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The urinary collecting system (UCS) consists of organized ducts that collect urine from the nephrons and transport it to the ureter and bladder. Understanding the histogenesis of the UCS is critical. Thirty human embryos between the Carnegie stages (CS) 18 and 23 were selected from the Congenital Anomaly Research Center, Kyoto, Japan. Epithelia of the UCS, ureter, and bladder of each sample were randomly selected. Histological findings of the epithelia were analyzed according to the following criteria: type of epithelium, presence or absence of glycogen, percentage of migrated nuclei, percentage of cells in mitosis, and the surrounding mesenchyme. A thickened epithelium lining a narrow luminal cavity was observed in the pre-expanded pelvic specimens at CS18-CS23. At CS23, after pelvic expansion, the UCS showed a thin epithelium with a large luminal cavity mainly located on the early branches, whereas the epithelium covering the subsequent branches had medium thickness. Histological characteristics differed depending on the UCS part and sample stage. The degree of differentiation was evaluated, revealing that in CS18-CS23 pre-expanded pelvis specimens, the undifferentiated epithelium was found in the zeroth to third/fifth generation, whereas at CS23, after pelvic expansion, a differentiated epithelium covered the UCS zeroth to seventh generation. In a comparison of the urothelial epithelium between the UCS, ureter, and bladder, we found that urinary tract differentiation may be initiated in the bladder, followed by the ureter, UCS zeroth to seventh generations, and finally, UCS eighth to end generations. An understanding of the histogenesis of embryonic stage UCS can aid in the clinical management of congenital urinary tract defects and other diseases. [ABSTRACT FROM AUTHOR]

Background: Melatonin (MEL) is an indole amine molecule primarily produced in the pineal gland. Melatonin has been shown in numerous studies to have antifibrotic effects on the kidney, liver, and other organs. However, it is still unclear how melatonin works in bladder fibrosis. We explored how melatonin affects animals with bladder fibrosis and the underlying mechanisms. Materials and methods: MEL was used to treat human bladder smooth muscle cells (HBdSMCs) after they were stimulated with transforming growth factor-β1 (TGF-β1) in vitro. Proteomic analysis and bioinformatic analysis of the altered expression of these proteins were subsequently performed on HBdSMCs from the different processing methods. To construct an in vivo bladder fibrosis model, we injected protamine sulfate (PS) and lipopolysaccharide (LPS) twice a week into the rat bladder for six weeks. After two weeks of PS/LPS treatment, the mice in the treatment group were treated with MEL (20 mg/kg/d) for 4 weeks. Finally, we detected the expression of fibrosis markers from different perspectives. The TGF-β1/Smad pathway and epithelial–mesenchymal transition (EMT) in cell and bladder tissues were also identified. Further proteomic analysis was also performed. Results: In vitro, we found that TGF-β1 treatment enhanced the expression of the fibrosis markers collagen III and α-SMA in HBdSMCs. E-cadherin expression decreased while the TGF-β1/Smad pathway was activated. Vimentin and N-cadherin expression was also elevated at the same time. Similar findings were observed in the LPS group. After MEL treatment, the expression of collagen III and α-SMA decreased, the expression of E-cadherin increased, and the expression of vimentin and N-cadherin also decreased. According to our quantitative proteomics analysis, CCN1 and SQLE may be important proteins involved in the development of bladder fibrosis. MEL decreased the expression of these genes, leading to the relief of bladder fibrosis. Bioinformatics analysis revealed that the extracellular space structure related to metabolic pathways, actin filament binding, and stress fibers can serve as a pivotal focus in the management of fibrosis. Conclusion: Melatonin attenuates bladder fibrosis by blocking the TGF-β1/Smad pathway and EMT. CCN1 appears to be a possible therapeutic target for bladder fibrosis. [ABSTRACT FROM AUTHOR]

Uropathogenic Escherichia coli (UPEC) is the primary causative agent of urinary tract infections (UTIs) in humans. Moreover, as one of the most common bacterial pathogens, UPEC imposes a substantial burden on healthcare systems worldwide. Epithelial cells and macrophages are two major components of the innate immune system, which play critical roles in defending the bladder against UPEC invasion. Yet, the routes of communication between these cells during UTI pathogenesis are still not fully understood. In the present study, we investigated the role of membrane-bound nanovesicles (exosomes) in the communication between bladder epithelial cells and macrophages during UPEC infection, using an array of techniques such as flow cytometry, miRNA profiling, RNA sequencing, and western blotting. Moreover, our in vitro findings were validated in a mouse model of UPEC-induced cystitis. We found that UPEC infection induced the bladder epithelial MB49 cell line to secrete large numbers of exosomes (MB49-U-Exo), which were efficiently absorbed by macrophages both in vivo and in vitro. Assimilation of MB49-U-Exo induced macrophages to produce proinflammatory cytokines, including tumor necrosis factor (TNF)α. Exposure of macrophages to MB49-U-Exo reduced their phagocytic activity (by downregulating the expression of phagocytosis-related genes) and increased their rate of apoptosis. Mechanistically, we showed that MB49-U-Exo were enriched in miR-18a-5p, which induced TNFα expression in macrophages by targeting PTEN and activating the MAPK/JNK signaling pathway. Moreover, administration of the exosome secretion inhibitor GW4869 or a TNFα-neutralizing antibody alleviated UPEC-mediated tissue damage in mice with UPEC-induced cystitis by reducing the bacterial burden of the bladder and dampening the associated inflammatory response. Collectively, these findings suggest that MB49-U-Exo regulate macrophage function in a way that exacerbates UPEC-mediated tissue impairment. Thus, targeting exosomal -release or TNFα signaling during UPEC infection may represent promising non-antibiotic strategies for treating UTIs. Author summary: Urinary tract infections, which are typically caused by uropathogenic Escherichia coli (UPEC), affect over 150 million people each year, worldwide. Because the incidence of antibiotic resistance among UPEC strains is on the rise, urinary tract infections are becoming increasingly challenging to treat using this standard treatment method. Moreover, although the host immune response against UPEC has been intensively studied, the mechanism of communication between bladder epithelial cells and macrophages during UPEC infection remains largely unexplored. Here, we characterized the exosomes released from bladder epithelial cells following UPEC infection and evaluated their impact on macrophages. We demonstrated that bladder tissue destruction following excessive innate immune cell activation during UPEC infection may be driven by exosomes secreted from bladder epithelial cells. We further showed that pharmacologically inhibiting exosomal release from epithelial cells limited macrophage-associated inflammation, innate immune cell infiltration, and histopathological injuries in a mouse model of UPEC-induced cystitis. Collectively, our findings suggest that modulating exosome release represents a promising non-antibiotic therapy for UTIs. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) affects 50 million people worldwide. The immune system plays a major role in the pathogenesis of AD. Several retrospective analyses have reported a decreased risk of AD and other dementias in bladder cancer patients treated with immunotherapy in the form of Bacillus Calmette-Guerin (BCG) bladder instillations. We tested this hypothesis in a Swedish population-based prospective cohort of patients with non-muscle invasive bladder cancer (NMIBC). Methods and findings: We utilized the BladderBaSe 2.0 database, which contains tumor-specific, health-related, and socio-demographic information for patients diagnosed with NMIBC between 1997 and 2019. The database also includes a matched comparison cohort sampled from the general population, consisting of individuals free from urinary tract cancer at the time of the index case's diagnosis. Five controls were randomly selected for each index case without replacement on the date of the index case's diagnosis. Our inclusion criteria identified participants diagnosed with NMIBC who had received BCG as primary treatment, along with their corresponding comparison cohort. We excluded those diagnosed with dementia before or within 6 months of NMIBC diagnosis. To compare the NMIBC cohort with their matched comparison cohort, we used a stratified Cox model, treating each case with its controls as a stratum. We identified 38,934 patients in the NMIBC cohort, with 6,496 receiving BCG after primary diagnosis (cases). AD/dementia was diagnosed during follow-up in 6.1% of cases and 7.4% of controls. Cases had a slightly lower risk of dementia than controls, with a hazard ratio (HR) of 0.88 (95% confidence interval [CI] 0.780–0.991), and a HR of 0.89 (CI 0.703–1.119) for AD. Subgroup analysis for dementia showed that age over 75 years had an HR of 0.73 (CI 0.616–0.863), and female gender had an HR of 0.73 (CI 0.552–0.971). The associations were similar for AD specifically, but not statistically significant. Similar to previous studies, we analyzed bladder cancer patients treated with and without BCG therapy. Multivariate Cox analysis indicated that those treated with BCG had a lower risk of dementia (HR 0.81, 95% CI 0.71–0.92), and an HR of 0.98 (95% CI 0.75–1.27) for AD specifically. High age was a significant risk modifier; the HR was 3.8 (CI 3.44–4.11) for dementia and 3.1 (CI 2.59–3.73) for AD. Even patients not receiving BCG had a significantly lower risk for AD than controls (HR 0.86, CI 0.77–0.96). Conclusions: This study observed a marginally decreased risk of developing AD/dementia associated with earlier intravesical BCG treatment in NMIBC patients. This small benefit was most pronounced in those with high age and female gender. The disparity from previous highly positive studies underscores the importance of using an appropriate control cohort. [ABSTRACT FROM AUTHOR]

The goal of this study was to develop the novel analytical approach and to perform an in-depth dynamic analysis of individual bladder diaries to inform which behavioral modifications would best reduce lower urinary tract symptoms, such as frequency and urgency. Three-day bladder diaries containing data on timing, volumes, and types of fluid intake, as well as timing, volumes, and bladder sensation at voids were analyzed for 197 participants with lower urinary tract symptoms. A novel dynamic analytic approach to bladder diary time series data was proposed and developed, including intra-subject correlations between time-varying variables: rates of intake, bladder filling rate, and urge growth rate. Grey-box models of bladder filling rate and multivariable linear regression models of urge growth rate were developed for individual diaries. These models revealed that bladder filling rate, rather than urine volume, was the primary determinant of urinary frequency and urgency growth rate in the majority of participants. Simulations performed with the developed models predicted that the most beneficial behavioral modifications to reduce the number of urgency episodes are those that smooth profiles of bladder filling rate, which might include behaviors such as exclusion of caffeine and alcohol and/or other measures, e.g., increasing number and decreasing volumes of intakes. [ABSTRACT FROM AUTHOR]

