Bladder Inflammation Research Articles

Molecular pathways underlying tissue injuries in the bladder with ketamine cystitis.

Ketamine cystitis (KC) is a chronic bladder inflammation leading to urinary urgency, frequency, and pain. The pathogenesis of KC is complicated and involves multiple tissue injuries in the bladder. Recent studies indicated that urothelium disruption, lamina propria fibrosis and inflammation, microvascular injury, neuropathological alterations, and bladder smooth muscle (BSM) abnormalities all contribute to the pathogenesis of KC. Ketamine has been shown to induce these tissue injuries by regulating different signaling pathways. Ketamine can stimulate antiproliferative factor, adenosine triphosphate, and oxidative stress to disrupt urothelium. Lamina propria fibrosis and inflammation are associated with the activation of cyclooxygenase-2, nitric oxide synthase, immunoglobulin E, and transforming growth factor β1. Ketamine contributes to microvascular injury via the N-methyl-D aspartic receptor (NMDAR), and multiple inflammatory and angiogenic factors such as tumor necrosis factor α and vascular endothelial growth factor. For BSM abnormalities, ketamine can depress the protein kinase B, extracellular signal-regulated kinase, Cav1.2, and muscarinic receptor signaling. Elevated purinergic signaling also plays a role in BSM abnormalities. In addition, ketamine affects neuropathological alterations in the bladder by regulating NMDAR- and brain-derived neurotrophic factor-dependent signaling. Inflammatory cells also contribute to neuropathological changes via the secretion of chemical mediators. Clarifying the role and function of these signaling underlying tissue injuries in the bladder with KC can contribute to a better understanding of the pathophysiology of this disease and to the design of effective treatments for KC.

Ultrasonographic application in the diagnosis and treatment of cystitis‐ pyelonephritis syndrome in buffaloes (Bubalus bubalis): A novel approach

AbstractBovine cystitis is an inflammation of the urinary bladder that may ascend to ureters to cause pyelonephritis. The aim of this study performed in buffaloes was to investigate the use of ultrasonographic imaging in the diagnosis of cystitis‐pyelonephritis syndrome followed by a novel treatment regimen. In all four buffaloes, diagnosis was confirmed using trans‐rectal ultrasonography, revealing non‐specific thickening of bladder wall, with reduced capacity and floating hyperechoic contents. Kidneys showed dilatation of right and/or left ureter, with loss of lobulations and cortex medullary differentiation. Successful treatment was achieved by flushing of the urinary bladder using a number 18 Foleys catheter guided by ultrasound twice a day for 5 days with 2.5% liquid betadine in combination with oral administration of ammonium chloride (0.2 mg/kg body weight) for 7 days. A rapid recovery was confirmed by clinical examination after 7 days and a further follow‐up 2 months post‐treatment.

Pathogenesis evidence from human and animal models of detrusor underactivity

ABSTRACTDetrusor underactivity (DU) is a common urodynamic diagnosis in patients with lower urinary tract symptoms and large post-voiding residual volume. Animal and human studies showed the possible etiologies of DU include central or peripheral nerve injury, bladder outlet obstruction, chronic ischemia, aging, diabetes mellitus, and sympathetic inhibition of micturition reflex. Evidence from animal and human DU studies with various etiologies revealed highly similar gross and histological characteristics in the bladders, including increased bladder weight, bladder wall thickening, inflammation, collagen deposition, and fibrosis. In electron microscopy, smooth muscle destruction, swollen mitochondria, decreased nerve innervation, caveolae, and umbrella cell fusiform vesicles were noted in the DU bladders. Most animal DU models demonstrate detrusor contractility changes from compensatory to the decompensatory stage, and the change was compatible with human DU observation. The cystometry in the DU animal studies is characterized by impaired contractility, prolong intercontraction interval, and hyposensation, while in vitro bladder muscle strips experiment may exhibit normal detrusor contractility. Decreased bladder blood flow and increased oxidative stress in bladders had been proved in different animal DU models, suggesting they should be important in the DU pathogenesis pathway. Sensory receptors mRNA and protein expression changes in DU bladders had been observed in both animal and human studies, including muscarinic receptors M2, M3, adrenergic receptor β3, purinergic receptor P2X1, P2X3, and transient receptor potential vanilloid (TRPV) 1 and TRPV4. Although some of the sensory receptors changes remain controversial, it might be the target for further pharmacologic treatments.

