Association of detrusor underactivity with aging and metabolic syndrome: suggestions from animal models.

Detrusor underactivity, a condition in which the bladder muscle does not contract strongly or long enough to empty the bladder completely or within the normal time frame, is a common cause of lower urinary tract symptoms in older individuals of both sexes. Although aging is a known risk factor for detrusor underactivity, its pathophysiological mechanisms are not fully understood. Therefore, establishing animal models that closely mimic the pathophysiology of detrusor underactivity in humans is necessary to elucidate these mechanisms. Metabolic syndrome is a cluster of several risk factors, including obesity, hyperlipidemia, hyperglycemia, and hypertension, which are associated with the development of diabetes, cardiovascular disease, and lower urinary tract dysfunction in both sexes. Notably, bladder dysfunction resulting from detrusor underactivity is observed at an earlier age in animal models with diabetes mellitus than in those without. Recently, detrusor underactivity-like phenotypes have been observed at a relatively early age in animal models with metabolic syndrome, involving obesity, hyperlipidemia, and hypertension, compared with those without. Therefore, this review introduces the association of detrusor underactivity with aging and metabolic syndrome, as well as possible pathophysiological mechanisms for detrusor underactivity from reports of various animal models. Notably, metabolic syndrome may accelerate the onset of age-related detrusor underactivity, and further analysis of old animal models with metabolic syndrome may help elucidate the pathogenesis of detrusor underactivity in humans.

One-stage versus two-stage endoscopic management for acute cholangitis caused by common bile duct stones: A retrospective multicenter cohort study.

BACKGROUND: One-stage endoscopic management, where papillary interventions and stone removal are simultaneously performed, has been reported to be an effective treatment for acute cholangitis caused by common bile duct stones (CBDS). However, there have been few reports comparing it with two-stage management, and there is no established strategy for the indication of one-stage management. The aim of the present study was to compare the short- and long-term outcomes between one- and two-stage management for acute cholangitis caused by CBDS. METHODS: We retrospectively studied 577 patients who underwent one- or two-stage endoscopic management for acute cholangitis between May 2010 and December 2020. The patients were divided into one- and two-stage groups by endoscopic management. The clinical outcomes were compared between groups. RESULTS: The technical and clinical success were similar in both groups, although the length of hospital stay was significantly shorter in the one-stage group. Although there was no difference in the early adverse event (AE) between two groups, post-ERCP pancreatitis was recognized in 3.4% and 10.0%, which was significantly higher in the two-stage group. The cumulative late AE rate was 22.6% and 14.1%, which was significantly higher in the one-stage group. In the multivariate analyses, intervention (one-stage), number of CBDS ≥2, biliary drainage, the use of ML, and gallbladder stone were identified as significant factors associated with the recurrence of CBDS. CONCLUSION: Although one-stage endoscopic management is useful and safe with reducing hospital stays, diligent postoperative follow-up with consideration to recurrence of CBDS is essential.

Insights into the associative role of hypertension and angiotensin II receptor in lower urinary tract dysfunction.

In men, the lower urinary tract comprises the urinary bladder, urethra, and prostate, and its primary functions include urine storage and voiding. Hypertension is a condition that causes multi-organ damage and an age-dependent condition. Hypertension and the renin-angiotensin system activation are associated with the development of lower urinary tract dysfunction. Hypertensive animal models show bladder dysfunction, urethral dysfunction, and prostatic hyperplasia. In the renin-angiotensin system, angiotensin II and the angiotensin II type 1 receptor, which are expressed in the lower urinary tract, have been implicated in the pathogenesis of lower urinary tract dysfunction. Moreover, among the several antihypertensives, renin-angiotensin system inhibitors have proven effective in human and animal models of lower urinary tract dysfunction. This review aimed to elucidate the hitherto known mechanisms underlying the development of lower urinary tract dysfunction in relation to hypertension and the angiotensin II/angiotensin II type 1 receptor axis and the effect of renin-angiotensin system inhibitors on lower urinary tract dysfunction. Possible mechanisms through which hypertension or activation of Ang II/AT1 receptor axis causes LUTD such as bladder dysfunction, urethral dysfunction, and prostatic hyperplasia. LUT: lower urinary tract, LUTD: lower urinary tract dysfunction, AT1: angiotensin II type 1, ACE: angiotensin-converting enzyme.

