Review of Animal Models to Study Urinary Bladder Function

The urinary bladder (UB) serves as a storage and elimination organ for urine. UB dysfunction can cause multiple symptoms of failure to store urine or empty the bladder, e.g., incontinence, frequent urination, and urinary retention. Treatment of these symptoms requires knowledge on bladder function, which involves physiology, pathology, and even psychology. There is no ideal animal model for the study of UB function to understand and treat associated disorders, as the complexity in humans differs from that of other species. However, several animal models are available to study a variety of other bladder disorders. Such models include animals from rodents to nonhuman primates, such as mice, rats, rabbits, felines, canines, pigs, and mini pigs. For incontinence, vaginal distention might mimic birth trauma and can be measured based on leak point pressure. Using peripheral and central models, inflammation, bladder outlet obstruction, and genetic models facilitated the study of overactive bladder. However, the larger the animal model, the more difficult the study is, due to the associated animal ethics issues, laboratory facility, and budget. This review aims at facilitating adapted animal models to study bladder function according to facility, priority, and disease.

Urothelial Calcium-Sensing Receptor Modulates Micturition Function via Mediating Detrusor Activity and Ameliorates Bladder Hyperactivity in Rats

The urothelium displays mechano- and chemosensory functions via numerous receptors and channels. The calcium-sensing receptor (CaSR) detects extracellular calcium and modulates several physiological functions. Nonetheless, information about the expression and the role of CaSR in lower urinary tract has been absent. We aimed to determine the existence of urothelial CaSR in urinary bladder and its effect on micturition function. We utilized Western blot to confirm the expression of CaSR in bladder and used immunofluorescence to verify the location of the CaSR in the bladder urothelium via colocalization with uroplakin III A. The activation of urothelial CaSR via the CaSR agonist, AC-265347 (AC), decreased urinary bladder smooth muscle (detrusor) activity, whereas its inhibition via the CaSR antagonist, NPS-2143 hydrochloride (NPS), increased detrusor activity in in vitro myography experiments. Cystometry, bladder nerve activities recording, and bladder surface microcirculation detection were conducted to evaluate the effects of the urothelial CaSR via intravesical administrations. Intravesical AC inhibited micturition reflex, bladder afferent and efferent nerve activities, and reversed cystitis-induced bladder hyperactivity. The urothelial CaSR demonstrated a chemosensory function, and modulated micturition reflex via regulating detrusor activity. This study provided further evidence of how the urothelial CaSR mediated micturition and implicated the urothelial CaSR as a potential pharmacotherapeutic target in the intervention of bladder disorders.

Intravenous infusion of 40% urotropine solution

Intravenous infusions of 40% urotropine solution are warmly recommended by Pasch (Zentr, f. Gyn., 1924, No. 13) as a measure against postoperative urinary retention, cystitis, as well as urinary bladder disorders after prolonged childbirth and obstetric operations.

Novel Applications of Non-Invasive Intravesical Botulinum Toxin a Delivery in the Treatment of Functional Bladder Disorders

Although intravesical botulinum toxin type A (BoNT-A) injection for functional bladder disorders is effective, the injection-related problems—such as bladder pain and urinary tract infection—make the procedure invasive and inconvenient. Several vehicles have recently been developed to deliver BoNT-A without injection, thereby making the treatment less or non-invasive. Laboratory evidence revealed that liposome can carry BoNT-A across the uroepithelium and act on sub-urothelial nerve endings. A randomized placebo controlled study revealed that intravesical administration of liposome-encapsulated BoNT-A and TC-3 hydrogel embedded BoNT-A can improve urinary frequency, urgency, and reduce incontinence in patients with overactive bladders. A single-arm prospective study also revealed that intravesical administration of TC-3 hydrogel embedded BoNT-A can relieve bladder pain in patients with interstitial cystitis/bladder pain syndrome (IC/BPS). We recently administered suprapubic energy shock wave (ESW) after BoNT-A intravesical administration in six patients with IC/BPS. Although pain reduction and symptom improvement were not significant, immunochemical staining showed cleaved synaptosome-associated protein 25 in the bladder after the procedure. This suggests that ESW can promote passage of BoNT-A across the uroepithelium. In conclusion, using vehicles to intra-vesically deliver BoNT-A for functional bladder disorders is promising. Further studies are necessary to confirm the efficacy and explore novel applications.

Daruharidra (Berberis aristata): Review based upon its Ayurvedic Properties

Berberis aristata is also known as daruharidra which is a famous plant and used in various medicinal systems like Ayurveda, Homeopathy, Unani, Chinese and Allopathy for a very long time. It is a spinous, hard, yellowish herb belongs to the family Berberidaceae. The plant is distributed in sub- Himalayan regions, Sri Lanka, Bhutan and hilly areas of Nepal. It played a significant role as an herbal remedy for more than 2500 years. It was used by ancient Egyptians to anticipate plague disease. European herbalists used this plant to treat liver and gall bladder disorders during the early middle ages. Russian therapists used B. aristata plant to cure inflammation, high blood pressure and abnormal menstrual cycle. It is used as a bitter tonic, stomachic, cholagogue, antiperiodic and alternative by American Indians to cure intermittent fever, neuralgia and menorrhagia. In the traditional medicinal system, the plant is used to treat skin diseases, menorrhagia, diarrhea, eye problem inflammation and wound healing. Fruit of the plant is a rich source of Vitamin C. The main active constituent of the plant is Berberine found mainly in its roots. The most important formulation of this plant is 'Rashut' that is acts as a tonic as well as blood purifier and also used to treat ulcer and ophthalmic diseases. Reported clinical and experimental studies showed that the plant possesses various pharmacological properties like antimicrobial, anti-inflammatory, analgesic, antipyretic, hepatoprotective, immunomodulatory and cardiotonic activity.