The mast cell activator Compound 48/80 increases bladder compliance through matrix metalloprotease release

Bladder wall stiffness and elasticity is essential to its storage and voiding functions. In addition to smooth muscle contractility, the integrity of the extracellular matrix plays a crucial role in maintaining the optimal balance between wall stiffness and compliance as the bladder distends. Lower urinary tract symptoms (e.g., bladder overactivity and fibrosis) can be caused by mast cell activation and inflammation, which increases wall stiffness and matrix remodeling. Thus, we hypothesize that mast cell activation increases muscle contractility and decreases compliance. Whole mouse bladders were dissected and mounted in a custom-designed pentaplanar reflected image macroscopy (PRIM) system for simultaneous measurement of the following parameters during ex vivo bladder filling: intravesical pressure, bladder volume, wall deformation, mechanical stress, and mechanical stretch. Bladders were filled at a constant rate (30 µl/min) until intravesical pressure reached 25 mmHg, at which point bladders were emptied and allowed to recover for approximately 10 minutes prior to the next fill cycle. During filling, baseline bladder pressure remained relatively low over a large infused volume (~350 µL), after which pressure increased rapidly. Transient contractions began on the lateral sides of the bladder wall near the trigone, expanded upwards as the bladder filled, and corresponded to transient increases in intravesical pressure (0-2 mmHg). Using the pressure-volume curves and associated image data, we next calculated the bladder wall compliance (defined as the stress vs stretch relationship of the bladder wall). As with pressure, wall stress was relatively low over a large change in stretch, implying that bladder wall was highly compliant until larger infused volumes. Subsequent exposure to the mast cell activator Compound 48/80 (10 µg/ml) significantly increased the amplitude of transient pressure events but decreased wall stress per change in stretch, indicating a paradoxical increase in compliance. Incubation with the matrix metalloprotease inhibitor doxycycline (10 µM) prior to addition of compound 48/80 prevented this increase in compliance without preventing the increased amplitude of transient pressure events. These findings suggest that Compound 48/80 activates bladder mast cells to release at least two things: (1) matrix metalloproteases that rapidly degrade the extracellular matrix and increase bladder wall compliance; and (2) compounds that increase smooth muscle excitability. Thus, both decreases in stiffness and increases in smooth muscle excitability may accompany inflammatory bladder pathologies such as diabetes and interstitial cystitis.

Eosinophilic Cystitis Presenting as Possible Pediatric Rhabdomyosarcoma in Conventional Imaging Including 18F-FDG-PET/CT/MRI-A Rare Case.

Eosinophilic cystitis (EC) is a relatively rare, but benign inflammatory bladder disease compared to that of the malignant pediatric rhabdomyosarcoma (RMS), in which it can be mimicking on initial suspicion. The origin, symptoms and findings of both EC and RMS are still discussed and hence, lead to the challenge in distinguishing them by cystoscopy and several image modalities. We present a case in which cross-sectional imaging modalities including fluorine-18-fluro-2-deoxy-D-glucose (18F-FDG)-positron emission tomography (PET) / computed tomography (CT) / magnetic resonance imaging (MRI) (18F-FDG-PET/CT/MRI (The imaging modality 18F-FDG-PET/CT/MRI referring to two continuous scans scanned on the same 18F-FDG-tracer dose for both the whole-body 18F-FDG-PET/CT and the regional 18F-FDG-PET/MRI of the pelvis.)) raised suspicion of RMS. Hence, the final diagnosis of EC was established by repeated histopathology. It is important to have EC in mind when seeking differential diagnosis of malignant diseases like RMS in order to provide the correct treatment for the patient and highly homogenously increased 18F-FDG-uptake should raise the suspicion of EC as a differential diagnosis. Furthermore, 18F-FDG-uptake rate is suggested as a future potential biomarker for monitoring of therapeutic response in eosinophilic inflammatory diseases, thus more research on this topic is needed.

