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Loss of bladder control is a challenging outcome facing patients with spinal cord injury (SCI). We report that systemic blocking of pro-nerve growth factor (proNGF) signaling through p75 with a CNS-penetrating small-molecule p75 inhibitor resulted in significant improvement in bladder function after SCI in rodents. The usual hyperreflexia was attenuated with normal bladder pressure, and automatic micturition was acquired weeks earlier than in the controls. The improvement was associated with increased excitatory input to the spinal cord, in particular onto the tyrosine hydroxylase-positive fibers in the dorsal commissure. The drug also had an effect on the bladder itself, as the urothelial hyperplasia and detrusor hypertrophy that accompany SCI were largely prevented. Urothelial cell loss that precedes hyperplasia was dependent on p75 in response to urinary proNGF that is detected after SCI in rodents and humans. Surprisingly, death of urothelial cells and the ensuing hyperplastic response were beneficial to functional recovery. Deleting p75 from the urothelium prevented urothelial death, but resulted in reduction in overall voiding efficiency after SCI. These results unveil a dual role of proNGF/p75 signaling in bladder function under pathological conditions with a CNS effect overriding the peripheral one.

Underactive bladder (UAB) is a common disorder that significantly affects patients’ quality of life, necessitating the exploration of underlying molecular mechanisms for more effective management. This study aims to elucidate the gene expression profiles associated with UAB by employing a combination of bioinformatics analyses and experimental validation to identify pivotal hub genes and potential therapeutic targets. We accessed the GSE122060 and GSE100219 datasets from the Gene Expression Omnibus (GEO) database to identify differentially expressed genes (DEGs), followed by functional enrichment analysis, construction of a protein-protein interaction (PPI) network, screening for hub genes and assess the accuracy and diagnostic value of the hub genes with the validation dataset GSE28242. Eighty-five DEGs were identified from the GEO dataset, with functional enrichment analysis focusing primarily on biological processes like neutrophil migration, cell chemotaxis, and bacterial defense responses. Twelve key genes were identified in the PPI network using CytoHubba and MCODE plugins. Of these, C3, CLEC4E, CSF3R, CXCR2, FPR2, and IDO1 showed significant upregulation in the validation set compared to the control group. Receiver operating characteristic (ROC) curve analysis demonstrated that these six hub genes possess high diagnostic potential, with area under the curve (AUC) values greater than 0.76. Additionally, a hub gene-transcription factor (TF) interaction network, a hub gene-TF-miRNA co-regulatory network and a hub gene-drug interaction network were constructed, revealing that five TFs and five miRNAs regulate three or more hub genes. Quantitative real-time polymerase chain reaction (qRT-PCR) validation confirmed the differential expression patterns of the 12 key genes in the PPI network in TGF-β1 treated SV-HUC-1 cells. In conclusion, our findings suggest that CLEC4E, CSF3R, CXCR2, FPR2, and IDO1 can serve as promising diagnostic biomarkers for UAB, while the identified TFs and miRNAs could unveil new avenues for drug discovery and therapeutic interventions targeting UAB progression.

Lower urinary tract and/or kidney malformations are collectively the most common cause of end-stage renal disease in children, and they are also likely to account for a major subset of young adults requiring renal replacement therapy. Advances have been made regarding the discovery of the genetic causes of human kidney malformations. Indeed, testing for mutations of key nephrogenesis genes is now feasible for patients seen in nephrology clinics. Unfortunately, less is known about defined genetic bases of human lower urinary tract anomalies. The focus of this review is the genetic bases of congenital structural and functional disorders of the urinary bladder. Three are highlighted. First, prune belly syndrome, where mutations of CHRM3 , encoding an acetylcholine receptor, HNF1B , encoding a transcription factor, and ACTA2 , encoding a cytoskeletal protein, have been reported. Second, the urofacial syndrome, where mutations of LRIG2 and HPSE2 , encoding proteins localised in nerves invading the fetal bladder, have been defined. Finally, we review emerging evidence that bladder exstrophy may have genetic bases, including variants in the TP63 promoter. These genetic discoveries provide a new perspective on a group of otherwise poorly understood diseases.

