Transcriptome signature changes in the liver of a migratory passerine.

The liver plays a principal role in avian migration. Here, we characterised the liver transcriptome of a long-distance migrant, the Northern Wheatear (Oenanthe oenanthe), sampled at different migratory stages, looking for molecular processes linked with adaptations to migration. The analysis of the differentially expressed genes suggested changes in the periods of the circadian rhythm, variation in the proportion of cells in G1/S cell-cycle stages and the putative polyploidization of this cell population. This may explain the dramatic increment in the liver's metabolic capacities towards migration. Additionally, genes involved in anti-oxidative stress, detoxification and innate immune responses, lipid metabolism, inflammation and angiogenesis were regulated. Lipophagy and lipid catabolism were active at all migratory stages and increased towards the fattening and fat periods, explaining the relevance of lipolysis in controlling steatosis and maintaining liver health. Our study clears the way for future functional studies regarding long-distance avian migration.

Treatment Patterns Among Patients With Advanced Prostate Cancer in Brazil: An Analysis of a Private Healthcare System Database.

Background: With the ongoing expansion of life-prolonging therapies approved to treat advanced prostate cancer, there is currently an unmet need to better understand real-world treatment patterns and identify optimal treatment sequencing for men with metastatic castration-resistant prostate cancer (mCRPC). Methods: In this retrospective, observational cohort analysis, patients with confirmed mCRPC were identified in the Auditron claims database and used to describe mCRPC treatment patterns and trends in the Brazilian private healthcare system from 2014 to 2019. Demographics and clinical characteristics, prostate cancer stage at diagnosis, and type and number of treatment lines were evaluated. The primary endpoint was identification of the drugs used in first-line therapies in mCRPC, and the secondary endpoint included a description of sequential lines of therapy (second and third lines) in mCRPC. Results: A total of 168 electronic patient records were reviewed. Docetaxel was the most frequently used first-line treatment (35.7%), followed by abiraterone (33.3%) and enzalutamide (13.1%). Docetaxel, abiraterone, and enzalutamide also accounted for 34.6%, 28.0%, and 15.0%, respectively, of second-line therapies. In third-line therapies, cabazitaxel (26.1%), enzalutamide (23.9%), docetaxel (15.2%), and abiraterone (15.2%) were most commonly prescribed. Irrespective of stage at diagnosis, treatment patterns were similar once the disease progressed to the metastatic castration-resistance stage. Conclusions: Docetaxel was the most frequently utilized therapy for mCRPC treatment, followed by abiraterone and enzalutamide. Although the current analyses provide real-world insights into treatment patterns for patients with mCRPC in Brazil, additional real-world data are needed to further validate and expand on these findings.

Custo-efetividade de mirabegrona no tratamento de primeira escolha da síndrome da bexiga hiperativa: uma análise sob a perspectiva do sistema de saúde brasileiro / Cost-effectiveness of mirabegron as first-choice treatment for overactive bladder syndrome: an analysis from the Brazilian health system perspective

Objetivo: Avaliar a relação de custo-efetividade de mirabegrona como tratamento de primeira escolha de pacientes adultos com síndrome da bexiga hiperativa (SBH) comparada a antimuscarínicos orais comumente prescritos no manejo dessa condição. Métodos: O modelo de Markov foi utilizado, com ciclos mensais e horizonte temporal de um ano, para analisar a relação de custo-efetividade de mirabegrona em comparação a tolterodina, oxibutinina, darifenacina e solifenacina. Os pacientes iniciaram o modelo em tratamento com mirabegrona ou um dos comparadores, sendo distribuídos em cinco níveis de gravidade da doença, de acordo com a frequência miccional e número de episódios de incontinência, e a cada ciclo mensal poderiam melhorar, piorar ou permanecer no mesmo nível de severidade do ciclo anterior. Os resultados foram apresentados por meio de uma razão de custo-efetividade incremental. Resultados: Considerando a perspectiva do sistema de saúde suplementar, o custo total do tratamento com mirabegrona foi de R$ 2.455,26 e os parâmetros de efetividade em 0,491 e 0,498 (melhora na gravidade da incontinência e frequência miccional, respectivamente), sendo mais efetivo que os comparadores. Com relação à perspectiva pública, foi estimado um custo com o tratamento de R$ 1.396,01, com características similares de efetividade. De maneira geral, o tratamento com mirabegrona foi dominante quando comparado à tolterodina e custo-efetivo na comparação com os demais antimuscarínicos, em ambas as perspectivas analisadas. Conclusão: Mirabegrona demonstrou ser a melhor opção para tratamento de primeira escolha da SBH com potencial de redução de custos ao longo do tempo, tanto para o sistema público quanto para o sistema de saúde suplementar brasileiro.