Potential urine biomarkers in bladder outlet obstruction-related detrusor underactivity.

Detrusor underactivity (DU), an important but under-researched issue, is thought to be complex and multifactorial in etiology, pathophysiology, and diagnosis. Bladder outlet obstruction (BOO) is one of the important known etiologies of DU, with significant morphologic and physiologic changes of the urothelium, suburothelium, and detrusor muscle in the urinary bladder. Chronic urinary bladder ischemia and repeated cycles of ischemia and reperfusion injury cause excessive oxidative stress, and it is thought to be responsible for the development of DU. DU might be the late phase or decompensated status of BOO, with the possible mechanisms of afferent nervous dysfunction, increased inflammation, denervation of the detrusor muscle, and myogenic failure. Prostaglandin E2 (PGE2) involves in the physiological detrusor contraction, and might provide the prognostic value for the recoverability of DU. Neurotrophins, including nerve growth factor and brain-derived neurotrophic factor, involve in the neuroplastic changes in many inflammatory bladder diseases, including BOO and DU. Oxidative stress biomarkers, including 8-hydroxy-2-deoxyguanosine, F2-isoprostane, and the involved pro-inflammatory cytokines, have been applied in BOO due to their involvements in chronic bladder ischemia. PGE2, neurotrophins, inflammatory cytokines, and oxidative stress biomarkers are the potential urine biomarkers in BOO-related DU.

Clinical Pattern and Frequency of Co-morbidities among Patients Presented with Cholelithiasis’ at Tertiary Care Hospital

Background: Gallstone disease (cholelithiasis) remains the commonest medical issue leading to surgical intervention. Causes of the Gall stone has been not properly understood, but it is thought to have several factors. Untreated gall stones can cause the various complications like inflammation of gall bladder, tissue damage, gallbladder tears and infection.
 Objective: To determine the clinical pattern and frequency of comorbidities among patients presented with cholelithiasis at Isra University Hospital Hyderabad, Pakistan.
 Materials and methods: This cross-sectional study was conducted at general Surgery department, Isra University Hospital, Hyderabad. All the patients having diagnosis of gall stone disease, age>18 years and either of gender were included in the study. Patients were selected on outpatient department (OPD) basis. Complete clinical examination was done including abdominal ultrasound and required laboratory investigations. Data regarding demographic information including clinical presentational and comorbidities like diabetes, hypertension and obesity was recorded and also smoking status was assessed. All the data was recorded via study proforma and was analyzed by SPSS version 20.
 Results: A total of 149 patients were studied, their mean age was 49.23+7.33 years. Females were commonest as 57(38.3%) and males were 92(61.7%). As per clinical presentation pain was found to be most common, particularly as epigastrium pain was found in (93.95%) cases, right Hypochondrium pain (73.82%), pain radiation was more towards scapula (50.33%), dyspepsia was noted in (49.66%), nausea was observed in 44 patients, flatulence in 45 patients and vomiting was least common (21.47%). Diabetes mellitus was 76(51.0%), hypertension was 67(45.0%), overweight were 63(42.3%), obese were 25(16.8%), HCV positive cases were 34(22.8%) and HBV positive cases were 09(59.7%). However smokers were 48(32.2%) and 06(4.0%) were alcohol consumers. Diabetes mellitus, hypertension and obesity were significantly more prevalent in females as compared to males (p=<0.05). Smoking habits and alcohol consumption were mostly found in males (p=<0.05). However HCV and HBV infections were statically insignificant according to gender.
 Conclusion: It was concluded that gallstone is a common problem and most of the patients who were diagnosed with gallstones were females, obese (BMI>27kg/m2), diabetes mellitus and belonged to fourth decade (40 to 50 years) of their life. Commonest clinical presentations were epigastrium pain, right Hypochondrium pain, pain radiation towards scapula and dyspepsia.