Amyloidosis is a group of protein-misfolding disorders characterized by the accumulation of amyloid in organs, both in humans and animals. AA-amyloidosis is considered a reactive type of amyloidosis and in humans is characterized by the deposition of AA-amyloid fibrils in one or more organs. In domestic shorthair cats, AA-amyloidosis was recently reported to be frequent in shelters. To better characterize this pathology, we report the distribution of amyloid deposits and associated histological lesions in the organs of shelter cats with systemic AA-amyloidosis. AA-amyloid deposits were identified with Congo Red staining and immunofluorescence. AA-amyloid deposits were then described and scored, and associated histological lesions were reported. Based on Congo Red staining and immunofluorescence nine shelter cats presented systemic AA-amyloidosis. The kidney (9/9), the spleen (8/8), the adrenal glands (8/8), the small intestine (7/7) and the liver (8/9) were the organs most involved by amyloid deposits, with multifocal to diffuse and from moderate to severe deposits, both in the organ parenchyma and/or in the vascular compartment. The lung (2/9) and the skin (1/8) were the least frequently involved organs and deposits were mainly focal to multifocal, mild, vascular and perivascular. Interestingly, among the organs with fibril deposition, the stomach (7/9), the gallbladder (6/6), the urinary bladder (3/9), and the heart (6/7) were reported for the first time in cats. All eye, brain and skeletal muscle samples had no amyloid deposits. An inflammatory condition was identified in 8/9 cats, with chronic enteritis and chronic nephritis being the most common. Except for secondary cell compression, other lesions were not associated to amyloid deposits. To conclude, this study gives new insights into the distribution of AA-amyloid deposits in cats. A concurrent chronic inflammation was present in almost all cases, possibly suggesting a relationship with AA-amyloidosis. [ABSTRACT FROM AUTHOR]

Rodents have the capacity for spontaneous bladder regeneration and bladder smooth muscle cell (BSMC) migration following a subtotal cystectomy (STC). YAP/WWTR1 and BDNF (Brain-derived neurotrophic factor) play crucial roles in development and regeneration. During partial bladder outlet obstruction (PBO), excessive YAP/WWTR1 signaling and BDNF expression increases BSMC hypertrophy and dysfunction. YAP/WWTR1 and expression of BDNF and CYR61 were examined in models of regeneration and wound repair. Live cell microscopy was utilized in an ex vivo model of STC to visualize cell movement and division. In Sprague-Dawley female rats, STC was performed by resection of the bladder dome sparing the trigone, followed by closure of the bladder. Smooth muscle migration and downstream effects on signaling and expression were also examined after scratch wound of BSMC with inhibitors of YAP and BDNF signaling. Sham, PBO and incision (cystotomy) were comparators for the STC model. Scratch wound in vitro increased SMC migration and expression of BDNF, CTGF and CYR61 in a YAP/WWTR1-dependent manner. Inhibition of YAP/WWTR1 and BDNF signaling reduced scratch-induced migration. BDNF and CYR61 expression was elevated during STC and PBO. STC induces discrete genes associated with endogenous de novo cell regeneration downstream of YAP/WWTR1 activation. [ABSTRACT FROM AUTHOR]

Roles of redox signaling in bladder function is still under investigation. We explored the physiological role of reactive oxygen species (ROS) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox) in regulating bladder function in humans and dogs. Mucosa-denuded bladder smooth muscle strips obtained from 7 human organ donors and 4 normal dogs were mounted in muscle baths, and trains of electrical field stimulation (EFS) applied for 20 minutes at 90-second intervals. Subsets of strips were incubated with hydrogen peroxide (H2O2), angiotensin II (Ang II; Nox activator), apocynin (inhibitor of Noxs and ROS scavenger), or ZD7155 (specific inhibitor of angiotensin type 1 (AT1) receptor) for 20 minutes in continued EFS trains. Subsets treated with inhibitors were then treated with H2O2 or Ang II. In human and dog bladders, the ROS, H2O2 (100μM), caused contractions and enhanced EFS-induced contractions. Apocynin (100μM) attenuated EFS-induced strip contractions in both species; subsequent treatment with H2O2 restored strip activity. In human bladders, Ang II (1μM) did not enhance EFS-induced contractions yet caused direct strip contractions. In dog bladders, Ang II enhanced both EFS-induced and direct contractions. Ang II also partially restored EFS-induced contractions attenuated by prior apocynin treatment. In both species, treatment with ZD7155 (10μM) inhibited EFS-induced activity; subsequent treatment with Ang II did not restore strip activity. Collectively, these data provide evidence that ROS can modulate bladder function without exogenous stimuli. Since inflammation is associated with oxidative damage, the effects of Ang II on bladder smooth muscle function may have pathologic implications. [ABSTRACT FROM AUTHOR]

There is a growing consensus that a significant proportion of recurrent urinary tract infections are linked to the persistence of uropathogens within the urinary tract and their re-emergence upon the conclusion of antibiotic treatment. Studies in mice and human have revealed that uropathogenic Escherichia coli (UPEC) can persist in bladder epithelial cells (BECs) even after the apparent resolution of the infection. Here, we found that, following the entry of UPEC into RAB27b+ fusiform vesicles in BECs, some bacteria escaped into the cytoplasmic compartment via a mechanism involving hemolysin A (HlyA). However, these UPEC were immediately recaptured within LC3A/B+ autophagosomes that matured into LAMP1+ autolysosomes. Thereafter, HlyA+ UPEC-containing lysosomes failed to acidify, which is an essential step for bacterial elimination. This lack of acidification was related to the inability of bacteria-harboring compartments to recruit V-ATPase proton pumps, which was attributed to the defragmentation of cytosolic microtubules by HlyA. The persistence of UPEC within LAMP1+ compartments in BECs appears to be directly linked to HlyA. Thus, through intravesicular instillation of microtubule stabilizer, this host defense response can be co-opted to reduce intracellular bacterial burden following UTIs in the bladder potentially preventing recurrence. Author summary: Many strains of uropathogenic E.coli are capable of secreting the soluble toxin α-hemolysin (HlyA). Intracellular UPEC persistence within bladder epithelial cells is highly correlated with their ability to express HlyA. HlyA disrupted cytosolic microtubules, which are required for the recruitment of V-ATPase proton pumps to LAMP1+ vesicles. Therefore, the majority of LAMP1+ vesicles carrying UPEC in host cells were unable to be acidified, which is a critical step for killing bacteria. Since HlyA-mediated microtubule fragmentation is essential for UPEC persistence in the bladder, treatment with paclitaxel (a microtubule stabilizer) in the bladders of UPEC-infected mice significantly reduced the bladder bacterial burden even in the absence of antibiotic treatment. [ABSTRACT FROM AUTHOR]

Background: Intravesical recurrence (IVR) after surgery for upper tract urothelial carcinoma (UTUC) is a clinical problem. We investigated if preoperative invasive diagnostic modalities (IDM) such as antegrade/retrograde uretero-pyelography and/or selective urine cytology/barbotage, and URS with or without concomitant biopsy are associated with IVR after radical surgery for UTUC. Risk of death from urothelial cancer and all causes was investigated as secondary outcomes. Methods: We investigated a population-based cohort of 1038 consecutive patients subjected to radical surgery for UTUC 2015–2019 in Sweden, using the Bladder Cancer Data Base Sweden (BladderBaSe 2.0), comprising all patients in the Swedish National Registry of Urinary Bladder Cancer. Risk estimates of IVR, death from urothelial cancer, and all causes was assessed using multivariable Cox regression models. Results: The study included 536 cases with and 502 without preoperative IDM. IDM was associated with increased risk of IVR (HR 1.24, 95% CI 1.03–1.52) and risk of urothelial cancer death (HR 1.56, CI 1.12–2.18), compared to no IDM after a median follow-up of 1.3 yrs. Stratified analysis for tumor location showed that IDM was associated with risk of IVR in ureteric cancer (HR 1.66, 95% CI 1.21–2.28) but not in renal pelvic cancer (HR 1.07, 95% CI 0.81–1.41). Limitations included the observational setting and the lack of variables such as tumour grade, multifocality and preoperative hydronephrosis. Conclusions: Worse outcomes for patients subjected to preoperative IDM highlight the need for carefully considering diagnostic decisions for UTUC patients, specifically in tumours located in the ureter. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) often leads to the development of neurogenic lower urinary tract symptoms (LUTS). We previously characterized neurogenic bladder dysfunction in a mouse model of MS induced by a coronavirus, mouse hepatitis virus (MHV). The aim of the study was to identify genes and pathways linking neuroinflammation in the central nervous system with urinary bladder (UB) dysfunction to enhance our understanding of the mechanisms underlying LUTS in demyelinating diseases. Adult C57BL/6 male mice (N = 12) received either an intracranial injection of MHV (coronavirus-induced encephalomyelitis, CIE group), or sterile saline (control group). Spinal cord (SC) and urinary bladders (UB) were collected from CIE mice at 1 wk and 4 wks, followed by RNA isolation and NanoString nCounter Neuroinflammation assay. Transcriptome analysis of SC identified a significantly changed expression of >150 genes in CIE mice known to regulate astrocyte, microglia and oligodendrocyte functions, neuroinflammation and immune responses. Two genes were significantly upregulated (Ttr and Ms4a4a), and two were downregulated (Asb2 and Myct1) only in the UB of CIE mice. Siglec1 and Zbp1 were the only genes significantly upregulated in both tissues, suggesting a common transcriptomic link between neuroinflammation in the CNS and neurogenic changes in the UB of CIE mice. [ABSTRACT FROM AUTHOR]

The purpose of this study was to evaluate and compare positive cystography techniques at 5%, 10%, and 20%, as well as three different double-contrast protocols for detecting radiolucent uroliths with a diameter of less than 3.0 mm in dogs. Six cadavers were used, one was selected at random to represent the negative control, and the others were submitted to urolith implantation in the bladder by urethral catheter. Three radiology professionals blindly accessed ventrodorsal and -lateral projections of each test. Contrast at 20% showed greater diagnostic sensitivity, but with greater difficulty identifying the number and size of the uroliths. Consequently, double-contrast techniques are better and should be used for diagnostic and therapeutic planning. Sensitivity and specificity tests demonstrated that positive 5% cystography and different concentrations of double contrast obtained better results in terms of sensitivity and specificity. However, due to the presence of a greater amount of artifacts in the 5% cystography, it is suggested that double contrast is used for this purpose, especially with the removal of contrast excess (protocol 2). [ABSTRACT FROM AUTHOR]

