Magnetic resonance imaging-guided transurethral ultrasound ablation of prostate tissue in patients with localized prostate cancer: single-center evaluation of 6-month treatment safety and functional outcomes of intensified treatment parameters.

OBJECTIVES: To evaluate the effect of intensified treatment parameters on safety, functional outcomes, and PSA after MR-Guided Transurethral Ultrasound Ablation (TULSA) of prostatic tissue. PATIENTS AND METHODS: Baseline and 6-month follow-up data were collected for a single-center cohort of the multicenter Phase I (n = 14/30 at 3 sites) and Pivotal (n = 15/115 at 13 sites) trials of TULSA in men with localized prostate cancer. The Pivotal study used intensified treatment parameters (increased temperature and spatial extent of ablation coverage). The reporting site recruited the most patients to both trials, minimizing the influence of physician experience on this comparison of adverse events, urinary symptoms, continence, and erectile function between subgroups of both studies. RESULTS: For Phase I and TACT patients, median age was 71.0 and 67.0 years, prostate volume 41.0 and 44.5 ml, and PSA 6.7 and 6.7 ng/ml, respectively. All 14 Phase I patients had low-risk prostate cancer, whereas 7 of 15 TACT patients had intermediate-risk disease. Baseline IIEF, IPSS, quality of life, and pad use were similar between groups. Pad use at 1 month and quality of life at 3 months favored Phase I patients. At 6 months, there were no significant differences in functional outcomes or adverse events. CONCLUSION: TULSA demonstrated acceptable clinical safety in Phase I trial. Intensified treatment parameters in the TACT Pivotal trial increased ablation coverage from 90 to 98% of the prostate without affecting 6-month adverse events or functional outcomes. Long-term follow-up and 12-month biopsies are needed to evaluate oncological safety.

Comparison of adjustable male slings and artificial urinary sphincter in the treatment of male urinary incontinence: a retrospective analysis of patient selection and postoperative continence status.

PURPOSE: To analyze and compare preoperative patient characteristics and postoperative results in men with stress urinary incontinence (SUI) selected for an adjustable male sling system or an artificial urinary sphincter (AUS) in a large, contemporary, multi-institutional patient cohort. METHODS: 658 male patients who underwent implantation between 2010 and 2012 in 13 participating institutions were included in this study (n = 176 adjustable male sling; n = 482 AUS). Preoperative patient characteristics and postoperative outcomes were analyzed. For statistical analysis, the independent T test and Mann-Whitney U test were used. RESULTS: Patients undergoing adjustable male sling implantation were less likely to have a neurological disease (4.5% vs. 8.9%, p = 0.021), a history of urethral stricture (21.6% vs. 33.8%, p = 0.024) or a radiation therapy (22.7% vs. 29.9%, p = 0.020) compared to patients that underwent AUS implantation. Mean pad usage per day (6.87 vs. 5.82; p < 0.00) and the ratio of patients with a prior incontinence surgery were higher in patients selected for an AUS implantation (36.7% vs. 22.7%; p < 0.001). At maximum follow-up, patients that underwent an AUS implantation had a significantly lower mean pad usage during daytime (p < 0.001) and nighttime (p = 0.018). Furthermore, the patients' perception of their continence status was better with a subjective complete dry rate of 57.3% vs. 22.0% (p < 0.001). CONCLUSIONS: Patients selected for an AUS implantation showed a more complex prior history and pathogenesis of urinary incontinence as well as a more severe grade of SUI. Postoperative results reflect a better continence status after AUS implantation, favoring the AUS despite the more complicated patient cohort.

Respiratory syncytial virus (RSV) infection in children with medical complexity.