Selective blockade of transient receptor potential vanilloid 4 reduces cyclophosphamide-induced bladder pain in mice

Transient receptor potential vanilloid 4 (TRPV4) is a non-selective cation channel activated by various physical stimuli such as cell swelling and shear stress. TRPV4 is expressed in bladder sensory nerves and epithelium, and its activation produces urinary dysfunction in rodents. However, there have been few reports regarding its involvement in bladder pain. Therefore, we investigated whether TRPV4 is involved in bladder pain in mouse cystitis model. Intraperitoneal injection of cyclophosphamide (CYP; 300 mg/kg) produced mechanical hypersensitivity in the lower abdomen associated with a severe inflammatory bladder in mice. The mechanical threshold was reversed significantly in Trpv4-knockout (KO) mice. Repeated injections of CYP (150 mg/kg) daily for 4 days provoked mild bladder inflammation and persistent mechanical hypersensitivity in mice. Trpv4-KO mice prevented a reduction of the mechanical threshold without an alteration in bladder inflammation. A selective TRPV4 antagonist also reversed the mechanical threshold in chronic cystitis mice. Although expression of Trpv4 was unchanged in the bladders of chronic cystitis mice, the level of phosphorylated TRPV4 was increased significantly. These results suggest involvement of TRPV4 in bladder pain of cystitis mice. A TRPV4 antagonist might be useful for patients with irritable bladder pain such as those with interstitial cystitis/painful bladder syndrome.

P0756 / #2111: ABDOMINAL IMAGING FINDINGS IN CRITICALLY ILL CHILDREN WITH MIS-C

Aims & Objectives: We sought to describe abdominal imaging findings on ultrasound and computed tomography on children presenting with abdominal symptoms and multisystem inflammatory syndrome (MIS-C) related to coronavirus disease (COVID-19). Methods: We report findings on abdominal imaging in 7 critically ill children admitted with MIS-C to a tertiary, urban intensive care unit. All children had clinical and laboratory criteria of MIS-C including positive antibody testing to COVID-19. Results: Of 23 children diagnosed with MIS-C, 7 children (30%) had abdominal imaging, including ultrasound (all 7) and CT (3/7). Indications for abdominal imaging included concern for acute abdomen, gall bladder inflammation and intestinal obstruction. Hepatomegaly was the most common finding, while nephromegaly, gall bladder wall edema, ascites, intestinal inflammation and mesenteric lymphadenopathy were also seen on ultrasound. Two children had incidental finding of bilateral lower lobe consolidations on CT abdomen. One child had a thickened, enlarged appendix with diffuse inflammation of intestinal wall of descending colon and ileum on CT. Another patient with severe MIS-C had fluid-filled small bowel loops, terminal ileal inflammation, diffuse lymphadenopathy and moderate ascites on abdominal CT. This patient also had large vessel vasculitis involving the junction of the aortic arch and brachiocephalic trunk. Conclusions: Common with abdominal imaging findings in Kawasaki disease, our patients had reactive lymphadenopathy, abdominal free fluid, bowel wall thickening and vasculitis. Gall bladder hydrops, intestinal pseudo-obstruction or dilated bowel loops, commonly found in Kawasaki disease with prominent abdominal symptoms were not seen in our patients.

Ketamine-induced urological toxicity: potential mechanisms and translation for adults with mood disorders receiving ketamine treatment.

Intravenous (IV) ketamine has been shown to have rapid and robust antidepressant effects in adults with treatment-resistant depression (TRD). Urological toxicity has been observed in chronic ketamine abusers as evidenced by dysuria, urgency, and hematuria. The foregoing observation provides the basis for evaluating whether ketamine-induced urological toxicity (KIUT) is associated with sub-anesthetic doses of ketamine (0.5-1.0 mg/kg) in adults with mood disorders. The overarching objective of this article is to identify potential mechanisms of KIUT which appears to be dose and frequency dependent. Available research indicates that high-frequency ketamine is associated with disruption of the urothelial barrier as well as direct ketamine toxicity (i.e., decreased expression of junction proteins) in KIUT of the bladder. Chronic and high-frequency ketamine use is also associated with bladder inflammation mediated via neurogenic and IgE inflammation. Other non-mutually exclusive causes are nerve hyperplasia, hypersensitivity, cell apoptosis, microvascular damage, and overexpression of carcinogenic genes. Notwithstanding the evidence of KIUT in ketamine abusers, there is no evidence that ketamine and/or esketamine treatment in adults with mood disorders is associated with KIUT. However, all patients receiving ketamine/esketamine for mood disorder treatment should be queried about genitourinary symptoms during acute and, where applicable, maintenance dosing.