Xq28 duplications encompassing MECP2 have been described in male patients with a severe neurodevelopmental disorder associated with hypotonia and spasticity, severe learning disability and recurrent pneumonia. We identified an Xq28 duplication in three families where several male patients had presented with intestinal pseudo-obstruction or bladder distension. The affected boys had similar dysmorphic facial appearances. Subsequently, we ascertained seven further families where the proband presented with similar features. We demonstrated duplications of the Xq28 region in five of these additional families. In addition to MECP2, these duplications encompassed several other genes already known to be associated with diseases including SLC6A8, L1CAM and Filamin A (FLNA). The two remaining families were shown to have intragenic duplications of FLNA only. We discuss which elements of the Xq28 duplication phenotype may be associated with the various genes in the duplication. We propose that duplication of FLNA may contribute to the bowel and bladder phenotype seen in these seven families.

Study Design: An experimental study. Objectives: To investigate the effect of replication-defective herpes simplex virus (HSV) vectors encoding the kynurenine aminotransferase II (HSVrd-KATII) gene on detrusor-sphincter dyssynergia (DSD) in spinal cord injury (SCI) rats. Setting: Beijing, China. Methods: Sprague–Dawley rats (240–265 g) were spinalized with complete transaction at the T10 level of the spinal cord. The rats were randomly divided into the following three groups: sham group ( n =12, with normal saline); HSVrd group ( n =12, with HSVrd) and HSVrd-KATII group ( n =12, with HSVrd-KATII). One week after spinalization normal saline, HSVrd or HSVrd-KATII was injected into the bladder walls of the three groups, respectively. Three weeks after virus injection, the urethral pressure profile (UPP) and continuous cystometry were performed under awake conditions and gene expression was evaluated in all of the SCI rats. Results: In the HSVrd-KATII group, the maximum urethral closure pressure (Pclo.max), maximum voiding pressure (MVP), and the number and amplitude of non-voiding contraction (NVCs) were significantly decreased (34.7–39.1%, 46.7–56.2% and 31.5–32.5%, respectively), along with an increase in voiding efficiency (49.1–52.1%) compared with the sham and HSVrd groups. In addition, the levels of KATII protein and mRNA were significantly increased in the L6-S1 dorsal root ganglia (DRG) and L6-S1 spinal cord segments in the HSVrd-KATII group compared with the HSVrd group. Conclusions: HSVrd vector encoding the KATII gene effectively improved DSD and detrusor overactivity by bladder-wall injection, perhaps by blocking N-methyl- d -aspartate receptors in the L6-S1 dorsal root ganglion and L6-S1 spinal cord.

Inflammatory myofibroblastic tumours (IMFT) may arise at any anatomical site, including lung, soft tissues, retroperitoneum and bladder. Although morphologically similar, these lesions encompass a spectrum of entities with differing aetiology, ranging from reactive/regenerative proliferations to low-grade neoplasms with a risk of local recurrence, but no significant metastatic potential. Vesical IMFT usually presents as a polypoid mass with a pale firm cut surface and can be of considerable size, mimicking a malignant tumour clinically and radiologically. Its good outcome, however, warrants conservative surgical excision, emphasising the importance of identification and distinction from malignant tumours of the bladder that may require more radical surgery and/or adjuvant therapy. We conducted a preliminary retrospective, comparative immunocytochemical study of 20 bladder tumours, including nine IMFTs, five spindle cell (sarcomatoid) carcinomas, two rhabdomyosarcomas, two leiomyosarcomas and two neurofibromas. The results confirmed IMFT positivity for smooth muscle actin, desmin and cytokeratin in 78–89% cases, resulting in potential confusion with sarcomatoid carcinoma or leiomyosarcoma. In contrast, cytoplasmic anaplastic lymphoma kinase (ALK 1) staining was present in eight IMFT (89%), but was not seen in any other lesion examined. The ALK 1 staining was confirmed by fluorescence in situ hybridisation, with translocation of the ALK gene present in 15–60% tumour cells in four of six IMFT examined, but not in four cases of sarcomatoid carcinoma or three of leiomyosarcoma. In conclusion, ALK 1 staining may be of value in the distinction of vesical IMFT from morphologically similar entities, and often reflects ALK gene translocations in these lesions.

