Intravesical botulinum toxin for lower urinary tract dysfunction

Botulinum neurotoxin has achieved substantial clinical benefits in neurogenic detrusor overactivity. More contentious has been its extension to management of refractory idiopathic detrusor overactivity, in which risk of impaired voiding function and consequent need for intermittent catheterisation may counteract the quality-of-life benefits of improved storage function. Several issues remain uncertain for this unlicensed treatment, and clear insights into long-term consequences are needed before it can be regarded as an established mainstream treatment

The Validation of a Functional, Isolated Pig Bladder Model for Physiological Experimentation

Characterizing the integrative physiology of the bladder requires whole organ preparations. The purpose of this study was to validate an isolated large animal (pig) bladder preparation, through arterial and intravesical drug administration, intravesical pressure recording, and filming of surface micromotions. Female pig bladders were obtained from the local abattoir and arterially perfused in vitro. Arterial and intravesical pressures were recorded at varying volumes. Bladder viability was assessed histologically and by monitoring inflow and outflow pH. Arterial drug administration employed boluses introduced into the perfusate. Intravesical administration involved slow instillation and a prolonged dwell-time. Surface micromotions were recorded by filming the separation of surface markers concurrently with intravesical pressure measurement. Adequate perfusion to all bladder layers was achieved for up to 8 h; there was no structural deterioration nor alteration in inflow and effluent perfusate pH. Arterial drug administration (carbachol and potassium chloride) showed consistent dose-dependent responses. Localized movements (micromotions) occurred over the bladder surface, with variable correlation with fluctuations of intravesical pressure. The isolated pig bladder is a valid approach to study integrative bladder physiology. It remains viable when perfused in vitro, responds to different routes of drug administration and provides a model to correlate movements of the bladder wall directly to variation of intravesical pressure

Estimation of bladder contractility from intravesical pressure–volume measurements

© 2016 Wiley Periodicals, Inc. Aims: To describe parameters from urodynamic pressure recordings that describe urinary bladder contractility through the use of principles of muscle mechanics. Methods: Subtracted detrusor pressure and voided flow were recorded from patients undergoing filling cystometry. The isovolumetric increase of detrusor pressure, P, of a voluntary bladder contraction before voiding was used to generate a plot of (dP/dt)/P versus P. Extrapolation of the plot to the y-axis and the x-axis generated a contractility parameter, vCE (the maximum rate of pressure development) and the maximum isovolumetric pressure, P0, respectively. Similar curves were obtained in ex vivo pig bladders with different concentrations of the inotropic agent carbachol and shown in a supplement. Results: Values of vCE, but not P0, diminished with age in female subjects. vCE was most significantly associated with the 20–80% duration of isovolumetric contraction t20–80; and a weaker association with maximum flow rate and BCI in women. P0 was not associated with any urodynamic variable in women, but in men was with t20–80 and isovolumetric pressure indices. Conclusions: The rate of isovolumetric subtracted detrusor pressure (t20–80) increase shows a very significant association with indices of bladder contractility as derived from a derived force–velocity curve. We propose that t20–80 is a detrusor contractility parameter (DCP). Neurourol. Urodynam. 36:1009–1014, 2017. © 2016 Wiley Periodicals, Inc

Expression and localization of aquaporin water channels in adult pig urinary bladder

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Loss of Tet1 associated 5-hydroxymethylcytosine is concomitant with aberrant promoter hypermethylation in liver cancer

Aberrant hypermethylation of CpG islands (CGI) in human tumors occurs predominantly at repressed genes in the host tissue, but the preceding events driving this phenomenon are poorly understood. In this study, we temporally tracked epigenetic and transcriptomic perturbations which occur in a mouse model of liver carcinogenesis. Hypermethylated CGI events in the model were predicted by enrichment of the DNA modification 5-hydroxymethylcytosine (5hmC) and the histone H3 modification H3K27me3 at silenced promoters in the host tissue. During cancer progression, CGI underwent hypo-hydroxymethylation prior to hypermethylation, whilst retaining H3K27me3. In livers from mice deficient in Tet1, a tumor suppressor involved in cytosine demethylation, we observed a similar loss of promoter core 5hmC, suggesting that reduced Tet1 activity at CGI may contribute to epigenetic dysregulation observed during hepatocarcinogenesis. Consistent with this possibility, mouse liver tumors exhibited reduced Tet1 protein levels. Similar to humans, DNA methylation changes at CGI in mice did not appear to be direct drivers of hepatocellular carcinoma progression, rather, dynamic changes in H3K27me3 promoter deposition correlated strongly with tumor-specific activation and repression of transcription. Overall, our results suggest that loss of promoter-associated 5hmC in liver tumors licenses reprogramming of DNA methylation at silent CGI during progression