Prostate-to-bladder cross-sensitization in a model of zymosan-induced chronic pelvic pain syndrome in rats.

The aim of the present study was to investigate the effects of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) on bladder function and pathophysiology. To create a model for CPPS, rats were intraprostatically injected with zymosan or saline, serving as control. Metabolic cage experiments were performed 7, 14, or 21 days after zymosan injection and after 14 days in the control group. Thereafter, cystometry was performed in which simulated micturition cycles were induced by saline infusion and contractile responses to the cholinergic agonist methacholine and the purinergic agonist ATP were measured. Following cystometry, the prostate and urinary bladder were excised and assessed histopathologically for possible inflammatory changes. Metabolic cage data revealed a significantly increased urinary frequency in zymosan treated rats. Likewise, the volume per micturition was significantly lower in all CPPS groups compared to controls. Cystometry showed a significant increase in the number of nonvoiding contractions, longer voiding time, and a trend towards lower compliance in CPPS rats compared to controls. Induction of CPPS led to significantly reduced cholinergic and purinergic contractile responses. Histopathological analysis demonstrated prostatic inflammation in all CPPS groups, in particular in later stage groups. Both the extent and grade of bladder inflammation were significantly higher in CPPS groups compared to controls. The current findings demonstrate a potential prostate-to-bladder cross-sensitization leading to symptoms of bladder overactivity and signs of bladder inflammation. Future clinical studies are required to verify the outcomes of the current study and enable advancement of patient care.

Neuronal Dual Leucine Zipper Kinase Mediates Inflammatory and Nociceptive Responses in Cyclophosphamide-Induced Cystitis

Interstitial cystitis is associated with neurogenic inflammation and neuropathic bladder pain. Dual leucine zipper kinase (DLK) expressed in sensory neurons is implicated in neuropathic pain. We hypothesized that neuronal DLK is involved in the regulation of inflammation and nociceptive behavior in cystitis. Mice deficient in DLK in sensory neurons (cKO) were generated by crossing DLK floxed mice with mice expressing Cre recombinase under Advillin promoter. Cystitis was induced by cyclophosphamide (CYP) administration in mice. Nociceptive behavior, bladder inflammation, and pathology were assessed following cystitis induction in control and cKO mice. The role of DLK in CYP-induced cystitis was further determined by pharmacological inhibition of DLK with GNE-3511. Deletion of neuronal DLK attenuated CYP-induced pain-like nociceptive behavior and suppressed histamine release from mast cells, neuronal activation in the spinal cord, and bladder pathology. Mice deficient in neuronal DLK also showed reduced inflammation induced by CYP and reduced c-Jun activation in the dorsal root ganglia (DRG). Pharmacological inhibition of DLK with GNE-3511 recapitulated the effects of neuronal DLK depletion in CYP treatment mice. Our study suggests that DLK is a potential target for the treatment of neuropathic pain and bladder pathology associated with cystitis.

ВЕТЕРИНАРНО-САНИТАРНАЯ ХАРАКТЕРИСТИКА И ТЕЧЕНИЕ БОЛЕЗНИ ВЫРАЩИВАЕМОЙ РЫБЫ В РЫБОВОДНОМ ХОЗЯЙСТВЕ, НАХОДЯЩЕМСЯ НА КАРАНТИНЕ ПО АЭРОМОНОЗУ И ВОСПАЛЕНИЮ ПЛАВАТЕЛЬНОГО ПУЗЫРЯ

The article reviews the diseases of cyprinid fish in the farm quarantined for aeromonosis and inflammation of the swim bladder. The etiology and symptoms of the disease are considered, and the pathoanatomical changes in fish. Modern methods of control and treatment of each age category of reared objects are considered. Preventive therapeutic feeding of farmed fish, vaccination, summer drying of ponds are offered. A veterinary and sanitary assessment of the farmed fish is given. Sick fish, if it has not lost its marketable appearance and meets the nutritional qualities, are allowed to eat people without restrictions. Non-market fish is sent to feed farm animals, poultry, fur-bearing animals in a boiled form or processed into fish flour. It is recommended to pay more attention to ecological methods of combating fish diseases – the use of polyculture for the effective production of marketable products (marketable fish); to increase the non-specific resistance of fish with probiotics; to use immunological methods, such as vaccination.