Cyanoacrylate closure for arteriovenous fistula in the lower extremity with saphenous vein insufficiency.

A lower extremity arteriovenous fistula (AVF) is sometimes associated with venous disease following venous hypertension, especially when the saphenous vein is the main return route. This can cause venous dilation, leading to valve insufficiency. A complete cure can be difficult in cases with multiple vascular branches. We report three surgical cases of lower extremity AVF with saphenous vein insufficiency. All patients had saphenous vein insufficiency with long duration leg symptoms and underwent full-length occlusion of saphenous vein using cyanoacrylate closure. Substantial improvements in leg symptoms and appearance were observed immediately after surgery in all three patients. Cyanoacrylate closure could be a treatment option for lower extremity AVF.

[Drug therapy targeting angiotensin II type 1 receptors in brain against frequent urination].

The production of angiotensin II (Ang II) in the brain plays important roles as neurotransmitter and neuropeptide. Central Ang II is involved in regulating various physiological processes, such as blood pressure and water homeostasis, via Ang II type 1 (AT1) receptors. We have demonstrated that Ang II induces frequent urination via AT1 receptors in the brain even at doses that does not seem to affect the blood pressure in animal experiment. Intracerebroventricular administration of Ang II was also found to reduce the bladder capacity without affecting the maximum voiding pressure, post voiding residual urine volume or voiding efficiency. Additionally, the activation of AT1 receptor downstream signal pathway (phospholipase C/protein kinase C/NADPH oxidase/superoxide anion) and suppression of GABAergic nervous system in the brain are involved in the mechanism underlying the central Ang II-inducted frequent urination. AT1 receptor blockers (ARBs) have been widely used to treat hypertension. We demonstrated that peripherally administered ARBs telmisartan, which can penetrate blood-brain barrier, exerted an inhibitory effect on central Ang II-inducted frequent urination. We present the possible drug therapy targeting AT1 receptors in the brain against frequent urination on the results obtained from our recent research work.

Therapeutic targets in the brain for overactive bladder: A focus on angiotensin II type 1 receptor.

Overactive bladder is a condition that affects both men and women, and significantly affects patients' quality of life. Anticholinergics, ß3-adrenoceptor agonists, and botulinum toxin are currently being used for treatment. However, several patients do not respond to these medications or discontinue them because of adverse events. Angiotensin II (Ang II) is a neuropeptide produced in both brain and peripheral tissues, and Ang II type 1 (AT1) receptors, which are important regions for the micturition reflex, are widely expressed in the cerebral cortex, paraventricular nucleus, solitary tract nucleus, and periaqueductal gray. Our data showed that cumulative central Ang II administration, even at low doses, shortened the intercontraction interval without affecting the blood pressure or blood catecholamine levels. Additionally, Ang II can enhance the micturition reflex by suppressing the GABAergic nervous system and stimulating the downstream pathway of the AT1 receptor. The peripherally administered AT1 receptor blocker telmisartan inhibited central Ang II-induced facilitation of the micturition reflex. Targeting the central AT1 receptor may be a potential treatment approach for patients with overactive bladder. This review introduces the brain AT1 receptor as a therapeutic target in overactive bladder.

Endoscopic internalization by cutting versus removal of the endoscopic transpapillary naso-gallbladder drainage tube in preoperative management of acute cholecystitis: A retrospective multicenter cohort study.