Objective: To assess the cost-effectiveness of mirabegron as first-choice treatment in adult patients with of overactive bladder (OAB) compared to oral antimuscarinics, usually prescribed for this condition. Methods: A Markov model has been adopted, with monthly cycles and a one-year time horizon, to analyze the cost-effectiveness of mirabegron compared to antimuscarinic agents: tolterodine; oxybutynin; darifenacin; and solifenacin. The model started with patients receiving treatment with mirabegron or one of the comparators and then, they were assigned to five disease severity levels according to micturition frequency and number of incontinence episodes, and within each monthly cycle they could improve, worsen or remain at the same symptom severity level. Results were presented using an incremental cost-effectiveness ratio. Results: Considering the Brazilian private perspective, treatment with mirabegron resulted in a total cost of R$ 2,455.26 and effectiveness parameters at 0.491 and 0.498 (improvement in incontinence severity and micturition, respectively), being more effective than the comparators. Regarding the Brazilian public perspective, treatment with mirabegron resulted in a total cost of R$ 1,396.01 with similar effectiveness estimation. In general, a dominance was observed when mirabegron was compared to tolterodine and a cost-effectiveness profile against the other muscarinic antagonists, considering both health perspectives. Conclusion: Mirabegron has proven to be the best option for OAB first-line treatment with potential cost savings over time for both the public and private health care systems in Brazil.

Imaging Factors Impacting on Accuracy and Radiation Dose in 3D Printing.

OBJECTIVES: To compare reconstructed area and surface roughness of 3D models acquired using nine image acquisition protocols. Radiation dose was also compared among acquisition protocols. METHODS: A dry craniofacial specimen was scanned using three CT devices (a cone beam CT, a 16-channel fan beam CT, and a 64-channel fan beam CT), with three different acquisition protocols each. Nine 3D models were manufactured using polylactic acid. Surface roughness and reconstructed area were determined for each 3D model. The radiation dose during acquisitions was measured using lithium crystals. ANOVA was used to compare the data among the 3D models. Linear function optimization techniques based on stochastic variables were applied to identify the most suitable protocol for use. RESULTS: For surface roughness, statistically significant differences were observed among all 3D models and the specimen. For reconstructed area, CBCT and one CT-16 channel protocols originated 3D models statistically significant different from the specimen. Higher radiation doses were observed with fan beam CT acquisitions. CONCLUSIONS: All three CT devices were suitable for 3D printing when used at full resolution. The highest reconstruct area vs. radiation dose ratio was found for 64-channel CT devices.

Morphological and functional response to injury to the external urethral sphincter - similarities and differences between male and female rats.