Gabapentin reduces painful bladder hypersensitivity in rats with lipopolysaccharide-induced chronic cystitis.

Although interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic condition causing bladder pain and urinary symptoms, effective treatments have not been established. The aim of this study was to adapt a chronic cystitis model in rats using lipopolysaccharide (LPS), which reflects IC/BPS pathology, and characterize the model's histological and behavioral effects. Furthermore, we investigated the effect of an α2δ subunit ligand, gabapentin (GBP), on bladder hypersensitivity of rats with chronic cystitis. Cystitis models were created by repeated intravesical injections of LPS. In the histological examination, the LPS‐injected group had greater inflammatory response, fibrosis, and abnormally thick re‐epithelialization. In the LPS‐injected group, LPS prompted hyperalgesia in both the lower abdomen and hind paw regions after day 1 of the first injection compared with the saline‐injected controls, without any recovery for 21 days at least. During cystometry, the LPS‐injected group showed bladder hyperactivity at all times. Systemic administration of GBP reduced cystitis‐related pain due to chronic inflammation and reduced the increased frequency of voiding in the LPS‐injected group. These results suggest that repeated intravesical injections of LPS induce long‐lasting bladder inflammation, pain, and overactivity in rats, while GBP is effective in the management of those symptoms in this chronic cystitis model. The current study identifies a relatively simple method to develop an animal model for chronic cystitis and provides evidence that GBP may be an effective treatment option for patients with IC/BPS.

Autoimmunity to urothelial antigen causes bladder inflammation, pelvic pain, and voiding dysfunction: a novel animal model for Hunner-type interstitial cystitis.

Recent evidence revealed that Hunner-type interstitial cystitis (HIC) is a robust inflammatory disease potentially associated with enhanced immune responses and histologically characterized by epithelial denudation and lymphoplasmacytic infiltration with frequent clonal expansion of infiltrating B cells. To date, few animal models that reproduce the histological and clinical correlates of HIC have yet been established. In the present study, we aimed to develop a novel animal model for HIC via autoimmunity to the bladder urothelium using the transgenic mouse model (URO-OVA) that expresses the membrane form of the model antigen ovalbumin (OVA) as a self-antigen on the bladder urothelium. OVA-specific lymphocytes (splenocytes) were generated by immunization of C57BL/6 mice with OVA protein and injected intravenously into URO-OVA mice. The splenocytes from OVA-immunized C57BL/6 mice showed increased interferon (IFN)-γ production in response to OVA stimulation in vitro. URO-OVA mice adoptively transferred with OVA-primed splenocytes developed cystitis exhibiting histological chronic inflammatory changes such as remarkable mononuclear cell infiltration predominantly composed of T and B lymphocytes, increased vascularity, and mucosal hyperemia in the bladder at days 7-28 with a peak at day 21 tested. No systemic inflammation was found in cystitis-induced URO-OVA mice, nor was any inflammation found in wild-type C57BL/6 mice adoptively transferred with OVA-primed splenocytes. Along with bladder inflammation, URO-OVA mice demonstrated significantly increased pelvic nociceptive responses, voiding dysfunction, and upregulated mRNA expression levels for IFN-γ, tumor necrosis factor-α (TNF-α), and substance P precursor in the bladder. This model reproduces the histological and clinical features of human HIC, providing a novel model for HIC research.

Utilization of an Intraoperative Grading Scale in Laparoscopic Cholecystectomy: A Nepalese Perspective.

