed and the bladder smooth muscle is quiescent. When bladder volume reaches the micturition threshold, activation of a micturition center in the dorsolateral pons (the pontine micturition center) induces a bladder contraction and a reciprocal relaxation of the urethra, leading to bladder emptying. During voiding, sacral parasympathetic (pelvic) nerves provide an excitatory input (cholinergic and purinergic) to the bladder and inhibitory input (nitrergic) to the urethra. These peripheral systems are integrated by excitatory and inhibitory regulation at the levels of the spinal cord and the brain. Therefore, injury or diseases of the nervous system, as well as disorders of the peripheral organs, can produce lower urinary tract dysfunction, leading to lower urinary tract symptoms, including both storage and voiding symptoms, and pelvic pain. Neuroplasticity underlying pathological changes in lower urinary tract function is discussed.

Liver Fibrosis Markers Reflect the Quality of Fontan Circulation / 日本心臓血管外科学会雑誌

<b>Background</b> : Several studies have shown that Fontan circulation may lead to liver congestion and possible structural liver alteration. The aim of this study is to analyze the relationships between biochemical fibrosis markers and hemodynamic parameters in the long term after the Fontan operation.<br><b>Methods</b> : The study enrolled 51 patients who underwent total cavopulmonary connection between March 1994 and July 2010. We analyzed the relationships between the 5 liver fibrosis markers (hyaluronic acid, retinol-binding protein, procollagen type III peptide, type IV collagen 7S, type IV collagen) and the 6 hemodynamic parameters (pulmonary artery pressure, pulmonary artery index, pulmonary vascular resistance, ejection fraction, atrioventricular valve regurgitation, cardiac index).<br><b>Results</b> : Hyaluronic acid and type IV collagen 7S positively correlated with pulmonary artery pressure. Hyaluronic acid negatively correlated with ejection fraction, and type IV collagen 7S positively correlated with atrioventricular valve regurgitation in patients followed up for more than 8 years after Fontan completion. Pulmonary artery pressure was significantly higher in patients in whom type IV collagen 7S was elevated. Hyaluronic acid correlated with pulmonary vascular resistance (<i>p</i>=0.0035) and ejection fraction (<i>p</i>=0.014), as well as type IV collagen 7S with pulmonary artery pressure (<i>p</i>=0.0001) by multiple regression analysis.<br><b>Conclusion</b> : Hyaluronic acid and type IV collagen 7S reflected the degree of hepatic congestion, and cardiac function, in the long term after the Fontan operation.

Ross Operation for a Case of Secondary Aortic Regurgitation due to Infective Endocarditis / 日本心臓血管外科学会雑誌

A 6-year-old boy was admitted with infective endocarditis and aortic regurgitation. Clinical signs of infection were severe. The leukocyte count was 13, 100/μl and the C-reactive protein (CRP) was elevated to 17.2mg/dl. Blood culture was positive for <i>Staphylococcus aureus</i>. Echocardiography showed a vegetation 3mm in diameter on the aortic valve, and a perforation of the right coronary cusp with moderate aortic regurgitation. With antibiotic therapy, clinical signs and laboratory data of infection improved at an early stage. We decided to operate after his complete recovery from infection. Laboratory data normalized completely in 6 weeks, but echocardiography demonstrated aneurysmal change of the right coronary sinus and severe aortic regurgitation. The Ross operation was performed on the 44th day. At operation, it was noted that the non-coronary cusp was destroyed completely leaving only strings of fibrous tissue. A perforation of 3mm in diameter was also found on the right coronary cusp. There was a mural aneurysm near the right coronary orifice without abscess formation in the surrounding structure. A pulmonary autograft was transplanted to the aortic root after resection of the destroyed aortic cusps, aortic root and the mural aneurysm. The right ventricular outflow tract was reconstructed using an autologous pericardium as a posterior wall and the Monocusp ventricular outflow patch (MVOP) #22 as an anterior transannular patch. The postoperative course was uneventful. Postoperative echocardiography revealed no aortic regurgitation.

A Case of Right Atrial Thrombus and Left Pulmonary Embolus after the Bjork Procedure / 日本心臓血管外科学会雑誌

A 5-year-old boy with tricuspid atresia who underwent the Björk procedure died due to right atrial thrombus and left pulmonary embolus 37 days after operation. It is suggested that thromboembolism may be a frequent complication after the Björk procedure due to the turbulent blood flow at the right atrio-ventricular anastomosis and also due to congestive blood flow. Anticoagulation therapy seems to be essential for postoperative management.

Successful Surgical Treatment by Intraoperative Radiofrequency Current Ablation for Atrial Flutter with ASD and PS / 日本心臓血管外科学会雑誌

Drug refractory atrial flutter (AF) with secundum atrial septal defect (ASD) and pulmonary valvular stenosis was treated by surgical correction and intraoperative radiofrequency (RF) current ablation. Supraventricular arrhythmia, especially AF, is frequently found in aged patients with ASD. Perioperative managements for this arrhythmia were difficult because of drug refractoriness. We performed this ablation combined with intracardiac corrections, and sinus rhythm has been maintained without any drugs for 18 months. This case indicated that RF current ablation during open-heart surgery is useful and safe method of treatment of AF.

Abdominal Aortic Aneurysm Complicated with Chronic Consumption Coagulopathy / 日本心臓血管外科学会雑誌

We report an unusual case of a 71 year-old man who developed chronic consumption coagulopathy caused by an abdominal aortic aneurysm. He was diagnosed as having the dissecting aortic aneurysm (DeBakey type IIIa) and the abdominal aortic aneurysm in 1989, and had been attending to our hospital as an outpatient since then. He developed macrohematuria in March 1990. The laboratory data showed the decrease in platelet, fibrinogen, plasminogen and α₂ plasmin inhibitor and the increase in FDP. The bleeding tendency was controlled by the administration of gabexate mesilate and heparin, but the laboratory data revealed that consumption coagulopathy continued. The abdominal aortic aneurysm was successfully replaced with a prosthetic vascular graft in June 1992. Postoperative hematological findings revealed the improvement, and he discharged 32nd day and doing well after operation.

Clinical Evaluation of Delayed Sternal Closure following Open Heart Surgery in Neonates and Infants / 日本心臓血管外科学会雑誌

The cases of neonates and infants who underwent successful delayed sternal closure (DSC) using silastic rubber after open heart surgery were reviewed. The indication for DSC was cardiac dilatation with tamponade-like behavior upon attempted sternal closure in all. In 7 of 10 cases, DSC were possible within 4 days after operation. There were statistical decrease in heart rate (HR), left atrial pressure (LAP), cardiothoracic ratio (CTR) and inspiratory oxygen concentration of the respirator at the time of DSC compared to those in the early postoperative period. None of the patients had mediastinitis or other severe infection in the postoperative course. One patient each died of progressive pulmonary venous obstruction and of non-cardiac disease late postoperatively and 8 patients are long-term survivors. It is concluded that DSC is recommended whenever there is any hemodynamic deterioration due to attempted sternal closure following open heart surgery in infancy as it could be safely performed within 3 to 4 days after operation without any complication.