Background: The role of interferon gamma (IFN-γ) expression in long-term survival has not been studied in patients with urinary bladder cancer (UBC). IFN-γ expression was characterized among various UBC patient cohorts to assess if IFN-γ status is associated with overall survival (OS). Methods: A tumor-based IFN-γ gene signature was evaluated among adult UBC patients newly diagnosed between 2004 and 2017 from two hospital systems in New York. Patient cohorts included metastatic (stage IV or progressing to stage IV [MBC]), muscle-invasive (stages T2a to T4a [MIBC]), and non–muscle-invasive (carcinoma in situ or stages 0a, 0is, and I [NMIBC]) disease. Descriptive analyses were conducted comparing IFN-γ signature in the highest tertile to those in the lowest two tertiles. Results: 234 patients with bladder cancer were evaluated (56 MBC, 38 MIBC, and 140 NMIBC). Median OS was only reached in the MIBC cohort for those with an IFN-γ signature in the lowest two tertiles (15.03 months [95% CI, 8.50–50.60]). Those with an IFN-γ signature in the highest tertile had a decreased risk of mortality in all cohorts indicating better survival, but this was statistically significant in only the MIBC cohort (adjusted HR = 0.09 [95% CI, 0.01–0.73]). Conclusion: IFN-γ signature status was associated with a decreased mortality risk in all cohorts, particularly MIBC, indicating that it may be a prognostic marker of survival in patients with UBC. [ABSTRACT FROM AUTHOR]

Class II myosin complexes are responsible for muscle contraction as well as other non-sarcomeric contractile functions in cells. Myosin heavy chain molecules form the core of these structures, while light chain molecules regulate their stability and function. MYL9 is a light chain isoform that is thought to regulate non-sarcomeric myosin. However, whether this in only in specific cell types or in all cells remains unclear. To address this, we generated MYL9 deficient mice. These mice die soon after birth with abnormalities in multiple organs. All mice exhibited a distended bladder, shortening of the small intestine and alveolar overdistension in the lung. The Myl9 allele in these mice included a LacZ reporter knockin that allowed for mapping of Myl9 gene expression. Using this reporter, we show that MYL9 expression is restricted to the muscularis propria of the small intestine and bladder, as well as in the smooth muscle layer of the bronchi in the lung and major bladder vessels in all organs. This suggests that MYL9 is important for the function of smooth muscle cells in these organs. Smooth muscle dysfunction is therefore likely to be the cause of the abnormalities observed in the intestine, bladder and lung of MYL9 deficient mice and the resulting neonatal lethality. [ABSTRACT FROM AUTHOR]

Psychological stress causes bladder dysfunction in humans and in rodent models, with increased urinary frequency and altered contractile responses evident following repeated environmental stress exposure. However, whether these changes persist after removal of the stressor is unknown, and the aim of this study was to determine if stress-induced changes in voiding behaviour and bladder function recover following removal of the stressor. Adult female mice were allocated to three groups: Unstressed, Stressed or Stressed + Recovery. Animals in the stressed groups were exposed to water avoidance stress for 1h/day for 10-days, with unstressed animals age-matched and housed under normal conditions. For recovery studies, animals were housed without stress exposure for an additional 10-days. Voiding behaviour was assessed periodically and animals sacrificed on day 10 (Unstressed and Stressed) or day 20 (Unstressed and Stressed + Recovery). Isolated whole bladder studies were used to assess compliance, urothelial mediator release and contractile responses. Exposure to stress increased plasma corticosterone levels almost three-fold (P<0.05) but this returned to baseline during the recovery period. Contractile responses of the bladder to carbachol and KCl were also increased following stress, and again fully recovered after a 10-day stress-free period. In contrast, stress increased urinary frequency four-fold (P<0.001), but this did not return fully to baseline during the recovery period. Bladder compliance was unchanged by stress; however, it was increased in the stressed + recovery group (P<0.05). Thus, following a stress-free period there is partial recovery of voiding behaviour, with an increase in bladder compliance possibly contributing to the compensatory mechanisms. [ABSTRACT FROM AUTHOR]

The progress in translational cancer research relies on access to well-characterized samples from a representative number of patients and controls. The rationale behind our biobanking are explorations of post-zygotic pathogenic gene variants, especially in non-tumoral tissue, which might predispose to cancers. The targeted diagnoses are carcinomas of the breast (via mastectomy or breast conserving surgery), colon and rectum, prostate, and urinary bladder (via cystectomy or transurethral resection), exocrine pancreatic carcinoma as well as metastases of colorectal cancer to the liver. The choice was based on the high incidence of these cancers and/or frequent fatal outcome. We also collect age-matched normal controls. Our still ongoing collection originates from five clinical centers and after nearly 2-year cooperation reached 1711 patients and controls, yielding a total of 23226 independent samples, with an average of 74 donors and 1010 samples collected per month. The predominant diagnosis is breast carcinoma, with 933 donors, followed by colorectal carcinoma (383 donors), prostate carcinoma (221 donors), bladder carcinoma (81 donors), exocrine pancreatic carcinoma (15 donors) and metachronous colorectal cancer metastases to liver (14 donors). Forty percent of the total sample count originates from macroscopically healthy cancer-neighboring tissue, while contribution from tumors is 12%, which adds to the uniqueness of our collection for cancer predisposition studies. Moreover, we developed two program packages, enabling registration of patients, clinical data and samples at the participating hospitals as well as the central system of sample/data management at coordinating center. The approach used by us may serve as a model for dispersed biobanking from multiple satellite hospitals. Our biobanking resource ought to stimulate research into genetic mechanisms underlying the development of common cancers. It will allow all available "-omics" approaches on DNA-, RNA-, protein- and tissue levels to be applied. The collected samples can be made available to other research groups. [ABSTRACT FROM AUTHOR]

This study aimed to identify potential lateralization of bladder function. Electrical stimulation of spinal roots or the pelvic nerve's anterior vesical branch was performed bilaterally in female dogs. The percent difference between the left and right stimulation-induced increased detrusor pressure was determined. Bladders were considered left or right-sided if differences were greater or less than 25% or 10%. Based on differences of 25%, upon stimulation of spinal roots, bladders were left-sided in 17/44 (38.6%), right-sided in 12/44 (27.2%) and bilateral in 15/44 (34.2%). Using ± 10%, 48% had left side dominance (n = 21/44), 39% had right side dominance (n = 17/44), and 14% were bilateral (n = 6/44). With stimulation of the pelvic nerve's anterior vesical branch in 19 dogs, bladders were left-sided in 8 (42.1%), right-sided in 6 (31.6%) and bilateral in 5 (26.3%) using 25% differences and left side dominance in 8 (43%), right sided in 7 (37%) and bilateral in 4 (21%) using 10% differences. These data suggest lateralization of innervation of the female dog bladder with left- and right-sided lateralization occurring at similar rates. Lateralization often varied at different spinal cord levels within the same animal. [ABSTRACT FROM AUTHOR]

Urogenital schistosomiasis remains a major public health concern worldwide. In response to egg deposition, the host bladder undergoes gross and molecular morphological changes relevant for disease manifestation. However, limited mechanistic studies to date imply that the molecular mechanisms underlying pathology are not well-defined. We leveraged a mouse model of urogenital schistosomiasis to perform for the first time, proteome profiling of the early molecular events that occur in the bladder after exposure to S. haematobium eggs, and to elucidate the protein pathways involved in urogenital schistosomiasis-induced pathology. Purified S. haematobium eggs or control vehicle were microinjected into the bladder walls of mice. Mice were sacrificed seven days post-injection and bladder proteins isolated and processed for proteome profiling using mass spectrometry. We demonstrate that biological processes including carcinogenesis, immune and inflammatory responses, increased protein translation or turnover, oxidative stress responses, reduced cell adhesion and epithelial barrier integrity, and increased glucose metabolism were significantly enriched in S. haematobium infection. S. haematobium egg deposition in the bladder results in significant changes in proteins and pathways that play a role in pathology. Our findings highlight the potential bladder protein indicators for host-parasite interplay and provide new insights into the complex dynamics of pathology and characteristic bladder tissue changes in urogenital schistosomiasis. The findings will be relevant for development of improved interventions for disease control. Author summary: The molecular mechanisms underlying the urinary and genital pathology from urogenital schistosomiasis have not been well-defined. This has mainly been due to limited mechanistic studies and the lack of a suitable animal model for S. haematobium infection. We leveraged a mouse model of urogenital schistosomiasis, along with proteomics analysis, to determine the early molecular events that occur in the bladder after exposure to S. haematobium eggs, and to define protein pathways that may be involved in morbidity from urogenital schistosomiasis infection. Our results show that S. haematobium egg deposition in the bladder results in significant changes in proteins and pathways that play a role in pathology. Biological processes including carcinogenesis, immune and inflammatory responses, increased protein translation or turnover, oxidative stress responses, reduced cell adhesion and epithelial barrier integrity, and increased glucose metabolism are significantly enriched in S. haematobium infection. Our findings highlight important protein indicators of host-parasite interactions in the bladder and their association with tissue changes in urogenital schistosomiasis. The findings presented here will be relevant for development of improved interventions for disease control, and contribute to realizing the 2021–2030 NTD goals by demonstrating evidence on the early events that occur during schistosome infection. [ABSTRACT FROM AUTHOR]