Introduction Difficult geographic diversity and late presentation to medical attention often make the laparoscopic cholecystectomy difficult and chances of conversion and complication remains. Various preoperative grading scales have been developed for predicting the difficulty of surgery in cholecystitis patients; however, intraoperative assessment of anatomical status and inflammation of the gall bladder has not been assessed till date except for some guidelines like the Parkland grading scale (PGS). We aimed to utilise this guideline in patients undergoing laparoscopic cholecystectomy in rural community of the developing nation. Methods PGS was applied for all the patients undergoing laparoscopic cholecystectomy and laboratory and outcome factors like preoperative white blood cells (WBC), open conversion, subtotal cholecystectomy, length of surgery, and bile leaks postoperatively were assessed. Results Among 178 patients who underwent cholecystectomy, there were 40 grade one GBs, 90 grade two GBs, 26 grade three GBs, 16 grade four GBs, and six grade five GBs. With a conversion rate of 6.74%, eight patients underwent subtotal cholecystectomy. Among them, four patients were graded as 5th grade, two as 4th grade, and two as 3rd grade according to PGS system. Postoperative bile leak was seen in three patients among which two were grade five GBs and one was grade four. Preoperative WBC, conversion to open, subtotal cholecystectomy, length of surgery, and postoperative bile leak all significantly increased with increasing grades (p < 0.05). Conclusion PGS can be applied in patients undergoing laparoscopic cholecystectomy in the rural setting of a developing nation. With its application, postoperative course could be predicted and adequate counselling can be done about the possibilities of the outcome.

Suppression of adenosine A2a receptors alleviates bladder overactivity and hyperalgesia in cyclophosphamide-induced cystitis by inhibiting TRPV1

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a type of chronic bladder inflammation characterized by increased voiding frequency, urgency and pelvic pain. The sensitization of bladder afferents is widely regarded as one of the pathophysiological changes in the development of IC/BPS. There is evidence that adenosine A2a receptors are involved in regulating the sensitization of sensory afferents. However, the effect of adenosine A2a receptors on cystitis remains unknown. In the present study, a rat model of chronic cystitis was established by intraperitoneal injection with cyclophosphamide (CYP). Cystometry and behavioral tests were performed to investigate bladder micturition function and nociceptive pain. The rats with chronic cystitis showed symptoms of bladder overactivity, characterized by an increase in bladder voiding frequency and voiding pressure. CYP treatment significantly increased the expression of the A2a receptor in bladder afferent fibers and dorsal root ganglion (DRG) neurons. The A2a receptor antagonist ZM241385 prevented bladder overactivity and hyperalgesia elicited by CYP-induced cystitis. In addition, the A2a receptor and TRPV1 were coexpressed on DRG neurons. The TRPV1 antagonist capsazepine blocked bladder overactivity induced by the A2a receptor agonist CGS21680. In contrast, ZM241385 significantly inhibited the capsaicin-induced increase in intracellular calcium concentration in DRG neurons. These results suggest that suppression of adenosine A2a receptors in bladder afferents alleviates bladder overactivity and hyperalgesia elicited by CYP-induced cystitis in rats by inhibiting TRPV1, indicating that the adenosine A2a receptor in bladder afferents is a potential therapeutic target for the treatment of IC/BPS.

Protective effect of Aster tataricus extract on NLRP3-mediated pyroptosis of bladder urothelial cells.

Aster tataricus L.f. is a traditional Eastern Asian herbal medicine used for the relief of uroschesis‐related illnesses and has been demonstrated clinically to exert satisfied effects. However, the mechanism of its therapeutic action remains unclear. The present study aimed to evaluate the protective mechanism of Aster tataricus extract (ATE) on CYP or LPS + ATP‐induced interstitial cystitis (IC), we successfully constructed the induced IC Sprague‐Dawley (SD) rat model and IC human urothelium cell (SV‐HUC‐1) model. The main compounds of ATE were determined by LC‐MS. After intervention, the changes on the bladder wall morphology and inflammation were observed in each group. SV‐HUC1 cell viability was measured by MTT and double stained with Hoechst 33342 and propidium iodide (PI). The expression levels of NLRP3, Pro‐caspase‐1, Caspsae‐1 p20, GSDMD, GSDMD‐N and Cleave‐IL‐1β in vivo and in vitro in different groups were detected by Western blotting. ATE significantly alleviated oedema and haemorrhage and reduced the inflammation index and histopathological score in SD rat bladder. The results of cell revealed that ATE could improve cell viability and decrease pyroptosis ratio. The expression of NLRP3 and other pyroptosis‐related protein was remarkably decreased by ATE both in vivo and in vitro. ATE may be used as an inhibitor of NLRP3 in treating IC. The discovery of NLRP3/Caspase‐1/GSDMD‐N as a new protective pathway provides a new direction for protecting cell against IC.