Background: Urofacial syndrome (UFS) is characterised by congenital bladder dysfunction accompanied by a characteristic abnormal grimace upon smiling and crying. In recent years, biallelic mutations of HPSE2 and LRIG2 have been reported in UFS patients. Non-neurogenic neurogenic bladder (NNNB) has a bladder identical to UFS without typical facial features. The aim of this study was to analyse HPSE2 mutations in patients with UFS and NNNB or severe lower urinary tract dysfunction (LUTD) without abnormal facial expression. Methods: Patients with UFS, NNNB and severe LUTD were enrolled in the study. We examined a total of 35 patients from 33 families. There were seven UFS patients from five different families, 21 patients with NNNB and seven with LUTD. HPSE2 gene mutation analysis was performed using the polymerase chain reaction protocol followed by Sanger sequencing in these patients. Results: A twin pair with UFS was found to be homozygous for c.457C>T (p.Arg153*) mutation. No other pathogenetic variant was detected. Conclusion:HPSE2 mutations were found in one UFS family but not detected in patients with NNNB and severe LUTD. Considering the increasingly recognised cases of NNNB that were diagnosed in early childhood period, genetic factors appear to be responsible. Thus, further genetic studies are needed to discover novel associated gene variants in these bladder anomalies.

Endometriosis is influenced by both genetic and environmental factors. Genetic factors make up about half of the variation in endometriosis. Nevertheless, the genetics of endometriosis remains complex and in part unsolved, but recently, based on the results of few genome-wide association studies, some genetic susceptibility loci have been identified as associated robustly with the disease, providing new insights into potential pathways leading to endometriosis. Here, we present the case of a familial cluster composed by 3 sisters and their mother, all affected by endometriosis. Very severe gynecological and obstetric complications caused by the invasiveness of the disease have been observed in all members of the single family. The entire family has been genotyped for 3 single-nucleotide polymorphisms identified as associated with endometriosis. All the family members were homozygotes for the risk allele G for the rs1333049 variant in the CDKN2BAS locus. The genotype-phenotype association is just at the beginning of endometriosis research promising to face novel concepts for disease diagnosis and treatment.

Objective To evaluate the gene and protein expression of nerve growth factor (NGF) and substance P (SP) in the bladder 8 weeks after diabetes induction and investigate the pathogenesis of diabetic cystopathy. Methods Thirty Wistar rats were divided into three groups: control ( n  = 10), streptozotocin-induced diabetic group ( n  = 10) and Pygeum africanum ( P. africanum ) group ( n  = 10; diabetic rats were given P. africanum (100 mg/kg/day)). Eight weeks later, the bladders were dissected. We measured the expression of NGF and SP in the bladders using RT–PCR, ELISA and immunohistochemistry. Results We found a significantly reduced expression of NGF in the bladders from the diabetic group compared with the control. Immunohistochemical studies showed a statistically significant reduction of SP in the bladders from the diabetic group compared with the control ( P  < 0.05). Expression of NGF was greatly increased in the P. africanum group compared with that of the diabetic group. Immunohistochemical studies showed an increased level of SP in the bladders from the P. africanum group compared with the control ( P  < 0.05). Conclusions Our findings indicated that the decrease in NGF and SP may be a contributory factor in diabetic cystopathy. In addition, P. africanum could significantly upregulate the expression of NGF and SP in diabetic rats.

Multistep alterations of chromosome 17 in the progression of human urinary bladder neoplasia were studied by superimposed histologic and genetic mapping. The p53 gene was included in the analysis as a model tumor suppressor gene that is frequently involved in urothelial carcinogenesis. The strategy provided a systematic approach to the study of multistep genomic alterations that occur as neoplasia progresses from precursor intraurothelial conditions to invasive cancer. This was accomplished by sampling the entire mucosa of the organ and displaying microscopically identified invasive cancer and precursor conditions in the form of a histologic map. Subsequent isolation of DNA provided a set of samples in which the search for genetic alterations was performed and superimposed on the histologic map. This approach disclosed multifocal allelic losses of chromosome 17 in the early preinvasive phases of urothelial neoplasia. The alterations were predominantly confined to the p12-13, q22-11 and q24-25 regions. Mutations and allelic losses of the p53 gene were mapped to early preinvasive phases of urothelial neoplasia. The data provide detailed analysis of chromosome 17 allelic losses that occur in the development and progression of urothelial neoplasia and represent the first step for genome-wide modeling of multistep human urothelial carcinogenesis.