Survival has improved in bladder cancer but few studies have considered extended periods or covered populations for which medical care is essentially free of charge. We analyzed survival in urothelial cancer (UC, of which vast majority are bladder cancers) in Finland and Sweden over a 50-year period (1967–2016) using data from the NORDCAN database. Finland and Sweden are neighboring countries with largely similar health care systems but higher economic resources and health care expenditure in Sweden. We present results on 1- and 5-year relative survival rates, and additionally provide a novel measure, the difference between 1- and 5-year relative survival, indicating how well survival was maintained between these two periods. Over the 50-year period the median diagnostic age has increased by several years and the incidence in the very old patients has increased vastly. Relative 1- year survival rates increased until early 1990s in both countries, and with minor gains later reaching about 90% in men and 85% in women. Although 5-year survival also developed favorably until early 1990s, subsequent gains were small. Over time, age specific differences in male 1-year survival narrowed but remained wide in 5-year survival. For women, age differences were larger than for men. The limitations of the study were lack of information on treatment and stage. In conclusion, challenges are to improve 5-year survival, to reduce the gender gap and to target specific care to the most common patient group, those of 70 years at diagnosis. The most effective methods to achieve survival gains are to target control of tobacco use, emphasis on early diagnosis with prompt action at hematuria, upfront curative treatment and awareness of high relapse requiring regular cystoscopy follow up. [ABSTRACT FROM AUTHOR]

Background: Non-schistosomiasis related-squamous cell carcinoma of urinary bladder (NSR-SCCUB) is a rare tumor subtype distinct from urothelial carcinoma (UC). Studies assessing molecular biomarkers in bladder cancer have generally focused on UC, and genomic data of NSR-SCCUB is limited. We aim to provide additional insight into the molecular underpinnings of this rare entity. Methods: NSR-SCCUB patients were identified retrospectively at Princess Margaret Cancer Centre between 2002 and 2017. Demographics, disease characteristics, therapeutic approaches, and outcomes were collected. Tissue samples were interrogated using the Oncomine Comprehensive Assay v3 (ThermoFisher). Kaplan-Meier method was used to estimate the disease-free survival and overall survival (OS). Results: Overall, 11 patients with NSR-SCCUB were identified between 2002 and 2017 with adequate tissue samples. Median age was 71 years (45–86), predominantly male (63.6%). At time of diagnosis, 9 patients (81.8%) had muscle-invasive disease, 1 (9.1%) had non-muscle invasive, and 1 (9.1%) had advanced disease. Nine (81.8%) patients had radical cystectomy and pelvic lymph nodes dissection. Eight (72.7%) patients had pT3 or pT4 with N0, and 5 (45.5%) were grade 3. Median OS was 12.5 months (95% CI 7.7–17.2 months). Single nucleotide variants or insertion/deletions were identified in TP53, TERT, PIK3CA, PTEN, CREBBP, FBXW7, and FGFR3. Amplifications were found in CCND1, and EGFR. Conclusions: NSR-SCCUB has potentially actionable genomic alterations with anticancer agents and many of these aberrations are also seen in UC. The recruitment of NSR-SCCUB patients harboring such mutations should be considered in biomarker driven urinary bladder cancer studies. [ABSTRACT FROM AUTHOR]

Aberrant activation of the Ras/Raf/ERK (extracellular-signal-regulated kinase)-MAPK (mitogen-activated protein kinase) pathway is involved in the progression of cancer, including urothelial carcinoma; but the negative regulation remains unclear. In the present study, we investigated pathological expression of Spred2 (Sprouty-related EVH1 domain-containing protein 2), a negative regulator of the Ras/Raf/ERK-MAPK pathway, and the relation to ERK activation and Ki67 index in various categories of 275 urothelial tumors obtained from clinical patients. In situ hybridization demonstrated that Spred2 mRNA was highly expressed in high-grade non-invasive papillary urothelial carcinoma (HGPUC), and the expression was decreased in carcinoma in situ (CIS) and infiltrating urothelial carcinoma (IUC). Immunohistochemically, membranous Spred2 expression, important to interact with Ras/Raf, was preferentially found in HGPUC. Interestingly, membranous Spred2 expression was decreased in CIS and IUC relative to HGPUC, while ERK activation and the expression of the cell proliferation marker Ki67 index were increased. HGPUC with membranous Spred2 expression correlated significantly with lower levels of ERK activation and Ki67 index as compared to those with negative Spred2 expression. Thus, our pathological findings suggest that Spred2 counters cancer progression in non-invasive papillary carcinoma possibly through inhibiting the Ras/Raf/ERK-MAPK pathway, but this regulatory mechanism is lost in cancers with high malignancy. Spred2 appears to be a key regulator in the progression of non-invasive bladder carcinoma. [ABSTRACT FROM AUTHOR]

The photochemically-induced thrombosis (photothrombosis) method can create focal cerebral infarcts anywhere in the relatively superficial layers of the cerebrum; it is easy to implement and minimally invasive. Taking advantage of this versatility, we aimed to establish a new rat model of urinary frequency with focal cerebral infarction, which was characterized by its simplicity, nonlethal nature, and high reproducibility. The prefrontal cortex and the anterior cingulate cortex, which are involved in lower urinary tract control, were targeted for focal cerebral infarction, and urinary parameters were measured by cystometrogram. Cystometric analysis indicated that micturition intervals significantly shortened in photothrombosis-treated rats compared with those in the sham operative group on Days 1 and 7 (P < 0.01), but prolonged after 14 days, with no difference between the two groups. Immunopathological evaluation showed an accumulation of activated microglia, followed by an increase in reactive astrocytes at the peri-infarct zone after photothrombotic stroke. Throughout this study, all postphotothrombosis rats showed cerebral infarction in the prefrontal cortex and anterior cingulate cortex; there were no cases of rats with fatal cerebral infarction. This model corresponded to the clinical presentation, in that the micturition status changed after stroke. In conclusion, this novel model combining nonlethality and high reproducibility may be a suitable model of urinary frequency after focal cerebral infarction. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to compare the clinical characteristics and the survival of CHEK2 mutation positive and CHEK2 mutation negative patients diagnosed with bladder or kidney cancer. Materials and methods: 1016 patients with bladder and 402 cases with kidney cancer and 8302 controls were genotyped for four CHEK2 variants: 1100delC, del5395, IVS2+1G>A and I157T. Predictors of survival were determined among CHEK2 pathogenic variant carriers using the Cox proportional hazards model. The median follow-up was 17.5 years. Covariates included age (≤60; >61 years), sex (female; male), clinical characteristics (stage: TNM, grade, histopathological type), smoking status (non-smoking; smoking) and cancer family history (negative; positive). Results: We found no impact of CHEK2 mutations on bladder or kidney cancer survival. However, we observed a possible increased survival in the subgroup of patients with stage T1 bladder cancer with CHEK2 mutations but this did not meet statistical significance (HR = 0.14; 95% CI 0.02–1.04; p = 0.055). Moreover, we observed that the missense mutations were more frequent in the low grade invasive bladder cancer patient group (OR = 7.9; 95% CI 1.50–42.1; p = 0.04) and in patients with bladder cancer with stage Ta (OR = 2.4; 95% CI 1.30–4.55; p = 0.006). The different results where missense mutations occurs less often we observed among patients with high grade invasive bladder cancer (OR = 0.12; 95% CI 0.02–0.66; p = 0.04) and those with stage T1 disease (OR = 0.2; 95% CI 0.07–0.76; p = 0.01). Our investigations revealed that any mutation in CHEK2 occurs more often among patients with stage Ta bladder cancer (OR = 2.0; 95% CI 1.19–3.47; p = 0.01) and less often in patients with stage T1 disease (OR = 0.31; 95% CI 0.12–0.78; p = 0.01). In the kidney cancer patients, truncating mutations were present more often in the group with clear cell carcinoma GII (OR = 8.0; 95% CI 0.95–67.7; p = 0.05). The 10-year survival for all CHEK2 mutation carriers with bladder cancer was 33% and for non-carriers 11% (p = 0.15). The 10-year survival for CHEK2 mutation carriers with kidney cancer 34% and for non-carriers 20% (p = 0.5). Conclusion: CHEK2 mutations were not associated with any change in bladder or kidney cancer survival regardless of their age, sex, smoking status and family history. We observed a potentially protective effect of CHEK2 mutations on survival for patients with stage T1 bladder cancer. CHEK2 missense mutations were more common among patients with low grade invasive bladder cancer and in patients with stage Ta diease. The frequencies of the I157T CHEK2 pathogenic variant were less in patients with high grade invasive bladder cancer and those with stage T1 disease. Among patients with bladder cancer with stage Ta disease, the OR for any mutation in CHEK2 was 2.0 but for those with stage T1 disease, the OR was 0.3. We observed truncating CHEK2 mutations were associated with kidney cancer patients with GII clear cell carcinoma. [ABSTRACT FROM AUTHOR]

Background: Activation of intravesical protease activated receptor 4 (PAR4) leads to release of urothelial macrophage migration inhibitory factor (MIF). MIF then binds to urothelial MIF receptors to release urothelial high mobility group box-1 (HMGB1) and elicit bladder hyperalgesia. Since MIF binds to multiple receptors, we investigated the contribution of individual urothelial MIF receptors to PAR4-induced HMGB1 release in vivo and in vitro and bladder pain in vivo. Methodology/Principal findings: We tested the effect of intravesical pre-treatment with individual MIF or MIF receptor (CD74, CXCR4, CXCR2) antagonists on PAR4-induced HMGB1 release in vivo (female C57/BL6 mice) and in vitro (primary human urothelial cells) and on PAR4-induced bladder hyperalgesia in vivo (mice). In mice, PAR4 induced HMGB1 release and bladder hyperalgesia through activation of intravesical MIF receptors, CD74 and CXCR4. CXCR2 was not involved in these effects. In primary urothelial cells, PAR4-induced HMGB1 release through activation of CD74 receptors. Micturition parameters in mice were not changed by any of the treatments. Conclusions/Significance: Urothelial MIF receptors CD74 and CXCR4 mediate bladder pain through release of urothelial HMGB1. This mechanism may set up persistent pain loops in the bladder and warrants further investigation. Urothelial CD74 and CXCR4 may provide novel targets for interrupting bladder pain. [ABSTRACT FROM AUTHOR]