BACKGROUND: Endoscopic transpapillary naso-gallbladder drainage (ENGBD) has been reported to be an effective treatment option for acute cholecystitis. At our institution, ENGBD was first placed for external fistula management, and endoscopic internalization by cutting was performed, shifting to endoscopic transpapillary gallbladder stenting (EGBS) after improvement of cholecystitis. However, there has been no comparative study to define which preoperative management is better: converting ENGBD to EGBS or removing ENGBD. The study aimed to compare the incidence rate of the late adverse events (AEs) related to biliary system between shifting from ENGBD to EGBS and removal of ENGBD. METHODS: We retrospectively studied 122 patients who underwent ENGBD for acute cholecystitis between January 2010 and October 2022. The patients were divided into two groups: the cutting group (converting ENGBD to EGBS) and the removal group (removal of ENGBD). The short and late clinical outcomes were compared between groups. RESULTS: Endoscopic transpapillary naso-gallbladder drainage was successfully placed in 78.6% (96/122), and elective cholecystectomy was performed in 31 and 36 patients in the cutting and removal groups, respectively. The cumulative late-AE rates were 6.4% and 33.3% (p = .007), with a median waiting period for elective cholecystectomy of 58 and 33 days (p = .390) in the cutting and removal groups, respectively. In the multivariate analysis, only endoscopic internalization by cutting was an independent factor affecting late AEs. CONCLUSION: Endoscopic internalization by cutting ENGBD after the resolution of acute cholecystitis was considered effective in reducing the risk of late AEs during the waiting period for an elective cholecystectomy.

Cell-free and concentrated ascites reinfusion therapy versus large-volume paracentesis for the treatment of cirrhotic patients with refractory ascites: A multicenter prospective observational study.

AIM: Cell-free and concentrated ascites reinfusion therapy (CART) and large-volume paracentesis (LVP) with albumin infusion are useful for managing refractory ascites (RA). However, it remains unclear which therapy is more effective in patients with cirrhosis with RA. METHODS: From June 2018 to March 2022, 25 patients with RA treated with CART or LVP with albumin infusion were enrolled in this multicenter prospective observational study to investigate the number of abdominal paracenteses, albumin preparations used, and drainage volume during an 8-week observation period. RESULTS: Among all patients at entry (median age, 63 years; 52% men; 60% Child-Pugh B and 40% Child-Pugh C), 92% were treated with furosemide (median, 20 mg/day), 92% with spironolactone (25 mg/day), and all with tolvaptan (7.5 mg/day). Patients with RA had a poor health-related quality of life (HRQOL) and prominent ascites-related symptoms. Four of the 20 eligible patients were treated with CART, 11 with LVP with albumin infusion, and five with their combination. The median number of paracenteses, total drainage volume, and albumin infusions were 1.5, 7.4 L, and 0, respectively, in the CART group; 5.0, 22.0 L, and 5.0, respectively, in the LVP group; and 5.0, 30.0 L, and 5.0, respectively in their combination group. The treatment effects did not differ significantly among the three groups regarding weight loss, liver function, renal function, electrolytes, and HRQOL. However, patients treated with CART had fewer paracenteses and albumin infusions than those treated with LVP. CONCLUSIONS: CART and LVP have comparable therapeutic efficacy for RA in patients with cirrhosis.

Endoscopic Transpapillary Gallbladder Drainage for Recurrent Cholecystitis after Covered Self-expandable Metal Stent Placement for Unresectable Malignant Biliary Obstruction.

A 76-year-old woman with advanced pancreatic cancer developed recurrent cholecystitis after covered self-expandable metal stent (CSEMS) placement. The cholecystitis was refractory to repeated percutaneous transhepatic gallbladder drainage (PTGBD). Cholecystography showed a patent cystic duct with right and cranial side bifurcation, which is indicative of an increased likelihood of success of endoscopic transpapillary gallbladder drainage (ETGBD). We were able to manage the cholecystitis by ETGBD without further recurrence. ETGBD is considered an effective internal drainage method for the management of acute cholecystitis after CSEMS placement, and its indication may be decided on the basis of the findings of cholecystography through the PTGBD route.

Effects of Rifaximin on Circulating Albumin Structures and Serum Ammonia Levels in Patients with Liver Cirrhosis: A Preliminary Study.