Lacking transient receptor potential melastatin2 attenuates lipopolysaccharide-induced bladder inflammation and its associated hypersensitivity in mice.

To study the role of transient receptor potential melastatin2 in bladder function and inflammation-associated hypersensitivity. We evaluated physiological function of the bladder and intravesical lipopolysaccharide-induced inflammatory nociceptive responses in female wild-type and transient receptor potential melastatin2-knockout mice. Invivo frequency/volume and decerebrated unanesthetized cystometry measurements, as well as invitro detrusor strip functional studies, were carried out to evaluate bladder function. Mice received intravesical lipopolysaccharide (2.0mg/mL) or saline instillation to evaluate responses to bladder inflammation. Voiding and bladder pain-like behaviors, cystometry measurements and histological evaluation were carried out before and after intravesical lipopolysaccharide instillation. Few phenotypic differences in invivo and invitro physiological function were found between the two genotypes. Comparison of measurements taken before and 24-48h after intravesical lipopolysaccharide instillation showed that voiding parameters did not change in transient receptor potential melastatin2-knockout mice, whereas an increased voiding frequency was observed in wild-type mice. At 24h after intravesical lipopolysaccharide instillation, the numbers of bladder pain-like behaviors and of infiltrated inflammatory cells in the bladder submucosal layer were significantly increased, and the voided volume and the intercontraction interval were significantly decreased on cystometry measurements in wild-type mice compared with those in both transient receptor potential melastatin2-knockout mice and in wild-type mice treated with saline instillation. Although the physiological roles of transient receptor potential melastatin 2 channels in the bladder might be limited, inflammation and associated hypersensitivity of the bladder caused by intravesical lipopolysaccharide instillation are attenuated in transient receptor potential melastatin2-knockout mice, suggesting pathophysiological roles of transient receptor potential melastatin2 channels in these processes.

New Frontiers or the Treatment of Interstitial Cystitis/Bladder Pain Syndrome - Focused on Stem Cells, Platelet-Rich Plasma, and Low-Energy Shock Wave

Interstitial cystitis/bladder pain syndrome (IC/BPS), which is characterized by bladder pain and irritative voiding symptoms, is a frustrating disease without effective treatment. The cause is still largely not understood, although urothelium ischemia/hypoxia, apoptosis, denudation, and infiltration of inflammatory cells are common histopathological findings. The current uncertainty regarding the etiology and pathology of IC/BPS has a negative impact on its timely and successful treatment; therefore, the development of new treatment modalities is urgently needed. Herein, we present advances in our knowledge on this topic and review the potential application of regenerative medicine for the treatment of IC/BPS. This article provides information on the basic characteristics and clinical evidence of stem cells, platelet-rich plasma (PRP), and low-energy shock waves (LESWs) based on a literature review with a search strategy for articles related to IC/BPS, stem cells, PRP, and LESW published in MEDLINE and PubMed. Stem cells, PRP, and LESW, which modulate inflammatory processes and promote tissue repair, have been proven to improve bladder regeneration, relieve bladder pain, inhibit bladder inflammation, and increase bladder capacity in some preclinical studies. However, clinical studies are still in their infancy. Based on the mechanisms of action of stem cells, PRP, and LESW documented in many preclinical studies, the potential applications of regenerative medicine for the treatment of IC/BPS is an emerging frontier of interest. However, solid evidence from clinical studies remains to be obtained.