Urodynamic studies in rats and mice are broadly used to examine pathomechnisms of disease and identify and test therapeutic targets. This review aims to highlight the effects of the anesthetics on the lower urinary tract function and seeks to identify protocols that allow recovery from anesthesia and repeated measurements while preserving the function which is being studied. All studies published in English language, which compared the data obtained under various types of anesthesia and the urodynamics performed in awake animals were included. It appears that urethane, an anesthetic recommended extensively for the investigation of lower urinary tract function, is appropriate for acute urodynamic studies only. Major advantages of urethane are its stability and ability to preserve the micturition reflex. Due to its toxicity and carcinogenicity, urethane anesthesia should not be used for recovery procedures. This review evaluated available alternatives including propofol, isoflurane and combinations of urethane, ketamine/xylazine, ketamine/medetomidine, and/or fentanyl/fluanisone/midazolam. Different effects have been demonstrated among these drugs on the urinary bladder, the urethral sphincter, as well as on their neuroregulation. The lowest incidence of adverse effects was observed with the use of a combination of ketamine and xylazine. Although the variations in the reviewed study protocols represent a limitation, we believe that this summary will help in standardizing and optimizing future experiments. [ABSTRACT FROM AUTHOR]

Background: World Health Organization (WHO) guidelines for measuring global progress in schistosomiasis control classify individuals with Schistosoma spp. infections based on the concentration of excreted eggs. We assessed the associations between WHO infection intensity categories and morbidity prevalence for selected S. haematobium and S. mansoni morbidities in school-age children. Methodology: A total of 22,488 children aged 6–15 years from monitoring and evaluation cohorts in Burkina Faso, Mali, Niger, Uganda, Tanzania, and Zambia from 2003–2008 were analyzed using Bayesian logistic regression. Models were utilized to evaluate associations between intensity categories and the prevalence of any urinary bladder lesion, any upper urinary tract lesion, microhematuria, and pain while urinating (for S. haematobium) and irregular hepatic ultrasound image pattern (C-F), enlarged portal vein, laboratory-confirmed diarrhea, and self-reported diarrhea (for S. mansoni) across participants with infection and morbidity data. Principal findings: S. haematobium infection intensity categories possessed consistent morbidity prevalence across surveys for multiple morbidities and participants with light infections had elevated morbidity levels, compared to negative participants. Conversely, S. mansoni infection intensity categories lacked association with prevalence of the morbidity measures assessed. Conclusions/significance: Current status infection intensity categories for S. haematobium were associated with morbidity levels in school-age children, suggesting urogenital schistosomiasis morbidity can be predicted by an individual's intensity category. Conversely, S. mansoni infection intensity categories were not consistently indicative of childhood morbidity at baseline or during the first two years of a preventive chemotherapy control program. Author summary: Infections with Schistosoma parasites are commonly classified by the presence and concentration of excreted Schistosoma eggs. Guidelines put forward by the World Health Organization (WHO) include classifications of S. haematobium infections assessed by urine filtration into light and heavy infections and S. mansoni infections assessed by Kato-Katz thick smears into light, moderate, and heavy infections. Past evidence has demonstrated an association between intensity of infection with morbidity for severe morbidities, but this was before recognition of the effect of light-intensity infections on morbidity and was done in treatment naïve populations. In these analyses, we assessed the associations between the WHO classifications for infection intensity and a wide array of S. haematobium and S. mansoni morbidity indicators in school-age children ascertained in monitoring and evaluation cohorts before and after initiation of deworming. Our analyses found a high correlation with S. haematobium intensity categories and morbidity indicators, especially microhematuria, but weaker correlation between S. mansoni intensity categories and morbidity indicators. The results indicate that, on the aggregate, the intensity categories represent a person's S. haematobium-related morbidity but are poor at representing a person's S. mansoni-related morbidity. [ABSTRACT FROM AUTHOR]

Objective: To present the clinical and radiological characteristics of women with severe structural deterioration of the bladder and upper urinary tract secondary to Primary Bladder Neck Obstruction (PBNO), and their outcomes after bladder neck incision (BNI). Methods: Retrospective evaluation of adult women who underwent BNI for PBNO at one institution. Patients were assessed for symptoms, renal function, structural abnormalities of the urinary tract and video-urodynamics. PBNO diagnosis was confirmed with video-urodynamics in all patients. BNI was performed at the 4–5 and/or 7–8 o'clock positions. Postoperative symptoms, PVR, uroflowmetry and renal function were evaluated and compared to baseline. Results: Median patient age was 56.5 years (range 40–80). All presented with urinary retention–four were on clean intermittent Catheterization (CIC) and two with a Foley catheter. All patients had bladder wall thickening and diverticula. Four women had elevated creatinine levels, bilateral hydronephrosis was present in five (83.3%). After BNI, all patients resumed spontaneous voiding without the need for CIC. Median Qmax significantly improved from 2.0 [1.0–4.0] mL/s to 15 [10–22.7] mL/s (p = 0.031). Median PVR decreased from 150 to 46 [22–76] mL (p = 0.031). There were no postoperative complications. Creatinine levels returned to normal in 3/4 (75%) patients. Conclusion: PBNO in women may result in severe damage to the bladder and upper urinary tract. Despite severe structural abnormalities of the bladder, BNI was effective in reducing symptoms and improving structural and functional abnormalities of the lower and upper urinary tract. [ABSTRACT FROM AUTHOR]

Urinary tract infections (UTIs) are among the most common outpatient infections, with a lifetime incidence of around 60% in women. We analysed urine samples from 223 patients with community-acquired UTIs and report the presence of the cleavage product released during the synthesis of colibactin, a bacterial genotoxin, in 55 of the samples examined. Uropathogenic Escherichia coli strains isolated from these patients, as well as the archetypal E. coli strain UTI89, were found to produce colibactin. In a murine model of UTI, the machinery producing colibactin was expressed during the early hours of the infection, when intracellular bacterial communities form. We observed extensive DNA damage both in umbrella and bladder progenitor cells. To the best of our knowledge this is the first report of colibactin production in UTIs in humans and its genotoxicity in bladder cells. Author summary: Colibactin is a bacterial genotoxin suspected of being involved in cancer. So far, the focus has been on colorectal cancer following asymptomatic intestinal carriage of genotoxic Escherichia coli. Here, we show for the first time that this genotoxin is produced in humans, by detecting it in the urine of patients suffering from urinary tract infections. We subsequently show in a rodent UTI model the genotoxic activity of colibactin in the bladder, including in regenerative cells. These results raise the hypothesis of a role of UTI in bladder cancer, which could be an interesting perspective for future investigation. [ABSTRACT FROM AUTHOR]

Background and objective: To study the cumulative incidence and surgical treatment of midline incisional hernia (MIH) after cystectomy for bladder cancer. Methods: In the nationwide Bladder Cancer Data Base Sweden (BladderBaSe), cystectomy was performed in 5646 individuals. Cumulative incidence MIH and surgery for MIH were investigated in relation to age, gender, comorbidity, previous laparotomy and/or inguinal hernia repair, operative technique, primary/secondary cystectomy, postoperative wound dehiscence, year of surgery, and period-specific mean annual hospital cystectomy volume (PSMAV). Results: Three years after cystectomy the cumulative incidence of MIH and surgery for MIH was 8% and 4%, respectively. The cumulative incidence MIH was 12%, 9% and 7% in patients having urinary diversion with continent cutaneous pouch, orthotopic neobladder and ileal conduit. Patients with postoperative wound dehiscence had a higher three-year cumulative incidence MIH (20%) compared to 8% without. The corresponding cumulative incidence surgery for MIH three years after cystectomy was 9%, 6%, and 4% for continent cutaneous, neobladder, and conduit diversion, respectively, and 11% for individuals with postoperative wound dehiscence (vs 4% without). Using multivariable Cox regression, secondary cystectomy (HR 1.3 (1.0–1.7)), continent cutaneous diversion (HR 1.9 (1.1–2.4)), robot-assisted cystectomy (HR 1.8 (1–3.2)), wound dehiscence (HR 3.0 (2.0–4.7)), cystectomy in hospitals with PSMAV 10–25 (HR 1.4 (1.0–1.9)), as well as cystectomy during later years (HRs 2.5–3.1) were all independently associated with increased risk of MIH. Conclusions: The cumulative incidence of MIH was 8% three years postoperatively, and increase over time. Avoiding postoperative wound dehiscence after midline closure is important to decrease the risk of MIH. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study was to estimate the prevalence of anemia among patients newly diagnosed with solid malignancies at King Faisal Hospital in Taif Province, Kingdom of Saudi Arabia. Methods: A descriptive, cross-sectional, hospital-based study was conducted from December 2017 to March 2020. A total of 320 patients newly diagnosed with solid malignancy were examined to assess anemia prevalence. Results: Of 320 patients with solid cancers, 245 (76.6%) were female and 75 (23.4%) were male. The median (interquartile range) age of 57 (45 ─ 66) years, range between 16 and 108 years. The types of cancer included were breast (29.1%), female genital tract (20.0%), colorectal (25.3%), head and neck (10.3%), urinary bladder (4.7%), prostate (5.0%), lung (2.5%), liver (2.2%) and lymphoma (0.9%). The prevalence of anemia at diagnosis of cancer was 44.1% across all cancer types. A higher anemia prevalence was noted in colorectal (n = 46/81, 56.8%) (p = 0.047). Conclusion: Patients with colorectal or female genital tract cancers had a higher anemia prevalence (56.8% and 43.8%, respectively) than did patients with other cancers. [ABSTRACT FROM AUTHOR]

Introduction: Cigarette smoke is suggested to be a risk factor for coronary artery disease (CAD), urinary bladder cancer (UBCa) or lung cancer (LCa). However, not all heavy smokers develop these diseases and elevated cancer risk among first-degree relatives suggests an important role of genetic factor. Methods: Three hundred and ten healthy blood donors (controls), 98 CAD, 74 UBCa and 38 LCa patients were included in this pilot study. The influence of 92 single nucleotide polymorphisms (SNPs) and impact of cigarette smoking were analysed. Results: Out of 92 SNPs tested, differences in distribution of 14 SNPs were detected between controls and patient groups. Only CTLA4 rs3087243 showed difference in both CAD and UBCa patient group compared to control group. Stratified by smoking status, the impact of smoking was associated to frequencies of 8, 3 and 4 SNPs in CAD, UBCa, LCa patients, respectively. None of these 92 SNPs showed a statistically significant difference to more than one type of disease among smoking patients. In non-smoking patients, 7, 3 and 6 SNPs were associated to CAD, UBCa, LCa, respectively. Out of these 92 SNPs, CTLA4 rs3087243 was associated to both non-smoking CAD and UBCa. The XRCC1 rs25487 was associated to both non-smoking UBCa and LCa. Conclusion: SNPs might be important risk factors for CAD, UBCa and LCa. Distribution of the SNPs was specific for each patient group, not a random event. Impact of cigarette smoking on the disease was associated to the specific SNP sequences. Thus, smoking individuals with SNPs associated to risk of these serious diseases is an important target group for smoking cessation programs. [ABSTRACT FROM AUTHOR]