Children with medical complexity (CMC) are vulnerable to respiratory illness hospitalization (RIH) and respiratory syncytial virus (RSV)-related hospitalization (RSVH) due to multisystem disorders and compromised airways. It is unknown whether RSV prophylaxis is effective, or if RSVH is associated with significant morbidities in CMC. The study objectives were to (1) determine the incidence of RSV-related infection in prophylaxed CMC during the first 3 years of life and (2) assess the burden of illness following RSVH. A single tertiary center, retrospective study, was conducted of CMC who received palivizumab during the 2012-2016 RSV seasons. Fifty-four subjects were enrolled; most received one (38.9%, n = 21) or two (57.4%, n = 31) seasons of prophylaxis (mean = 4.2 [SD = 1.24], palivizumab doses per season). The cohort comprised children with multiple medical conditions (n = 22, 40.8%), tracheostomy (n = 18, 33.3%), and invasive (n = 10, 18.5%) or non-invasive (n = 4, 7.4%) ventilation. Of the CMC, 24 were hospitalized 47 times for a viral-related respiratory illness. RSV incidence in the first 3 years of life was 7.4%. Viral-related RIH and RSVH rates were 44.4% (n = 24/54) and 1.9% (n = 1/54), respectively. Of the four RSV-positive children, one was ventilated for 9 days, two acquired nosocomial RSV that was managed on the ward, and one was discharged home under close complex care supervision. All four RSV-positive cases required additional oxygen during their illness. CMC experience a high viral-related RIH rate and palivizumab likely minimizes RSV-related events and associated morbidities. The efficacy of palivizumab in CMC, especially in those ≤ 3 years, should be prospectively evaluated.

Post-prostatectomy radiotherapy adversely affects urinary continence irrespective of radiotherapy regime.

PURPOSE: To investigate the influence of different postoperative radiotherapy (RT) regimes on post-prostatectomy continence and QoL. METHODS: Men after prostatectomy (RP) and RT were assigned in adjuvant (ART), early salvage (ESRT) and salvage radiotherapy (SRT) groups depending on time of initiation, indication and pre-RT-PSA (≤/>0.5 ng/ml). Continence and QoL outcomes were evaluated by validated questionnaire. Statistical analysis included students t test, Chi square, Fisher's test, ROC- and McNemar-Bowker-Analyses. RESULTS: The mean follow-up was 5.1 years. 33.5, 38.2 and 28.3% received ART, ESRT and SRT, respectively. Mean time to RT was 0.3 (±0.4), 1.8 (±2.5) and 3.3 (±3.6) years respectively. Differences in age at RP (p = 0.54) and RT (p = 0.47) between groups were not significant. Mean-RT-dose was similar (p = 0.70). Differences in continence distribution between groups before (p = 0.56) and after RT (p = 0.38) were not significant. No significant differences were observed for frequency (p = 0.58) or amount (p = 0.88) of urine loss, impact on QoL (p = 0.13) and ICIQ-SF scores (p = 0.69) between groups. Even though no significant difference in post-RT-continence (p = 0.89) was observed in the direct comparison between groups, a significant worsening of long-term continence was observed in all groups (p < 0.001). We found no cutoff and no time-point after RP at which this negative effect of RT on continence became insignificant (AUC = 0.474). A subgroup with apparent local recurrence showed no differences for ICIQ-SF-score (p = 0.155), QoL (0.077), incontinence grade (p = 0.387), frequency (p = 0.182) and amount (p = 0.415) of urine loss. Proportionally more men in this subgroup remembered deterioration of continence after RT (p = 0.029). CONCLUSION: Postoperative RT adversely affects long-term continence; this negative effect is irrespective of time of initiation or indication for RT. These results suggest a need for innovative strategies of prostate cancer therapy with lasting oncological, functional and QoL outcomes.

Quality of life and functional outcome after infravesical desobstruction and HIFU treatment for localized prostate cancer.

BACKGROUND: To evaluate quality of life, functional and oncological outcome after infravesical desobstruction and HIFU treatment for localized prostate cancer. METHODS: One hundred thirty-one patients, treated with TURP and HIFU in a single institution were followed up for oncological and functional outcome. Oncological outcome was quantified by biochemical recurrence free survival using the Stuttgart and Phoenix criteria. Quality of life was assessed by usage of standardized QLQ-C30 and QLQ-PR25 questionnaires. In addition, functional questionnaires such as IPSS and IIEF-5 were used. Complications were assessed by the Clavien-Dindo classification. RESULTS: One hundred thirty-one patients with a mean age of 72.8 years (SD: 6.0) underwent HIFU for prostate cancer (29.0% low risk, 58.8% intermediate risk, 12.2% high risk). PSA nadir was 0.6 ng/ml (SD: 1.2) after a mean of 4.6 months (SD: 5.7). Biochemical recurrence free survival defined by Stuttgart criteria was 73.7%, 84.4% and 62.5% for low-, intermediate- and high-risk patients after 22.2 months. Complications were grouped according to Clavien-Dindo and occurred in 10.7% (grade II) and 11.5% (grade IIIa) of cases. 35.1% of patients needed further treatment for bladder neck stricture. Regarding incontinence, 14.3%, 2.9% and 0% of patients had de novo urinary incontinence grade I°, II° and III° and 3.8% urge incontinence due to HIFU treatment. Patients were asked for the ability to have intercourse: 15.8%, 58.6% and 66.7% of patients after non-, onesided and bothsided nervesparing procedure were able to obtain sufficient erection for intercourse, respectively. Regarding quality of life, mean global health score according to QLQ-C30 was 69.4%. CONCLUSION: HIFU treatment for localized prostate cancer shows acceptable oncological safety. Quality of life after HIFU is better than in the general population and ranges within those of standard treatment options compared to literature. HIFU seems a safe valuable treatment alternative for patients not suitable for standard treatment.