AIMS: The objective of this study was to evaluate the similarities and differences of the urethral morphological and functional changes following external urethral sphincter EUS injury in male and female rats. METHODS: 30 female and 30 male age-matched Wistar rats were used in the experiments. Half of them underwent electrocauterization of the surrounding tissues lateral to the urethra at the level of the (EUS) and the others, a sham operation. At 2, 6, and 16 weeks after surgeries they underwent anesthetized cystometry, measurement of leak point pressure (LPP) and their urethras were harvested for morphological analyses. RESULTS: There were no differences in cystometric parameters between sex-time-matched animals, ensuring normal bladder function in the manipulated animals. The mean LPP in male and female rats was lower compared with sham animals. Age-time-matched sham operated male rats exhibited a higher LPP compared with female rats. The reduction in LPP comparing electrocauterized and sham time-matched animals was more pronounced in male rats than in female rats. Electrocauterization produced urethral collagen deposition and nerve damage in both male and female animals. Muscle atrophy and disruption also occurred, being more evident in female rats. CONCLUSIONS: The urethras of male and female rats exhibited a similar morphological and functional response to electrocauterization. The time-course evaluation revealed that the male animal model is as reliable, reproducible and long-lasting as the female model. Intact males had a higher LPP than female rats and the nerve injury led to a more drastic impairment of this mechanism.

Prótesis Parcial Obturatriz Paralelizada, en Paciente Oncológico / Partial parallelized obturator prosthesis in oncological patient

Al enfrentarnos a casos que tienen relación con tumores de cabeza y cuello, hay que tener en cuenta la gran diversidad de presentaciones de las neoplasias, histopatología y topografía anatómica de las mismas. Sumado a esto intervendrán factores etiológicos o de riesgo, que darán distintas características epidemiológicas, sintomatológicas, tanto en la forma de progresión de la enfermedad, como en su pronóstico y plan de tratamiento. En este trabajo los autores presentan un caso clínico de una paciente femenino de 25 años con una maxilectomia, por mixoma odontogénico, en su variable histológica de Fibromixoma Odontogénico, ubicado en el seno maxilar derecho. El tratamiento rehabilitador protésico, se realiza con una prótesis obturatriz esquelética, preparando los pilares paralelizados, con los principios de un eje único y preciso de inserción y retiro...

When dealing with neck and head cancer patients, we must consider the many different types of such tumors that appear when conducting histopathologic and anatomic topography assessment. To this we must add etiological or risk factors that will result in various epidemiological and symptomatological characteristics, both regarding the progression of the disease and the prognosis and treatment plan. In this work a clinical case is presented: a 25-year-old female patient who underwent right maxillectomy for an odontogenic myxoma (fibromyxoma) located in her right maxillary sinus. Prosthetic rehabilitation is done with framework obturator prosthesis. The remaining teeth are prepared by creating parallel pillars to obtain a single and accurate axis for insertion and removal...

Evaluation of the metabolism of glycosaminoglycans in patients with interstitial cystis.

INTRODUCTION: Painful bladder syndrome/interstitial cystitis (PBS/IC) pathogenesis is not fully known, but evidence shows that glycosaminoglycans (GAG) of bladder urothelium can participate in its genesis. The loss of these compounds facilitates the contact of urine compounds with deeper portions of bladder wall triggering an inflammatory process. We investigated GAG in urine and tissue of PBS/IC and pure stress urinary incontinence (SUI) patients to better understand its metabolism. MATERIALS AND METHODS: Tissue and urine of 11 patients with PBS/IC according to NIDDK criteria were compared to 11 SUI patients. Tissue samples were analyzed by histological, immunohistochemistry and immunofluorescence methods. Statistical analysis were performed using t Student test and Anova, considering significant when p < 0.05. RESULTS: PBS/IC patients had lower concentration of GAG in urine when compared to SUI (respectively 0.45 ± 0.11 x 0.62 ± 0.13 mg/mg creatinine, p < 0.05). However, there was no reduction of the content of GAG in the urothelium of both groups. Immunofluorescence showed that PBS/IC patients had a stronger staining of TGF-beta, decorin (a proteoglycan of chondroitin/dermatan sulfate), fibronectin and hyaluronic acid. CONCLUSION: the results suggest that GAG may be related to the ongoing process of inflammation and remodeling of the dysfunctional urothelium that is present in the PBS/IC.