Type 1 pili have long been considered the major virulence factor enabling colonization of the urinary bladder by uropathogenic Escherichia coli (UPEC). The molecular pathogenesis of pyelonephritis is less well characterized, due to previous limitations in preclinical modeling of kidney infection. Here, we demonstrate in a recently developed mouse model that beyond bladder infection, type 1 pili also are critical for establishment of ascending pyelonephritis. Bacterial mutants lacking the type 1 pilus adhesin (FimH) were unable to establish kidney infection in male C3H/HeN mice. We developed an in vitro model of FimH-dependent UPEC binding to renal collecting duct cells, and performed a CRISPR screen in these cells, identifying desmoglein-2 as a primary renal epithelial receptor for FimH. The mannosylated extracellular domain of human DSG2 bound directly to the lectin domain of FimH in vitro, and introduction of a mutation in the FimH mannose-binding pocket abolished binding to DSG2. In infected C3H/HeN mice, type 1-piliated UPEC and Dsg2 were co-localized within collecting ducts, and administration of mannoside FIM1033, a potent small-molecule inhibitor of FimH, significantly attenuated bacterial loads in pyelonephritis. Our results broaden the biological importance of FimH, specify the first renal FimH receptor, and indicate that FimH-targeted therapeutics will also have application in pyelonephritis. Author summary: Urinary tract infections (UTIs) are among the most common bacterial infections in humans. While much has been discovered about how E. coli cause bladder infections, less is known about the host-pathogen interactions that underlie kidney infection (pyelonephritis). We employed recently developed mouse models to show that bacterial surface fibers called type 1 pili, which bear the adhesive protein FimH and are known to mediate E. coli binding to bladder epithelium, are also required for ascending kidney infection. We developed a cell-culture model of bacterial binding to renal collecting duct, then performed a screen using the gene-editing tool CRISPR to identify the first known FimH receptor in the kidney. This epithelial cell-surface protein, desmoglein-2, was shown to directly bind FimH, and we localized this binding to specific extracellular domains of DSG2. Further, we showed that mannosides, small-molecule FimH inhibitors currently in development to treat bladder infection, are also effective in experimental kidney infection. Our study reveals a novel host-pathogen interaction during pyelonephritis and demonstrates how this interaction may be therapeutically targeted. [ABSTRACT FROM AUTHOR]

Lower urinary track symptoms (LUTS) affect many older adults. Multi-channel urodynamic studies provide information about bladder pressure and urinary flow but offer little insight into changes in bladder anatomy and detrusor muscle function. Here we present a novel method for real time MRI during bladder voiding. This was performed in a small cohort of healthy men and men with benign prostatic hyperplasia and lower urinary tract symptoms (BPH/LUTS) to demonstrate proof of principle; The MRI urodynamic protocol was successfully implemented, and bladder wall displacement and urine flow dynamics were calculated. Displacement analysis on healthy controls showed the greatest bladder wall displacement in the dome of the bladder while men with BPH/LUTS exhibited decreased and asymmetric bladder wall motion. Computational fluid dynamics of voiding showed men with BPH/LUTS had larger recirculation regions in the bladder. This study demonstrates the feasibility of performing MRI voiding studies and their potential to provide new insight into lower urinary tract function in health and disease. [ABSTRACT FROM AUTHOR]

Minimizing the toxicity of radiotherapy is challenging. We investigated the effects of a phosphodiesterase type-5 inhibitor (PDE5I) on the urinary bladder after pelvic radiotherapy. Eight rats were assigned to each group (group 1: control; group 2: radiation; group 3: radiation plus PDE5I). Radiation dose was 10 Gy/one fraction. Udenafil (20 mg/kg, daily for 4 weeks) was administered in group 3. Cystometry was performed 4 weeks after treatment, followed by real-time PCR for PDE5, vascular endothelial growth factor (VEGF), and endothelial nitric oxide synthase (eNOS) mRNA, western blotting for PDE5, cyclic GMP-dependent protein kinase (PRKG), VEGF164, Akt, eNOS and NADPH oxidase (NOX)-2 proteins, and immunohistochemistry for eNOS. The expression of both VEGF mRNA and eNOS mRNA was higher in group 3 than in group 2. VEGF and eNOS protein expression improved with PDE5I treatment. Akt protein phosphorylation was higher in group 3 than in group 2, but NOX-2 protein expression was lower in group 3 than in group 2. Immunohistochemistry showed that the mean density of arterioles expressing eNOS was higher in group 3 than in group 2. Cystometry revealed that the intercontraction interval was remarkably longer in group 3 than in group 2 but that the maximal voiding pressure was higher in group 2 than in group 3. Daily treatment with a PDE5I after radiotherapy may prevent bladder storage dysfunction, potentially due to its effects on vasodilation and angiogenesis and through minimizing tissue oxidative damage by means of the VEGF/Akt/eNOS pathway. [ABSTRACT FROM AUTHOR]

Purpose: Accurate measurement of body temperature is important for the timely detection of fever or hypothermia in critically ill patients. In this prospective study, we evaluated whether the agreement between temperature measurements obtained with TAT (test method) and bladder catheter-derived temperature measurements (BT; reference method) is sufficient for clinical practice in critically ill patients. Methods: Patients acutely admitted to the Intensive Care Unit were included. After BT was recorded TAT measurements were performed by two independent researchers (TAT1; TAT2). The agreement between TAT and BT was assessed using Bland-Altman plots. Clinical acceptable limits of agreement (LOA) were defined a priori (<0.5°C). Subgroup analysis was performed in patients receiving norepinephrine. Results: In total, 90 critically ill patients (64 males; mean age 62 years) were included. The observed mean difference (TAT-BT; ±SD, 95% LOA) between TAT and BT was 0.12°C (-1.08°C to +1.32°C) for TAT1 and 0.14°C (-1.05°C to +1.33°C) for TAT2. 36% (TAT1) and 42% (TAT2) of all paired measurements failed to meet the acceptable LOA of 0.5°C. Subgroup analysis showed that when patients were receiving intravenous norepinephrine, the measurements of the test method deviated more from the reference method (p = NS). Conclusion: The TAT is not sufficient for clinical practice in critically ill adults. [ABSTRACT FROM AUTHOR]

Objectives: To determine if the URO-MCP-1 mouse model for bladder IC/BPS is associated with in vivo bladder hyper-permeability, as measured by contrast-enhanced MRI (CE-MRI), and assess whether molecular-targeted MRI (mt-MRI) can visualize in vivo claudin-2 expression as a result of bladder hyper-permeability. Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic, painful condition of the bladder that affects primarily women. It is known that permeability plays a substantial role in IC/BPS. Claudins are tight junction membrane proteins that are expressed in epithelia and endothelia and form paracellular barriers and pores that determine tight junction permeability. Claudin-2 is a molecular marker that is associated with increased hyperpermeability in the urothelium. Materials and methods: CE-MRI was used to measure bladder hyper-permeability in the URO-MCP-1 mice. A claudin-2-specific mt-MRI probe was used to assess in vivo levels of claudin-2. The mt-MRI probe consists of an antibody against claudin-2 conjugated to albumin that had Gd-DTPA (gadolinium diethylenetriamine pentaacetate) and biotin attached. Verification of the presence of the mt-MRI probe was done by targeting the biotin moiety for the probe with streptavidin-horse radish peroxidase (SA-HRP). Trans-epithelial electrical resistance (TEER) was also used to assess bladder permeability. Results: The URO-MCP-1 mouse model for IC/BPS was found to have a significant increase in bladder permeability, following liposaccharide (LPS) exposure, compared to saline-treated controls. mt-MRI- and histologically-detectable levels of the claudin-2 probe were found to increase with LPS -induced bladder urothelial hyper-permeability in the URO-MCP-1 IC mouse model. Levels of protein expression for claudin-2 were confirmed with immunohistochemistry and immunofluorescence imaging. Claudin-2 was also found to highly co-localize with zonula occlidens-1 (ZO-1), a tight junction protein. Conclusion: The combination of CE-MRI and TEER approaches were able to demonstrate hyper-permeability, a known feature associated with some IC/BPS patients, in the LPS-exposed URO-MCP-1 mouse model. This MRI approach could be clinically translated to establish which IC/BPS patients have bladder hyper-permeability and help determine therapeutic options. In addition, the in vivo molecular-targeted imaging approach can provide invaluable information to enhance our understanding associated with bladder urothelium hyper-permeability in IC/BPS patients, and perhaps be used to assist in developing further therapeutic strategies. [ABSTRACT FROM AUTHOR]

In urothelial cell type non-muscle invasive urinary bladder carcinoma, TNM stage and WHO grade are widely used to classify patients into low and high‑risk groups for prognostic and therapeutic decision-making. However, stage and grade reproducibility and prediction accuracy are wanting. This may lead to suboptimal treatment. We evaluated whether proliferation features, nuclear area of the epithelial cancer cells and the composition of stromal and tumor infiltrating lymphocytes have independent prognostic value. In 183 primary non-muscle invasive bladder cancer patients with long follow-up (median for stage progression cohort: 119 months, range 5-173; median for tumor recurrence cohort: 82, range 3-165) proliferation features Ki67, PPH3 and Mitotic Activity Index (MAI), Mean Nuclear Area (MNA), lymphocyte subsets (CD8+, CD4+, CD25+) and plasma cells (CD138+) were assessed on consecutive sections. Post-resection instillation treatments (none, mitomycin, BCG) were strictly standardized during the intake period. Risk of recurrence was associated with expression of Ki67 (≤ 39 vs. > 39) and Multifocality (p = 0.01). Patients with low Ki67 had a higher recurrence rate than those with high Ki67. Lymphocyte composition did not predict recurrence. Stage progression was strongly associated with high values for MAI (>15) and CD25+ (>0.2%). In a multivariate analysis the combination of MAI and CD25+ was the single most prognostic feature (p<0.001). Validation of these results in additional, independent studies is warranted. [ABSTRACT FROM AUTHOR]