Circulating albumin structures, including their oxidized and reduced forms, are involved in hepatic encephalopathy (HE) development. However, the effects of rifaximin, a key drug in HE treatment, on the circulating albumin structure in patients with liver cirrhosis remain unclear. In this multicenter prospective study, eight patients with hyperammonemia (≥80 µg/dL) were enrolled. The circulating albumin structure was evaluated using the ratio of oxidized albumin (human nonmercaptalbumin, HNA). Patients were administered 400 mg rifaximin 3 times/day for 3 months, and laboratory data were assessed at baseline and during observation. Among the eight patients, three were men; the median age and body mass index were 70 years and 26.4 kg/m2, respectively. The median HNA and serum ammonia levels at baseline were 41% and 143 µg/dL, respectively. After rifaximin therapy, HNA showed a decreasing tendency (median; from 41% to 36%, p = 0.321), but serum albumin levels showed no significant change (from 3.5 g/dL to 3.5 g/dL, p = 1.00); serum ammonia levels significantly reduced (median: 143 µg/dL to 76 µg/dL, p = 0.015). Thus, rifaximin reduces serum ammonia levels and may improve circulating albumin structure in patients with cirrhosis. Further large-scale studies are required to confirm these preliminary results.

Endoscopic Internalization by Cutting the Endoscopic Transpapillary Nasogallbladder Drainage Tube in Management of Acute Cholecystitis: A Retrospective Multicenter Cohort Study.

BACKGROUND: Both endoscopic nasogallbladder drainage (ENGBD) and endoscopic gallbladder stenting (EGBS) are effective management for acute cholecystitis, although ENGBD can cause discomfort due to its nature of external drainage. Converting ENGBD to EGBS after improvement of cholecystitis might be one treatment strategy. The drainage tube of ENGBD could be endoscopically cut inside the stomach to convert to internal drainage without additional endoscopic retrograde cholangiography (ERCP). AIMS: To evaluate the feasibility, efficacy and safety of endoscopic internalization by cutting an ENGBD tube for acute cholecystitis. METHODS: Twenty-one patients who underwent endoscopic internalization by cutting the ENGBD tube were enrolled in this study. We initially placed an ENGBD tube for gallbladder lavage and continuous drainage. After improvement of cholecystitis, the tube was cut in the stomach by esophagogastroduodenoscopy (EGD) and placed as EGBS until surgery. RESULTS: The technical success rate of this procedure was 90.5% (19/21), and the clinical success rate was 100% (19/19). The median procedural time was 5 min (range: 2-14 min). Procedural-related adverse events (AEs) were observed in two patients where the tip of the ENGBD tube migrated into the common bile duct from the gallbladder during the procedure in both. During the waiting period for elective surgery, no AEs were identified, except for stent migration without symptoms in one patient (4.7%). CONCLUSION: Endoscopic internalization by cutting the ENGBD tube after improvement of cholecystitis could be an effective and safe treatment option for preventing recurrent cholecystitis in the waiting period until cholecystectomy.

Changes in ALBI Score and PIVKA-II within Three Months after Commencing Atezolizumab Plus Bevacizumab Treatment Affect Overall Survival in Patients with Unresectable Hepatocellular Carcinoma.

In this study, we aimed to evaluate the efficacy and safety of atezolizumab plus bevacizumab (Atez/Bev) treatment for unresectable hepatocellular carcinoma (HCC) and to analyze the factors affecting overall survival (OS). A total of 69 patients who received Atez/Bev at our institutions for unresectable HCC were enrolled in this study. OS and progression-free survival (PFS) were estimated using the Kaplan−Meier method. Changes in clinical indicators within 3 months were defined as delta (∆) values, and the Cox proportional hazards model was used to identify which ∆ values affected OS. The median OS, PFS, objective response rate, and disease control rate were 12.5 months, 5.4 months, 23.8%, and 71.4%, respectively. During the observational period, 62 patients (92.5%) experienced AEs (hypertension (33.3%) and general fatigue), and 27 patients (47.4%) experienced grade ≥ 3 AEs (hypertension (10.1%) and anemia (7.2%)). There was a significant deterioration in the albumin-bilirubin (ALBI) score (−2.22 to −1.97; p < 0.001), and a reduction in PIVKA-II levels (32,458 to 11,584 mAU/mL; p = 0.040) within 3 months after commencing Atez/Bev. Both the worsening ∆ ALBI score (p = 0.005) and increasing ∆ PIVKA-II (p = 0.049) were significantly associated with the OS of patients.