Evaluation of the metabolism of glycosaminoglycans in patients with interstitial cystis

Introduction: Painful bladder syndrome/interstitial cystitis (PBS/IC) pathogenesis is not fully known, but evidence shows that glycosaminoglycans (GAG) of bladder urothelium can participate in its genesis. The loss of these compounds facilitates the contact of urine compounds with deeper portions of bladder wall triggering an inflammatory process. We investigated GAG in urine and tissue of PBS/IC and pure stress urinary incontinence (SUI) patients to better understand its metabolism. Materials and Methods: Tissue and urine of 11 patients with PBS/IC according to NIDDK criteria were compared to 11 SUI patients. Tissue samples were analyzed by histological, immunohistochemistry and immunofluorescence methods. Statistical analysis were performed using t Student test and Anova, considering significant when p < 0.05. Results: PBS/IC patients had lower concentration of GAG in urine when compared to SUI (respectively 0.45 ± 0.11 x 0.62 ± 0.13 mg/mg creatinine, p < 0.05). However, there was no reduction of the content of GAG in the urothelium of both groups. Immunofluorescence showed that PBS/IC patients had a stronger staining of TGF-beta, decorin (a proteoglycan of chondroitin/dermatan sulfate), fibronectin and hyaluronic acid. Conclusion: the results suggest that GAG may be related to the ongoing process of inflammation and remodeling of the dysfunctional urothelium that is present in the PBS/IC. .

Effects of allogeneic bone marrow derived mesenchymal stromal cell therapy on voiding function in a rat model of Parkinson disease.

PURPOSE: Cellular therapy induced transient urodynamic improvement in a rat model of Parkinson disease in which bladder dysfunction was noted after unilateral injection of 6-hydroxydopamine into the medial forebrain bundle. We sought to prolong the effect by injecting allogeneic rat bone marrow mesenchymal stromal cells before and after microencapsulation into the substantia nigra pars compacta. MATERIALS AND METHODS: Female rats underwent unilateral stereotactic injection of 6-hydroxydopamine in the medial forebrain bundle. Injection was performed in the ipsilateral substantia nigra pars compacta using vehicle alone or vehicle with nonmicroencapsulated or microencapsulated rat bone marrow derived mesenchymal stromal cells. Rats were evaluated by cystometry 7, 14, 28 and 42 days after treatment. Brains were extracted for immunostaining. RESULTS: At 42 days the nonmicroencapsulated group had lower threshold and intermicturition pressure, spontaneous activity and AUC than vehicle treated animals. Rats that received microencapsulated cells had lower threshold pressure at 28 days and lower spontaneous activity at 42 days than vehicle treated rats. Microencapsulated and nonmicroencapsulated rat bone marrow derived mesenchymal stromal cells were noted in the substantia nigra pars compacta up to 42 days after transplantation. At 42 days tyrosine hydroxylase positive neurons were more numerous in the substantia nigra pars compacta of the nonmicroencapsulated group, followed by the microencapsulated and vehicle treated groups. CONCLUSIONS: Urodynamic effects of the 6-hydroxydopamine lesion persisted up to 42 days after vehicle injection. Transplantation of nonmicroencapsulated rat bone marrow derived mesenchymal stromal cells improved urodynamic pressure by 42 days after treatment more markedly than microencapsulated cells. This was associated with more tyrosine hydroxylase positive neurons in the treated substantia nigra pars compacta of the nonmicroencapsulated group, suggesting that functional improvement requires a juxtacrine effect.

Descentralización de la atención de prótesis buco maxilo facial en el Uruguay / Decentralized care of oral maxillofacial prosthetics in Uruguay

La rehabilitación integral del paciente mutilado facial implica un gran desafío, el poderle brindar un tratamiento económicamente accesible y en el mismo medio donde el paciente vive es de importancia capital.Independientemente de la cobertura de salud que el paciente tenga, de su nivel socioeconómico ó de su lugar de residencia en el territorio nacional.El objetivo de este artículo es la divulgación de los logros alcanzados en la descentralización de la Prótesis Buco Maxilo Facial en nuestro País, fruto del trabajo conjunto entre dos Instituciones, la Universidad de la República y la Administración de los Servicios de Salud del Estado.

