Electrical stimulation in the treatment of bladder dysfunction: Technology update

The urinary bladder has two functions: urine storage and voiding. Clinically, two major categories of lower urinary tract symptoms can be defined: storage symptoms such as incontinence and urgency, and voiding symptoms such as feeling of incomplete bladder emptying and slow urinary stream. Urgency to void with or without incontinence is called overactive bladder (OAB). Slow urinary stream, hesitancy, and straining to void with the feeling of incomplete bladder emptying are often called underactive bladder (UAB). The underlying causes of OAB or UAB can be either non-neurogenic (also referred to as idiopathic) and neurogenic, for example due to spinal cord injury or multiple sclerosis. OAB and UAB can be treated conservatively by lifestyle intervention or medication. In the case that conservative treatment does not provide sufficient benefit, electrical stimulation can be used. Sacral neurostimulation or neuromodulation (SNM) is offered as a third-line therapy to patients with non-neurogenic OAB or UAB. In SNM, the third or fourth sacral nerve root is stimulated and after a test period, a neuromodulator is implanted in the buttock. Until recently only a non-rechargeable neuromodulator was approved for clinical use. However, nowadays, a rechargeable sacral neuromodulator is also on the market, with similar safety and effectiveness to the non-rechargeable SNM system. The rechargeable device was approved for full body 1.5T and 3T MRI in Europe in February 2019. Regarding neurogenic lower urinary tract dysfunction, electrical stimulation only seems to benefit a selected group of patients

Contractility of the guinea pig bladder measured in situ and in vitro

To study the relative importance of neurogenic factors in detrusor contractility and to relate a total bladder in vitro contractility model to a previously described bladder wall strip model, active intravesical pressure values were compared in situ and in vitro in eight male guinea pigs. In situ, the active pressure was measured in spontaneous isometric and nonisometric micturition contractions. In vitro, the active pressure was measured in isometric contractions of the same bladders, developed in response to optimal electrical stimulation. The volume dependence of the active pressure generated by the bladder was measured in vitro in order to relate bladder capacity to the volume where the generated force is maximal and to determine the optimal volume at which to study detrusor contractility. The results indicated that in normal micturition the detrusor muscle was not fully stimulated: active pressure in isometric contractions in vivo was about 60% of the pressure values attained in vitro at the same bladder volume. Most micturitions occurred at a volume where the active pressure generated in vitro was about 80% of the maximal pressure. The active pressure-bladder volume relationship complied with the sliding filament-cross bridge theory. In whole bladder preparations act

A comparative study of voiding in rat and guinea pig: simultaneous measurement of flow rate and pressure

In this study, the voiding phase of the micturition cycle in the anesthetized rat and guinea pig is analyzed. In both animals, voiding is characterized by an increase in intravesical pressure and then a decrease, which is accompanied by flow through the urethra and emission of urine. An ultrasonic flow probe was used in both species to measure the flow rate in relation to the intravesical pressure. In the (male) rat, so-called high-frequency oscillations are superimposed on the decreasing bladder pressure. These oscillations do not occur in the guinea pig. It is concluded that the high-frequency oscillations are caused by intermittent flow and not by variations in the bladder contraction. The intermittent flow most likely is caused by the relaxation and contraction of the external urethral sphincter and may have a function in territory marking. In our view, it is not likely that the oscillations enhance bladder emptying, as has been suggested in the literature

Neurogenic modulation of urethral resistance in the guinea pig

Purpose: The resistance offered to urinary flow by the urethra is one of the factors determining the course of micturition. It was the aim of the present work to study the dependence of urethral resistance on the degree of relaxation of the urethra. Materials and Methods: Experiments were done in the guinea pig. Ten animals were used. In 5 animals saline was forced through the (unrelaxed) urethra at imposed flow rates in the range of 1.1 to 43.0 ml. per minute while the urethral pressure was measured. Second degree polynomials were fitted to the pressure/flow data. In the other 5 animals micturition contractions were evoked and pressure/flow plots were derived from the measured signals. A straight line was fitted to the lowest pressure values at each flow rate in these plots. These pressure values represent the most relaxed state of the urethra in these voidings. Results: The pressures measured in the unrelaxed urethra were much higher than the pressures measured during voiding in the same flow rate range, but the intercepts of the mathematical equations fitted to the pressure/flow data on the pressure axis were not significantly different in the 2 groups. Conclusions: The unrelaxed urethra has a much "steeper" pressure/flow characteristic than the relaxed urethra. However, the urethral closing pressure, that is, the intercept of the pressure/flow characteristic on the pressure axis, does not depend on the state of relaxation of the urethra

Tudásmenedzsment és a felsőoktatási intézmény, mint vállalat = Knowledge Management and the University as a Company