Protective effects of hydrogen sulfide pretreatment on cyclophosphamide-induced bladder dysfunction in rats via suppression of bladder afferent nerves.

Cyclophosphamide (CYP), a broad-spectrum anticancer drug, causes serious side effects, such as haemorrhagic cystitis (HC). Hydrogen sulfide (H2S), an endogenous gasotransmitter, has physiological properties, including anti-inflammation, anti-oxidation, and neuromodulation. In this study, we investigated the effects of NaHS (H2S donor) pretreatment on bladder dysfunction in CYP-treated rats. Male Wistar rats were intraperitoneally pretreated with NaHS (3 or 10 µmol/kg) or vehicle once daily for 7 days before cystometry, and CYP (150 mg/kg) or saline was intraperitoneally administered 2 days before cystometry. After cystometry, the bladder tissues were collected for haematoxylin and eosin staining. In some rats, capsaicin (CAP), which can desensitise CAP-sensitive afferent nerves, was subcutaneously injected at 125 mg/kg 4 days before cystometry. CYP reduced intercontraction intervals (ICI) and bladder compliance (Comp) and increased the number of non-voiding contractions (NVCs) compared with the saline-treated control group. NaHS pretreatment dose-dependently improved the CYP-induced these changes. In bladder tissues, CYP increased histological scores of neutrophil infiltration, haemorrhage, and oedema, while NaHS had no effect on these CYP-induced changes. CAP showed a tendency to suppress CYP-induced changes in ICI. NaHS-induced improvement in CYP-induced changes in urodynamic parameters were not detected in CAP-treated rats. These findings suggest that NaHS pretreatment prevented bladder dysfunction in CYP-treated rats by suppressing CAP-sensitive bladder afferent nerves, but not by suppressing bladder inflammation. Therefore, H2S represents a new candidate as a protective drug for bladder dysfunction induced by HC, a side effect of CYP chemotherapy.

Stimulation of brain corticotropin-releasing factor receptor type1 facilitates the rat micturition via brain glutamatergic receptors.

Corticotropin-releasing factor (CRF), a representative stress-related neuropeptide, in the central nervous system reportedly both facilitates and suppresses the micturition, therefore, roles of central CRF in regulation of the micturition are still controversial. In this study, we investigated (1) effects of intracerebroventricularly (icv)-administered CRF on the micturition, and (2) brain CRF receptor subtypes (CRFR1/CRFR2) and glutamatergic receptors (NMDA/AMPA subtypes) involved in the CRF-induced effects in male Wistar rats under urethane anesthesia. Intercontraction intervals (ICI), and maximal voiding pressure (MVP), were evaluated by continuous cystometry 45 min before CRF administration or intracerebroventricular pretreatment with other drugs as follows and 3 h after CRF administration. Single-voided volume (Vv), post-voiding residual volume (Rv), bladder capacity (BC), and voiding efficiency (VE) were evaluated by single cystometry 60 min before CRF administration and 60-120 min after the administration. Icv-administered CRF reduced ICI, Vv, and BC without changing MVP, Rv, or VE. The CRF-induced ICI reduction was attenuated by icv-pretreated CP154526 (CRFR1 antagonist), MK-801 (NMDA receptor antagonist), and DNQX (AMPA receptor antagonist), but not by K41498 (CRFR2 antagonist). These results indicate that stimulation of brain CRFR1 can be involved in facilitation of the rat micturition via brain NMDA/AMPA receptors.