The rehabilitation of facial maimed patients, means a great challenge. The chance to provide accessible and economic care in the same environment where the patient lives, is paramount, regardless the health coverage the patient might have, his socioeconomic status residence place in the country.The aim of this article is the dissemination of the achievements of the decentralization of Maxillofacial Prosthetics care, that is a joint work between of two institutions, the University of the Republic and the Administration of State Health Services.

Association between bacteremia due to Streptococcus gallolyticus subsp. gallolyticus (Streptococcus bovis I) and colorectal neoplasia: a case-control study.

BACKGROUND: The association between bacteremia by Streptococcus gallolyticus subsp. gallolyticus (SGG) and colorectal neoplasia (CRN) is well established but the frequency of the association varies widely in different studies. We conducted a case-control study to assess the association between SGG bacteremia and CRN. METHODS: An analysis of all SGG bacteremias was performed during the period 1988-2011. The frequency of CRN in patients with SGG bacteremia was compared with the frequency of CRN in a symptomatic control group of patients matched at a 1:2 ratio for gender and age (±3 years) without S. bovis bacteremia and personal history of CRN and with increased risk of CRN (by the presence of symptoms, signs, or test suspicious of colonic pathology or by family history of CRN). RESULTS: One hundred nine cases of SGG bacteremia were detected (mean age, 66 years; 87% male). Colonoscopy was performed in 98 cases, diagnosing 69 cases of CRN: 57 adenomas (39 advanced adenomas) and 12 invasive carcinomas. Only 4 cases had suspected CRN before the blood culture. The prevalence of CRN was higher in patients with SGG bacteremia than in the 196 control patients (70% vs 32%; odds ratio [OR], 5.1; 95% confidence interval [CI], 3.0-8.6). This difference was not significant when comparing nonadvanced adenomas (19% vs 12%), but we found significant differences in advanced adenomas (40% vs 16%; OR, 3.5; 95% CI, 2.0-6.1) and invasive carcinomas (12% vs 5%; OR, 2.9; 95% CI, 1.2-6.9). CONCLUSIONS: The frequency of CRN among SGG infected patients is significantly increased compared with symptomatic age-matched controls, indicating that SGG infection is a strong indicator for underlying occult malignancy.

Stem cell therapy ameliorates bladder dysfunction in an animal model of Parkinson disease.

PURPOSE: Different cell based therapies have been tested, focusing on motor function. We evaluated the effect of human amniotic fluid stem cells and bone marrow derived mesenchymal stem cells (ALLCELLS, Emeryville, California) on bladder dysfunction in a rat model of Parkinson disease. MATERIAL AND METHODS: A nigrostriatal lesion was induced by 6-hydroxydopamine in 96 athymic nude female rats divided into 3 treatment groups. After 2 weeks the groups were injected with human amniotic fluid stem cells, bone marrow derived mesenchymal stem cells and vehicle for sham treatment, respectively. At 3, 7, 14 and 28 days the bladder function of 8 rats per group was analyzed by conscious cystometry. Brains were extracted for immunostaining. RESULTS: The nigrostriatal lesion caused bladder dysfunction, which was consistent in sham treated animals throughout the study. Several cystometric parameters improved 14 days after human amniotic fluid stem cell or bone marrow derived mesenchymal stem cell injection, concomitant with the presence of human stem cells in the brain. At 14 days only a few cells were observed in a more caudal and lateral position. At 28 days the functional improvement subsided and human stem cells were no longer seen. Human stem cell injection improved the survival of dopaminergic neurons until 14 days. Human stem cells expressed superoxide dismutase-2 and seemed to modulate the expression of interleukin-6 and glial cell-derived neurotrophic factor by host cells. CONCLUSIONS: Cell therapy with human amniotic fluid stem cells and bone marrow derived mesenchymal stem cells temporarily ameliorated bladder dysfunction in a Parkinson disease model. In contrast to integration, cells may act on the injured environment via cell signaling.