Expression of Low Affinity Nerve Growth Factor Receptor p75 in Classic Bladder Exstrophy

Successful primary closure of classic bladder exstrophy (BE) is crucial for development of bladder capacity and voided continence. It is universally agreed that an intensive pain management including the use of caudal epidural anesthesia is an essential cornerstone for the outcome of this complex surgery. Whether and to what extent pain is caused by structural or functional changes is not yet known. The nerve growth factor (NGF) is regarded as a marker for pain in different bladder disorders. This prospective study investigated the role of histological alterations and NGF in patients with BE including 34 patients with BE and 6 patients with congenital vesicoureterorenal reflux (VUR) who served as controls. Between January 2015 and April 2020 transmural bladder biopsies were taken from the posterior bladder wall during delayed primary bladder closure. The samples were stained for histological evaluation and subjected to immunohistochemistry to analyze NGFR p75. Differences in histological alterations were examined with Fisher's exact test, and Mann-Whitney-U-test was used to compare the NGFR p75 staining intensity between patients with BE and controls. Patients with BE showed significantly more often acute inflammation (p < 0.001), squamous metaplasia (p = 0.002), and cystitis glandularis (p = 0.005) as well as NGFR p75 in the urothelium (p = 0.003) than patients with VUR. A limitation of this study is the small number of participants due to the rare disease entity. Similar to other painful bladder disorders, pain transmission in BE after intitial closure may in part be facilitated by elevated NGF signaling through its receptor.

Treatment Patterns With Antipsychotics in Long-Term Care Patients With Parkinson’s Disease Psychosis

This study assessed treatment change patterns in Parkinson’s disease psychosis (PDP) residents receiving antipsychotic (AP) therapies in U.S. long-term care (LTC) facilities. Residents with PDP in LTC between 01/01/13 and 06/30/16 were identified with ≥1 claim of psychosis, hallucinations, or delusions after PD diagnosis. Treatment patterns were evaluated during the 12 months post index. We identified 864 PDP residents: 408 (47.2%) on AP therapy and 456 (52.8%) on no AP therapy. A total of 335 residents (82.1%) continued, 13 (3.2%) discontinued, 11 (2.7%) switched, and 49 (12.0%) augmented (used ≥2 APs) their index AP therapy. Based on the multivariate regression analysis, younger age, male gender, anemia, anxiolytic use or anxiety, sedatives/hypnotic use, bladder disorders including urinary tract infections, coronary conditions, diabetes, hypertension, and dementia were associated with a higher likelihood of treatment change. Understanding the factors associated with treatment change may inform ways to improve management of PDP in the U.S. LTC setting.

Cellular Senescence in Renal and Urinary Tract Disorders

Cellular senescence is a state of cell cycle arrest induced by repetitive cell mitoses or different stresses, which is implicated in various physiological or pathological processes. The beneficial or adverse effects of senescent cells depend on their transitory or persistent state. Transient senescence has major beneficial roles promoting successful post-injury repair and inhibiting malignant transformation. On the other hand, persistent accumulation of senescent cells has been associated with chronic diseases and age-related illnesses like renal/urinary tract disorders. The deleterious effects of persistent senescent cells have been related, in part, to their senescence-associated secretory phenotype (SASP) characterized by the release of a variety of factors responsible for chronic inflammation, extracellular matrix adverse remodeling, and fibrosis. Recently, an increase in senescent cell burden has been reported in renal, prostate, and bladder disorders. In this review, we will summarize the molecular mechanisms of senescence and their implication in renal and urinary tract diseases. We will also discuss the differential impacts of transient versus persistent status of cellular senescence, as well as the therapeutic potential of senescent cell targeting in these diseases.

Swim Bladder Disorders in Koi Carp (Cyprinus carpio)

Swim bladder disorders and consequent buoyancy problems are encountered in ornamental fish, including koi carp. Nevertheless, beyond clinical and pharmacological management, they are largely underdiagnosed. In this study, nine koi carp showing abdominal swelling and abnormal swimming behavior were investigated. Clinical approach, varying from case to case, included ultrasonographic and X-ray investigations, bacteriological analysis of the collected fluid, antimicrobial susceptibility pattern, and possibly histological analysis. Diagnostic imaging, corroborating gross examination, documented swim bladder deformation/dislocation and serous fluid within the swim bladder chambers of most animals. Bacteria belonging to the Aeromonas hydrophila/caviae group and Shewanella xiamenensis were identified. S. xiamenensis strains showed a sensibility to all tested molecules except for one strain, which was resistant to tetracycline and cyprofloxacin. Antibiotic treatment succeeded in the full recovery of three cases in which S. xiamemensis infection was detected. Chronic aerocystitis was histologically documented where tissue was available. The swim bladder histopathological findings highlighted a chronic process that had compromised the quality of life of the animals. A multidisciplinary clinical–pathological and microbiological approach is highly suggested to recognize swim bladder conditions as early as possible, aiming to drive medical intervention and raising the chances of fish survival.