Effects of losartan on bladder dysfunction due to aging-related severe hypertension in rats.

Aging is a major risk factor for bladder dysfunction. Anti-hypertensive drugs, angiotensin II type 1 receptor blockers (ARBs), are reported to ameliorate lower urinary tract dysfunction in rodent models and humans. We aimed to examine the preventive effect of an ARB, losartan, against bladder dysfunction due to aging-related severe hypertension. Male spontaneously hypertensive rats (SHRs) (36-week-old) were administered losartan (0, 3, or 10 mg/kg, p.o.) for 18 weeks. Age-matched, vehicle-treated Wistar Kyoto rats (WKYs) were used as controls. After the treatments, bladder and renal weight, mean blood pressure, and voiding parameters were measured. Additionally, detrusor thickness and bladder arterial wall thickness were evaluated using hematoxylin and eosin staining. Renal morphology was also assessed using periodic acid-Schiff staining. Compared to WKYs, SHRs demonstrated significantly higher bladder weight/body weight ratio (BBR), renal weight/body weight ratio, mean blood pressure, detrusor thickness, bladder arterial wall thickness, urine output, water intake, post-voiding residual urine volume, bladder capacity, intercontraction interval, and rate of glomerular and tubular injury and a lower urine osmolality. A low dose of losartan decreased the urine output, post-voiding residual urine volume, and bladder capacity in SHRs but not mean blood pressure in SHRs. A high dose of losartan decreased the BBR, mean blood pressure, detrusor thickness, bladder arterial wall thickness, post-voiding residual urine volume, bladder capacity, intercontraction interval, and glomerular and tubular injury in SHRs. Losartan inhibits bladder dysfunction in aged SHRs. The ARB losartan might be a preventive drug for bladder dysfunction due to aging-related severe hypertension.

[Pharmacological training with small animals in Kochi University].

The use of animals for scientific purposes is still a subject of debate. The current regulatory position in most western countries allows regulated animal use to occur because of the perceived benefits in generating new knowledge. The use of animals for scientific purposes engenders a wide range of ethical perspectives, with some people looking for the complete termination of animal use, and others strongly support their continued use. Although regulatory systems vary from country to country, in most jurisdictions, research and teaching institutions are required to ensure that staff and students using animals for scientific purposes are appropriately trained, that animals are well cared for, and that the ethical review process for projects is robust. In the curriculum of the Kochi Medical School, it is mandatory for all medical students to perform laboratory exercises in the class of Pharmacology. For the purpose of this experimental class it is common to use small animals in these exercises. However, in recent years in many countries, alternative methods to replace the use of small animals have been introduced. Such methods are experiment simulations with the use of computers and they have been used in some medical schools. In this manuscript, I will make an introduction on how we perform pharmacological laboratory exercises with the use of small animals in Kochi Medical School. Additionally, I would like to discuss the necessity of the use of small animals in exercises as part of the training of medical students.

Psychological/mental stress-induced effects on urinary function: Possible brain molecules related to psychological/mental stress-induced effects on urinary function.

Exposure to psychological/mental stress can affect urinary function, and lead to and exacerbate lower urinary tract dysfunctions. There is increasing evidence showing stress-induced changes not only at phenomenological levels in micturition, but also at multiple levels, lower urinary tract tissues, and peripheral and central nervous systems. The brain plays crucial roles in the regulation of the body's responses to stress; however, it is still unclear how the brain integrates stress-related information to induce changes at these multiple levels, thereby affecting urinary function and lower urinary tract dysfunctions. In this review, we introduce recent urological studies investigating the effects of stress exposure on urinary function and lower urinary tract dysfunctions, and our recent studies exploring "pro-micturition" and "anti-micturition" brain molecules related to stress responses. Based on evidence from these studies, we discuss the future directions of central neurourological research investigating how stress exposure-induced changes at peripheral and central levels affect urinary function and lower urinary tract dysfunctions. Brain molecules that we explored might be entry points into dissecting the stress-mediated process for modulating micturition.