Predictive factors for immediate continence after radical prostatectomy.

PURPOSE: To identify predictive factors for immediate continence after radical prostatectomy. PATIENTS AND METHODS: A total of 1553 patients underwent radical prostatectomy in a single institution (670 RRP, 883 RARP), had complete perioperative data and follow-up for urinary continence and were included in this prospective analysis. Immediate continence was defined as no pad usage after catheter removal. Evaluated parameters included age, body mass index, ECOG performance status, erectile function, prostate volume, PSA, Gleason score, tumor stage and D'Amico risk groups, as well as surgical approach (RRP, RARP), surgeon volume, nerve-sparing, lymphadenectomy, blood transfusions and duration of catheterization. RESULTS: A total of 240 men (15.5 %) did not require any pads 1 day or later after removal of the transurethral catheter. Correlation of parameters with immediate continence revealed significance for age (p < 0.001), ECOG-score (p = 0.025), erectile function (p = 0.001), nerve-sparing (p = 0.022), Gleason score (p = 0.002) and surgeon volume (p ≤ 0.022). Multivariate analyses identified IIEF-score >21 (p = 0.031), ECOG (p < 0.05), bilateral nerve-sparing (p = 0.049), Gleason score <3 + 4 (p ≤ 0.028), less blood transfusion (p ≤ 0.044) and surgeon volume (p ≤ 0.042) as the remaining prognostic parameters for immediate continence after radical prostatectomy. The type of surgical approach (robotic vs. open radical prostatectomy) did not yield significant influence. CONCLUSION: Evaluating continence in a contemporary prospective cohort revealed 15.5 % of patients never requiring a pad postoperatively. Predictive parameters for immediate continence were erectile function, ECOG, bilateral nerve-sparing, less blood transfusion and Gleason score. Furthermore, the surgeon's experience but not his operative technique had a significant impact on immediate postoperative continence.

Clutter suppression and classification using twin inverted pulse sonar in ship wakes.

Twin inverted pulse sonar (TWIPS) is here deployed in the wake of a moored rigid inflatable boat (RIB) with propeller turning, and then in the wake of a moving tanker of 4580 dry weight tonnage (the Whitchallenger). This is done first to test its ability to distinguish between scatter from the wake and scatter from the seabed, and second to test its ability to improve detectability of the seabed through the wake, compared to conventional sonar processing techniques. TWIPS does this by distinguishing between linear and nonlinear scatterers and has the further property of distinguishing those nonlinear targets which scatter energy at the even-powered harmonics from those which scatter in the odd-powered harmonics. TWIPS can also, in some manifestations, require no range correction (and therefore does not require the a priori environment knowledge necessary for most remote detection technologies).

A generative co-design framework for healthcare innovation: development and application of an end-user engagement framework.