Rodent models for urodynamic investigation.

Rodents, most commonly rats, mice, and guinea pigs are widely used to investigate urinary storage and voiding functions, both in normal animals and in models of disease. An often used methodology is cystometry. Micturitions in rodents and humans differ significantly and this must be considered when cystometry is used to interpret voiding in rodent models. Cystometry in humans requires active participation of the investigated patient (subject), and this can for obvious reasons not be achieved in the animals. Cystometric parameters in rodents are often poorly defined and do not correspond to those used in humans. This means that it is important that the terminology used for description of what is measured should be defined, and that the specific terminology used in human cystometry should be avoided. Available disease models in rodents have limited translational value, but despite many limitations, rodent cystometry may give important information on bladder physiology and pharmacology. The present review discusses the principles of urodynamics in rodents, techniques, and terminology, as well as some commonly used disease models, and their translational value.

Beta3-adrenoceptors in the rat sacral spinal cord and their functional relevance in micturition under normal conditions and in a model of partial urethral obstruction.

AIMS: Beta3-adrenoceptor selective agonists are evaluated as a new treatment for patients with lower urinary tract symptoms . It is believed that ß3-AR selective agonists exert their effects via a peripheral site of action. However, ß3-ARs have been found in brain tissue. This study examined whether ß3-ARs are present in rat sacral spinal cord, and whether there are differences in ß3-AR expression between normal and partial urethral obstruction (PUO) animals, and furthermore assessed the functional relevance of spinal ß3-ARs for micturition. METHODS: Thirty-eight male Sprague-Dawley rats underwent either PUO or sham-operation. Two weeks after operation, half of the animals were used for histomorphological analysis. Remaining animals were used for functional experiments, where a ß3-AR selective agonist, BRL 37344, was given intrathecally. Bladder function was assessed by continuous cystometry in non-anesthetized animals before and after drug administration. RESULTS: Beta3-ARs were found in sacral spinal cord segments with an accumulation in the ventral horn. There was a significant increase of ß3-AR expression in obstructed rats. In functional experiments obstructed rats showed increased bladder weight, micturition frequency, spontaneous activity, and bladder pressures (all P < 0.05) compared to controls. Intrathecally administered BRL 37344 showed no effect in non-obstructed rats. In obstructed rats intrathecal BRL 37344 significantly reduced bladder pressures, spontaneous activity, and micturition frequency (all P < 0.05). CONCLUSIONS: Beta3-ARs are present in rat sacral spinal cord, and are significantly up-regulated after PUO. Besides their well-established peripheral site of action in the treatment of voiding dysfunction, ß3-AR selective agonists might exert relevant effects at a central nervous site of action.

Vascular therapy for radiation cystitis.

PURPOSE: The underlying pathology of radiation cystitis is cellular and vascular damage followed by increased fibrosis and inflammation. This study was to determine if neovascular-promoting therapy could reduce the pathological changes in the bladder wall associated with pelvic irradiation. METHODS: Adult female Lewis inbred rats were irradiated with a single dose of 20 Gy directed at their bladder. Four weeks later, 30 rats were divided equally into one of three treatment groups for bladder wall injection of: (1) PBS (Control); (2) PBS containing 50 ng vascular endothelial growth factor (VEGF (165)); or (3) PBS containing 1 × 10(6) rat endothelial cells (EC). Age-matched non-irradiated rats (n = 10) served as untreated controls. At either 1.5 or 3 months following radiation, bladders were analyzed for collagen deposition using Masson's Trichrome staining of collagen and muscle and vascularization using Von Willebrand factor staining of ECs. Quantitative-PCR was used to examine markers of angiogenesis, hypoxia, and fibrosis. RESULTS: The collagen/muscle ratio was doubled in the control group 3 months post-irradiation (P < 0.05 vs. non-irradiated bladders). Both ECs and VEGF inhibited increases in collagen content (P < 0.05 vs. control). Similarly, irradiation reduced bladder wall vessel counts compared to non-irradiated controls (P < 0.05) and both ECs and VEGF maintained vessel counts similar to that of non-irradiated controls (P < 0.05). PCR analysis showed a higher expression of neovascular markers (CD31, KDR) in the EC and VEGF groups compared to non-irradiated controls (P < 0.05). CONCLUSIONS: Angiogenesis therapy may be useful in the prevention and/or treatment of the underlying pathology of radiation cystitis.