Canine prostate adenocarcinoma (PAC) and transitional cell carcinoma (TCC) of prostate and urinary bladder are highly invasive and metastatic tumors of closely neighbored organs. Cell lines are valuable tools to investigate tumor mechanisms and therapeutic approaches in vitro. PAC in dogs is infrequent, difficult to differentiate from TCC and usually characterized by poor prognosis, enhancing the value of the few available cell lines. However, as cell lines adapt to culturing conditions, a thorough characterization, ideally compared to original tissue, is indispensable. Herein, six canine PAC cell lines and three TCC cell lines were profiled by immunophenotype in comparison to respective original tumor tissues. Three of the six PAC cell lines were derived from primary tumor and metastases of the same patient. Further, two of the three TCC cell lines were derived from TCCs invading into or originating from the prostate. Cell biologic parameters as doubling times and chemoresistances to commonly used drugs in cancer treatment (doxorubicin, carboplatin and meloxicam) were assessed. All cell lines were immunohistochemically close to the respective original tissue. Compared to primary tumor cell lines, metastasis-derived cell lines were more chemoresistant to doxorubicin, but equally susceptive to carboplatin treatment. Two cell lines were multiresistant. COX-2 enzyme activity was demonstrated in all cell lines. However, meloxicam inhibited prostaglandin E2 production in only seven of nine cell lines and did neither influence metabolic activity, nor proliferation. The characterized nine cell lines represent excellent tools to investigate PAC as well as TCC in prostate and urinary bladder of the dog. Furthermore, the profiled paired cell lines from PAC primary tumor and metastasis provide the unique opportunity to investigate metastasis-associated changes PAC cells undergo in tumor progression. The combination of nine differently chemoresistant PAC and TCC cell lines resembles the heterogeneity of canine lower urinary tract cancer. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate early recovery of urinary continence after robot-assisted radical prostatectomy (RARP) with urethral realignment using bladder neck preservation (BNP) and maximal urethral length preservation (MULP). Methods: Patients who underwent RARP between 2014 and 2017 owing to prostate cancer with a Gleason score ≤ 7 (3+4), ≤ cT2c stage, and prostate-specific antigen level < 20 ng/ml were investigated. Patients with tumors of the bladder neck or apex on magnetic resonance imaging were excluded. A total of 266 patients underwent the operation using the standard method between 2014 and 2015 (group 1), while 305 patients underwent urethral realignment between 2016 and 2017 (group 2). Continence was defined as wearing no pad or one security pad. Results: The continence rates immediately after Foley catheter removal, at 2 weeks, and at 1, 3, 6, and 12 months after operation in group 2 were 46.9%, 63.0%, 73.4%, 90.1%, 94.8%, and 98.7%, respectively. The continence rate at 1 month in group 2 was significantly higher than that in group 1 (65.4% versus 73.4%, p = 0.037). The multivariate regression analysis showed that age and surgical method were factors affecting early continence recovery. The positive surgical margin rates were 18.0% and 14.8% in groups 1 and 2, respectively (p = 0.288). Biochemical recurrence occurred in 14.7% and 8.2% in groups 1 and 2, respectively (p = 0.015). Conclusion: Urethral realignment using BNP and MULP resulted in rapid continence recovery and good oncological results after RARP in young patients with a Gleason score ≤ 7 and organ-confined disease. [ABSTRACT FROM AUTHOR]

Traditional urodynamics have poor correlation with urological symptoms. Ambulatory urodynamics may improve this correlation but the need for a transurethral catheter and the time-consuming nature of this examination limits its use. Therefore, the objective of this study was to develop a wireless real-time bladder pressure measurement device for repeated and prolonged-term measurement of bladder behavior in awake pigs. The Bladder Pill is an intravesical device with a pressure microsensor and a 3-dimensional inductive coupling coil for energy supply. A corresponding external coil provides wireless power transmission and real-time communication of bladder pressure data. To test the correlation between the pressure data measured by the device and by standard methods, we compared static water column pressures with this device and water-filled urodynamic catheter systems. In vivo assessment of awake voiding by the pill was done by introducing the bladder pill into the bladder of Göttingen minipigs. An air-charged urodynamic catheter was introduced transurethrally as control for pressure measurements. The optimal physical configuration of the pill was investigated to maximize the containment in the bladder. We used two versions of external signal receivers (one waistband and one rectangular frame) to test the optimal external signal capture. Next to that, we performed short-term and medium-term comparative pressure studies. The in vitro static pressure measurement demonstrated a mean difference of less than 1 cm H2O between the methods. The optimal design of the pill for maximal retainment in the bladder proved to be a pigtail configuration. The bending of the device during bladder contractions caused offset of 2.7 +/- 1.4 cm H2O (mean +/- SD) on the pressure measurements. The rectangular frame performed signal capture during 5 consecutive voids with a good correlation of the pressure measurements. The device can be inserted through the urethra and is retrieved using string or endoscopic extraction. In conclusion, wireless long-term measurement of bladder pressure is demonstrated and yields comparable results to current available catheter methods of measurement in a pig model. [ABSTRACT FROM AUTHOR]

Objectives: To investigate effects of postural changes and bladder distention on intrabladder pressure whilst estimating intra-abdominal pressure in horses. Design: Two-year cohort study. Patients admitted for elective surgical procedures unrelated to gastrointestinal or genitourinary tract. Setting: School of Agricultural and Veterinarian Sciences, Jaboticabal, SP, Brazil. Animals: 20 adult horses, 11 males (stallions and geldings) and 9 females; between 3.5 and 12 years, weighing 350 to 500 kg. Interventions: Intra-abdominal pressure was directly-recorded through abdominocentesis at the ventral midline with a fluid-filled system. Intrabladder pressure was obtained from a bladder catheter with the fluid-filled system zeroed at the level of the tuber ischia with patients in dorsal recumbency or pubic symphysis if in lateral recumbency. Measurements and main results: Body position directly influenced intra-abdominal pressure. In dorsal recumbency, intra-abdominal pressure differed (p < 0.05) from intrabladder pressure at end-inspiration and end-expiration regardless of whether the bladder was empty or distended. There was no correlation nor association between the two pressures in this body position. In lateral recumbency a difference (p <0.05) between intra-abdominal pressure and intrabladder pressure was recorded at end-inspiration with the bladder distended with 25 ml, and at end-expiration for distension volumes of 25 ml and 50 ml. There was a strong correlation between both pressures for left and right lateral recumbency, regardless of the distension volume. Ordinary least product (OLP) regression analysis showed no fixed or proportional bias between both pressures for distension volume of 50 ml, at both end-inspiration and end-expiration. Conclusions: Indirect assessment of equine intra-abdominal pressure cannot be made in dorsal recumbency. For that purpose, patients should be in left lateral recumbency with the bladder distended with 50 ml. Values can be recorded at end-inspiration or end-expiration. Restriction: Occlusion of the catheter tip by the bladder wall when minimally distended. [ABSTRACT FROM AUTHOR]

Background: We aim to examine the trend in the use of antimuscarinics and off-label alpha-adrenergic blockers for treatment of lower urinary tract symptoms (LUTS) in a Taiwanese Women Cohort between 2007 and 2012. Methods: This population-based National Health Insurance Research Database (NHIRD) was used to examine the trends in the use of antimuscarinics or off-label alpha-adrenergic blockers in Taiwan. A sample of 1,000,000 individuals randomly drawn from the whole population of 23 million individuals who were registered in the NHI in 2005. From 2007 through 2012, women aged over 18 years whose claim record contained prescriptions of either of the two drugs for treatment of any of the LUTS-related diagnoses were identified and analyzed. The annual usage of the two drug classes were calculated by defined daily dose (DDD). Results: From 2007–2012, there was a 0.80 fold (69676.8 to 125104.3) increase in DDD of antimuscarinics in our cohort. The overall healthcare seeking prevalence of LUTS was 7.33% in 2007 and 12.38% in 2012, in a rising trend. The prevalence of antimuscarinics-treated LUTS in our cohort increased from 2.53 in 2007 to 3.41 per 1000 women in 2012. The prevalence of LUTS treated by antimuscarinics increased especially for those older than 60 years during the study period. Conclusions: This 6-year observational study provided the epidemiologic information of clinically significant LUTS of Asian female population. Moreover, there was a rising trend in the use of antimuscarinics and off-label alpha-adrenergic blockers in the population-based cohort. [ABSTRACT FROM AUTHOR]

Objective: To compare the magnetic resonance imaging (MRI) features of deep infiltrating endometriosis (DIE) lesions before and after pregnancy. Design: Retrospective study. Setting: A single French university tertiary referral hospital. Patients: Twenty-one women without a prior history of surgery for endometriosis with a radiological diagnosis by MRI with two sets of examinations performed before and after pregnancy. Interventions: The volumes of the lesions were compared using the same protocol before and after pregnancy based on MRI (1.5 T) examinations by a single experienced radiologist who is a referring practitioner for image-based diagnosis of endometriosis. Main outcome measure(s): The DIE lesion volume. Measurements and main results: Between October 2012 and December 2016, a total of 21 patients (67 lesions) were included and compared before and after pregnancy. The mean time interval between the MRI before pregnancy and delivery was 19.6 ± 8.5 months (median: 17.6, IQR 13.5–25.2 months). The mean time interval between delivery and the MRI after pregnancy was 11.0 ± 6.4 months (median: 8.3, IQR 6–15.2 months). The mean overall DIE lesion volume by MRI was significantly higher before pregnancy compared to after pregnancy (2,552 ± 3,315 mm3 vs. 1,708 ± 3,266 mm3, respectively, p < 0.01). The mean volume by MRI of the largest lesion of each patient was significantly higher before pregnancy compared to after pregnancy (4,728 ± 4,776 mm3 vs. 3165 ± 5299 mm3; p < 0.01). Conclusion: Our data indicate a favorable impact of pregnancy on DIE lesion volumes as measured by MRI. [ABSTRACT FROM AUTHOR]