Background Continual improvements to health systems, products, and services are necessary for improvements in health. However, many of these improvements are not incorporated into everyday practice. When designing new health systems, products, and services, involving members of the healthcare community and the public with personal healthcare experience can help to make sure that improvements will be useful and relevant to others like them. Methods Together with healthcare workers and family members with healthcare experience, we developed and applied a step-by-step guide to involving those with personal experience in the design of health system improvements. Results Our guide has three phases- 'Pre-Design', 'Co-Design', and 'Post-Design'. This paper describes each of these phases and illustrates how we applied them to our own project, which is to use virtual healthcare methods to improve care for children with chronic healthcare conditions and their families. In our own work, we found that healthcare workers and family members with personal healthcare experiences were able to use their knowledge and creativity to help us imagine how to improve care for children with chronic healthcare conditions and their families. We have created action items from these family member- and healthcare worker-identified needs, which we will use to shape our virtual healthcare system. Conclusions This paper may be useful for those seeking to involve members of the healthcare community and the public in the creation of better healthcare systems, products, and services. Background Challenges with the adoption, scale, and spread of health innovations represent significant gaps in the evidence-to-practice cycle. In the health innovation design process, a lack of attention paid to the needs of end-users, and subsequent tailoring of innovations to meet these needs, is a possible reason for this deficit. In the creative field of health innovation, which includes the design of healthcare products, systems (governance and organization mechanisms), and services (delivery mechanisms), a framework for both soliciting the needs of end-users and translating these needs into the design of health innovations is needed. Methods To address this gap, our team developed and applied a seven-step methodological framework, called A Generative Co-Design Framework for Healthcare Innovation. This framework was developed by an interdisciplinary team that included patient partners. Results This manuscript contributes a framework and applied exemplar for those seeking to engage end-users in the creative process of healthcare innovation. Through the stages of 'Pre-Design', 'Co-Design', and 'Post-Design', we were able to harness the creative insights of end-users, drawing on their experiences to shape a future state of care. Using an expository example of our own work, the DigiComp Kids project, we illustrate the application of each stage of the Framework. Conclusions A Generative Co-Design Framework for Healthcare Innovation provides healthcare innovators, applied health science researchers, clinicians, and quality improvement specialists with a guide to eliciting and incorporating the viewpoints of end-users while distilling practical considerations for healthcare innovation and design.

[Reconstructive pelvic surgery. Current status and future perspectives]. / Rekonstruktive Beckenbodenchirurgie. Aktueller Stand und Perspektiven.

Pelvic organ prolapse is a widespread condition that especially affects women. There are a number of conservative and surgical therapeutic options. The choice of therapy should be individually made, depending on factors such as the grade of prolapse and concomitant secondary disorders as well as the age and general condition of the patient. This article presents current surgical options, analyzes recent studies, and offers future perspectives for reconstructive pelvic surgery.

The effect of follicular wave on fertility characteristics in beef cattle.

The objectives of this experiment were to determine the effects of follicular wave (first or second) on diameter of the dominant follicle, concentrations of progesterone and estradiol and the hepatic enzymes that inactivate them, thickness of the endometrium, and pregnancy rates to AI. Beef heifers ( = 101) and cows ( = 106) were randomly assigned to 1 of 2 treatments: insemination to the first follicular wave (FFW) or insemination to the second follicular wave (SFW). Estrous cycles of females were synchronized to ensure appropriate timing for the treatments. The MIXED procedure of SAS was used for analysis. A similar proportion of females in each treatment responded to presynchronization; however, females in the FFW group ovulated in response to the first injection of GnRH of the CO-Synch protocol more frequently. Only females ( = 94) that properly responded to ovulation synchronization were included in further analyses. Cows in the FFW group tended ( 0.06) to have larger ovulatory follicles 36 h post-PGF of the CO-Synch protocol compared to cows in the SFW group (14.22 ± 0.42 and 11.83 ± 0.49, respectively), whereas heifers were similar between treatment groups. Three d prior to AI, circulating concentrations of progesterone were lesser ( 0.01) in females in the FFW (3.63 ± 0.80 ng/mL) than in the SFW (7.12 ± 0.83 ng/mL), whereas concentrations of estradiol tended ( 0.08) to be greater in those in the FFW (82.72 ± 6.48 pg/mL) than in the SFW (65.55 ± 6.74 pg/mL). Concentrations of cytochrome P450 1A in the liver were lesser ( 0.01) in females in the FFW than those in the SFW (0.68 ± 0.08 vs. 0.96 ± 0.06, respectively). Endometrial thicknesses were similar between treatments but were thicker ( < 0.0001) in cows (9.73 ± 0.24 mm) than heifers (7.22 ± 0.26 mm). When considering all females or only those that were properly presynchronized, pregnancy rates were similar between treatments. However, when evaluating females that ovulated to the assigned follicular wave, there was a treatment by parity interaction ( = 0.04) with heifers in the FFW having a lesser pregnancy rate (25.9%) than heifers in the SFW (72.0%) while cows in both treatment groups were intermediate (45.4% in FFW and 50.0% in SFW). The differences in concentrations of steroids between treatment groups may affect fertility of heifers; however, additional research is necessary.