Purpose: ALK rearrangement detection using FISH is the standard test to identify patients with non–small cell lung carcinoma (NSCLC) eligible for treatment with ALK inhibitors. Recently, ALK protein expression in resectable NSCLC showed predictive value. We evaluated tumor response rate and survival after crizotinib treatment of patients with advanced NSCLC with ALK activation using both dichotomous immunohistochemical (IHC) staining and FISH. Experimental Design: Patients with stage IV NSCLC treated with crizotinib were selected. Tumor response was assessed. ALK rearrangements were detected by FISH (Vysis ALK-break-apart FISH-Probe KIT) and IHC [Ventana ALK (D5F3) CDx assay]. Cohorts of patients with ALK-FISH–positive advanced NSCLC from four other hospitals were used for validation. Results: Twenty-nine consecutive patients with ALK-positive advanced NSCLC diagnosed by FISH and/or IHC on small biopsies or fine-needle aspirations (FNA) were treated with ALK inhibitors. All ALK-IHC–positive patients responded to crizotinib except three with primary resistance. No tumor response was observed in 13 ALK-FISH–positive but ALK-IHC–negative patients. This was confirmed in an external cohort of 16 patients. Receiver operator characteristic (ROC) curves for ALK-IHC and ALK-FISH compared with treatment outcome showed that dichotomous ALK-IHC outperforms ALK-FISH [tumor response area under the curve: (AUC), 0.86 vs. 0.64, P ¼ 0.03; progression-free survival (PFS): AUC 0.86 vs. 0.36, P ¼ 0.005; overall survival (OS): AUC, 0.78 vs. 0.41, P ¼ 0.01, respectively]. Conclusions: Dichotomous ALK-IHC is superior to ALK-FISH on small biopsies and FNA to predict tumor response and survival to crizotinib for patients with advanced NSCLC. Our data strongly suggest adapting the guidelines and using dichotomous ALK-IHC as standard companion diagnostic test to select patients with NSCLC who benefit from ALK-targeting therapy

Blocking Sodium-Taurocholate Cotransporting Polypeptide Stimulates Biliary Cholesterol and Phospholipid Secretion in Mice

Active secretion of bile salts into the canalicular lumen drives bile formation and promotes biliary cholesterol and phospholipid output. Disrupting hepatic bile salt uptake, by inhibition of sodium‐taurocholate cotransporting polypetide (NTCP; Slc10a1) with Myrcludex B, is expected to limit bile salt flux through the liver and thereby to decrease biliary lipid excretion. Here, we show that Myrcludex B–mediated NTCP inhibition actually causes an increase in biliary cholesterol and phospholipid excretion whereas biliary bile salt output and bile salt composition remains unchanged. Increased lysosomal discharge into bile was excluded as a potential contributor to increased biliary lipid secretion. Induction of cholesterol secretion was not a consequence of increased ATP‐binding cassette subfamily G member 5/8 activity given that NTCP inhibition still promoted cholesterol excretion in Abcg8−/− mice. Stimulatory effects of NTCP inhibition were maintained in Sr‐b1−/− mice, eliminating the possibility that the increase in biliary lipids was derived from enhanced uptake of high‐density lipoprotein–derived lipids. NTCP inhibition shifts bile salt uptake, which is generally more periportally restricted, toward pericentral hepatocytes, as was visualized using a fluorescently labeled conjugated bile salt. As a consequence, exposure of the canalicular membrane to bile salts was increased, allowing for more cholesterol and phospholipid molecules to be excreted per bile salt. Conclusion: NTCP inhibition increases biliary lipid secretion, which is independent of alterations in bile salt output, biliary bile salt hydrophobicity, or increased activity of dedicated cholesterol and phospholipid transporters. Instead, NTCP inhibition shifts hepatic bile salt uptake from mainly periportal hepatocytes toward pericentral hepatocytes, thereby increasing exposure of the canalicular membrane to bile salts linking to increased biliary cholesterol secretion. This process provides an additional level of control to biliary cholesterol and phospholipid secretion.Biopharmaceutic

Landscape forming processes and diversity of forested landscapes : description and application of the model FORSPACE

In the project "Landschapsvormende processen en biodiversiteit" ("Landscape forming processes and bioversity") the spatial interactions between autonomous development of a vegetation and landscape forming processes were investigated and their implications for (bio)diversity at the landscape level were evaluated. For this purpose the model FORSPACE was developed which is a spatial explicit process model that describes vegetation dynamics and the impacts of landscape forming processes. In this study emphasis was paid to the effects of grazing by large herbivores and fire on the vegetation. Two approaches to analyse diversity at the landscape scale were developed: 1) a spatial analysis evaluating the time-evolution of dominant vegetation types, and 2) a metapopulation approach that describes the population dynamics of indicator species at the landscape scale depending on the availability of habitat. This report focuses on the methodological aspects of the study and thus acts as a reference for future applied studies. The model structure is described in detail, as well as the approach of spatial analysis and of the metapopulation dynamics of an indicator species. Much emphasis is paid on the validation of the driving processes for trees, herbs and grasses by evaluating controlled simulation experiments. In a case-study on the 200 ha of the Imbos, an area in the centre of the Netherlands, the impacts of grazing by herbivores and its interaction with different fire frequencies were evaluated

Cumulative live birth rates in low-prognosis women

No external funds were obtained for the present study. The OPTIMIST study was funded by The Netherlands Organization for Health Research and Development (ZonMW number 171102020).Peer reviewedPublisher PD