Background: Bowel and bladder problems affect more than 50% of people with Multiple Sclerosis (MS). These problems have a large impact on quality of life and place a significant burden on health systems. Objectives: This study aimed to ascertain the frequency of bladder and bowel problems in a select Australian MS cohort and to investigate the relationships between level of disability, bladder and bowel problems, and fatigue. Methods: Questionnaires on the nature and severity of MS symptoms were distributed to clients attending an Australian MS centre. Log-binomial regression and multiple linear regression models were used to investigate relationships between disability, fatigue, and bladder and bowel problems. Results and conclusions: Of 167 questionnaires distributed, 136 were completed. Bladder problems were reported by 87 (74.4%) respondents, whilst 66 (48.9%) experienced functional constipation and 43 (31.9%) faecal incontinence. This frequency in our select Australian MS population is similar to that reported globally. There was a significant correlation between level of disability and: bladder problems (p = 0.015), faecal incontinence (p = 0.001), fatigue (p<0.001) and constipation (p = 0.016, relative risk: 1.16). Further investigation into the causal relationships between various MS symptoms may be beneficial in the development of novel therapeutic strategies for people with MS. [ABSTRACT FROM AUTHOR]

Bladder urine volume has been estimated using an ellipsoid method based on triaxial measurements of the bladder extrapolated from two-dimensional ultrasound images. This study aimed to automate this process and to determine the accuracy of the automated estimation method for normal and small amounts of urine. A training set of 81 pairs of transverse and longitudinal ultrasound images were collected from healthy volunteers on a tablet-type ultrasound device, and an automatic detection tool was developed using them. The tool was evaluated using paired transverse/longitudinal ultrasound images from 27 other healthy volunteers. After imaging, the participants voided and their urine volume was measured. For determining accuracy, regression coefficients were calculated between estimated bladder volume and urine volume. Further, sensitivity and specificity for 50 and 100 ml bladder volume thresholds were evaluated. Data from 50 procedures were included. The regression coefficient was very similar between the automatic estimation (β = 0.99, R2 = 0.96) and manual estimation (β = 1.05, R2 = 0.97) methods. The sensitivity and specificity of the automatic estimation method were 88.5% and 100.0%, respectively, for 100 ml and were 94.1% and 100.0%, respectively, for 50 ml. The newly-developed automated tool accurately and reliably estimated bladder volume at two different volume thresholds of approximately 50 ml and 100 ml. [ABSTRACT FROM AUTHOR]

Genetic profiling studies on muscle-invasive bladder cancers (MIBCs) have discovered molecular subtypes with different biological characteristics. Immunohistochemical (IHC) markers such as GATA3, cytokeratin (CK) 20, CK5/6, and p53 are associated with these subtypes. In this study, we investigated the biological and prognostic significance of these IHC markers in MIBCs from 91 patients who underwent radical cystectomy. High Ki-67 indices were associated with negative CK20 (p = 0.002) and diffuse CK5/6 (p = 0.001) staining. By contrast, tumors with diffuse GATA3 expression had low Ki-67 index (p = 0.006). Regarding p53, three staining patterns were associated with a high Ki-67 index: (1) complete absence, (2) diffusely strong nuclear reactivity, and (3) diffusely strong cytoplasmic staining (p < 0.001 compared with other patterns). CK5/6 and CK20 expression was typically present in a reciprocal fashion; however, diffuse GATA3 and CK5/6 coexpression was observed in 13 (14.29%) cases. Among 78 chemotherapy-naïve patients, low GATA3 staining was associated with worse recurrence-free survival in both univariate (p = 0.008) and multivariate analyses (p = 0.002). CK20, CK5/6, or p53 expression was not associated with clinical outcome. Based on our results, IHC staining for GATA3 may help risk stratification in patients with MIBC receiving radical cystectomy. In addition, the differences in Ki-67 indices suggested that aberrant p53 expression was better defined by the three aforementioned patterns, rather than percentage of nuclear staining alone. [ABSTRACT FROM AUTHOR]

Introduction: Current treatments for overactive bladder (OAB) are often discontinued due to side effects or lack of efficacy. The goal of this study was to determine if combining a phosphodiesterase type 4 inhibitor (PDE4i); with a type 5 inhibitor (PDE5i); would have a beneficial effect on OAB symptoms and if a reduced dose of PDE4i in combination with PDE5i could also provide a beneficial effect in OAB. We hypothesized that PDE5i and PDE4i combination treatment could be utilized to reduce non-voiding contractions and smooth muscle disruption in a rat model of OAB. Methods: Fifty-eight age-matched Sprague-Dawley rats underwent PBOO and daily gavage with PDE4i alone (roflumilast; 1mg/kg), PDE5i alone (tadalafil;10mg/kg), high dose combination (PDE4i 1mg/kg, PDE5i 10mg/kg), low dose combination (PDE4i 0.2mg/kg, PDE5i 10mg/kg), or vehicle for 28 days. Fourteen animals underwent sham PBOO with vehicle. Rats underwent conscious and anesthetized cystometry 28 days after PBOO and were euthanized for qualitative bladder histology. One-way ANOVA on ranks with a Dunn’s post hoc test was used to indicate statistically significant differences between groups (p<0.05). Results: Bladder & urethral weight was significantly increased after PBOO with vehicle, PDE4i alone, and PDE5i alone, but not with either combination treatment. Frequency of non-voiding contractions during both conscious and anesthetized cystometry increased significantly after PBOO with vehicle, but not after PDE4i or high dose combination treatments compared to sham PBOO. Threshold pressure for voiding was significantly decreased with high dose combination compared to vehicle. PBOO treated with PDE4i alone or high dose combination showed less bladder smooth muscle fibrosis than vehicle, PDE5i alone, or low dose combination treatments. Conclusion: A PDE4i and PDE5i combination treatment has potential benefit in reducing OAB symptoms, but future research is needed. [ABSTRACT FROM AUTHOR]

Purpose: mARC (modulated arc) is the arc therapy technique provided by Siemens. The present study analyses the dose distributions and treatment times corresponding to preoperative rectal cancer mARC treatments. The results are compared to those corresponding to 3D-CRT plans. Methods: The plans of 30 patients, each having one mARC and one 3D-CRT plan, were evaluated. Every plan was calculated on a sequential two-phase treatment scheme with prescription doses of 45 Gy in the initial phase and 5.4 Gy in the boost phase. Dosimetric parameters and mean DVHs corresponding to the PTVs and OARs were assessed for both techniques. Results: All mARC plans were considered valid for treatment and yielded a highly significant improvement in the CI over 3D-CRT plans (p <0.001). They also showed statistically significant advantage on the parameters D98%, D95% and D2% of the high dose PTV. Regarding the OARs, mARC plans showed reductions in the mean dose of 3.5 Gy in the bladder and greater than 4 Gy in the femoral heads. Considering the small bowel, the mARC plans resulted in a 2.7 Gy mean reduction in the mean dose and lower irradiated volumes over the entire dose range. Conclusions: Arc therapy plans with the mARC technique for preoperative rectal cancer treatment in a sequential two-phase treatment scheme provide important advantages in the PTVs and OARs. mARC plans show superior protection of the femoral heads, bladder and small bowel, similar to the results found with other more widespread arc therapy techniques. [ABSTRACT FROM AUTHOR]

Chlamydial-induced cystitis in the koala (Phascolarctos cinereus) is currently treated by antibiotics. However, while reducing the chlamydial load, this treatment can also lead to gastrointestinal complications and death. Development of alternative treatments, such as a therapeutic chlamydial vaccine, are hindered by the lack of detailed understanding of the innate immune response to chlamydial clearance and disease regression during antibiotic treatment. Through clinical, microbiological and transcriptomic approaches, disease regression, bacterial clearance and innate immune responses were mapped in koalas with signs of chlamydial-induced cystitis while receiving anti-chlamydial antibiotics. Significant reduction in the signs of cystitis were observed during and post antibiotic treatment. This was observed as a thinning of the bladder wall and complete reversal of urinary incontinence. Transcriptomic analysis before treatment, at the end of treatment and prior to release identified significant down-regulation of specific genes involved in 21 biological pathways. Of these, the chemokine receptor signalling and NOD-like receptor signalling pathways where identified as important markers of inflammation. Specific genes within these pathways (NCF1 and NOX2) were significantly down-regulated, suggesting a decrease in reactive oxygen species production. Through the monitoring of specific clinical and transcriptomic markers, these findings allow detailed profiling of the clinical response to therapeutic vaccination in koalas with current signs of disease. This also adds to our understanding of innate immune responses to chlamydial infections and indicates that chlamydial-induced cystitis in the koala is linked to the regulation of reactive oxygen pathways. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate methods for the pre-treatment verification of volumetric modulated arc therapy (VMAT) based on the percentage gamma passing rate (%GP) and its correlation and sensitivity with percentage dosimetric errors (%DE). Methods: A total of 25 patients with prostate cancer and 15 with endometrial cancer were analysed. The %GP values of 2D and 3D verifications with different acceptance criteria (1%/1 mm, 2%/2 mm, and 3%/3 mm) were obtained using OmniPro and Compass. The %DE was calculated using a planned dose volume histogram (DVH) created in Monaco’s treatment planning system (TPS), which relates radiation dose to tissue and the patient’s predicted dose volume histogram in Compass. Statistical correlation between %GP and %DE was verified using Pearson’s correlation coefficient. Sensitivity was calculated based on the receiver operating characteristics (ROC) curve. Plans were calculated using Collapsed Cone Convolution and the Monte Carlo algorithm. Results: The t-test results of the planned and estimated DVH showed that the mean values were comparable (P > 0.05). For the 3%/3 mm criterion, the average %GP was acceptable for the prostate and endometrial cancer groups, with average rates of 99.68 ± 0.49% and 99.03 ± 0.59% for 2D and 99.86 ± 0.39% and 99.53 ± 0.44% for 3D, respectively. The number of correlations was poor for all analysed data. The mean Pearson’s R-values for prostate and endometrial cancer were < 0.45 and < 0.43, respectively. The area under the ROC curve for the prostate and endometrial cancer groups, was lower than 0.667. Conclusions: Analysis of the %GP versus %DE values revealed only weak correlations between 2D and 3D verifications. DVH results obtained using the Compass system will be helpful in confirming that the analysed plans respect dosimetric constraints. [ABSTRACT FROM AUTHOR]