Development of bladder dysfunction in a rat model of dopaminergic brain lesion.

AIMS: Parkinson's disease (PD) is one of the most common neurological disorders causing lower urinary tract dysfunction. We evaluated the temporal development of bladder dysfunction in rat PD model where urodynamic changes were induced by unilateral injection of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle (MFB). METHODS: Female Sprague-Dawley rats underwent a unilateral stereotaxic injection of 6-OHDA or vehicle (sham group) into the MFB. Cystometry was performed in conscious animals at 3, 14, and 28 days after the injury. Aged-matched unlesioned rats were used as healthy controls. RESULTS: Three days after lesion 6-OHDA rats showed higher threshold (TP), maximum pressures (MP), and spontaneous activity (SA) compared to healthy controls. Sham animals exhibited higher TP. After 14 days 6-OHDA rats had also higher micturition frequency, decreased bladder capacity, micturition volume and bladder compliance (Bcom) compared to sham and healthy controls. Sham animals showed lower Bcom and higher MP and SA. After 28 days, 6-OHDA rats exhibited the same changes as those in 14 days, while sham-operated animals showed parameters similar to those in healthy controls. CONCLUSIONS: These findings suggest that 6-OHDA lesion of the MFB causes bladder dysfunction already after 3 days. A pattern of detrusor overactivity was more clearly defined 14 days after the injection and persisted for 28 days. Cystometry may be a useful tool to study the pathophysiology of bladder dysfunction in PD, and urodynamic parameters may possibly be used to evaluate the effects of therapeutic interventions.

Bladder dysfunction in a new mutant mouse model with increased superoxide--lack of nitric oxide?

PURPOSE: Nitric oxide mediates urethral smooth muscle relaxation and may also be involved in detrusor activity control. Mice with mutation in the Immp2l gene have high superoxide ion levels and a consequent decrease in the bioavailable amount of nitric oxide. We studied bladder function in this mouse model. MATERIAL AND METHODS: Young male mutants at ages 4 to 6 months, old female mutants at age 18 months and healthy WT age matched controls were used. The detrusor contractile response to carbachol and electrical field stimulation was tested in isolated detrusor strips in organ baths. In vivo bladder function was evaluated by cystometry in conscious animals. RESULTS: Young male mutants had significantly lower micturition and higher post-void residual volume than WT controls. They had pronounced voiding difficulty and strained when initiating micturition. Detrusor contractile responses to carbachol and electrical field stimulation were similar in mutant and WT mice. Old female mutant mice had lower bladder capacity and micturition volume, and higher micturition frequency and bladder-to-body weight ratio than WT controls. In the in vitro study detrusor strips from mutants showed a lower maximum response to carbachol. CONCLUSIONS: Mice with mutation in the Immp2l gene have bladder dysfunction, mainly characterized by emptying abnormalities in young males and increased detrusor activity in old females. Detrusor function was preserved in young males and impaired in old females. These animals are a natural model of oxidative stress with low bioavailable nitric oxide. Thus, they are interesting tools in which to evaluate the role of these conditions on bladder dysfunction.