[Overactive bladder syndrome. Are there indications for surgical therapy?]. / Uberaktive Blase. Gibt es Indikationen für eine operative Therapie?

Conservative therapeutic options are considered the gold standard in therapy of overactive bladder syndrome. However, surgery may be beneficial in selected cases. Neuromodulation is well established in clinical practice. If conservative or minimally invasive therapy fails, augmentation techniques or urinary diversion may be considered. This review presents the current knowledge about surgical treatment options for idiopathic overactive bladder.

Van der Waals pressure and its effect on trapped interlayer molecules.

Van der Waals assembly of two-dimensional crystals continue attract intense interest due to the prospect of designing novel materials with on-demand properties. One of the unique features of this technology is the possibility of trapping molecules between two-dimensional crystals. The trapped molecules are predicted to experience pressures as high as 1 GPa. Here we report measurements of this interfacial pressure by capturing pressure-sensitive molecules and studying their structural and conformational changes. Pressures of 1.2±0.3 GPa are found using Raman spectrometry for molecular layers of 1-nm in thickness. We further show that this pressure can induce chemical reactions, and several trapped salts are found to react with water at room temperature, leading to two-dimensional crystals of the corresponding oxides. This pressure and its effect should be taken into account in studies of van der Waals heterostructures and can also be exploited to modify materials confined at the atomic interfaces.

Role of membrane proteins and lipids in water diffusion across red cell membranes.

When human red cells are treated with the mercurial sulfhydryl reagent, p-chloromercuribenzene sulfonate, osmotic water permeability is suppressed and only diffusional water permeability remains (Macey, R.I. and Farmer, R.E.L. (1970) Biochim. Biophys. Acta 211, 104-106). It has been suggested that the route for the remaining water permeation is by diffusion through the membrane lipids. However, after making allowance for the relative lipid area of the membrane, the water diffusion coefficient through lipid bilayers which contain cholesterol is too small by a factor of two or more. We have measured the permeability coefficient of normal human red cells by proton T1 NMR and obtained a value of 4.0 X 10(-3) cm X s-1, in good agreement with published values. In order to study permeation-through red cell lipids we have perturbed extracted red cell lipids with the lipophilic anesthetic, halothane, and found that halothane increases water permeability. The same concentration of halothane has no effect on the water permeability of human red cells, after maximal pCMBS inhibition. In order to compare halothane mobility in extracted red cell membrane lipids with that in red cell ghost membranes, we have studied halothane quenching of N-phenyl-1-naphthylamine by equilibrium fluorescence and fluorescence lifetime methods. Since halothane mobility is similar in these two preparations, we have concluded that the primary route of water diffusion in pCMBS-treated red cells is not through membrane lipids, but rather through a membrane protein channel.

Specific interaction of the water transport inhibitor, pCMBS, with band 3 in red blood cell membranes.

The human red cell anion transport protein, band 3, contains six pCMBS (p-chloromercuribenzene sulfonate) reactive SH groups, five of which react with N-ethylmaleimide. We have carried out equilibrium binding experiments using N-ethylmaleimide-treated red cell ghosts and found that the sulfhydryl reactive water transport inhibitor, pCMBS, inhibits the binding to band 3 of the specific anion exchange inhibitor DBDS (4,4'-dibenzoamido-2,2'-disulfonic stilbene) in a non-competitive manner. Stopped-flow kinetic studies, in which DBDS is mixed with ghosts in the presence of pCMBS, show that pCMBS slows the DBDS induced conformational change in band 3. A non-competitive reaction scheme has been developed which incorporates the quantitative results of equilibrium and kinetic studies. The pCMBS effect on DBDS binding and kinetics is reversed with 5 mM cysteine suggesting a sulfhydryl bond is involved in pCMBS binding to band 3. These data suggest that pCMBS has a specific binding site on band 3, consistent with the hypothesis that band 3 mediates red cell water transport.

Target analysis studies of red cell water and urea transport.

Radiation inactivation was used to determine the nature and molecular weight of water and urea transporters in the human red cell. Red cells were frozen to -50 degrees C in a cryoprotectant solution, irradiated with 1.5 MeV electrons, thawed, washed and assayed for osmotic water and urea permeability by stopped-flow light scattering. The freezing and thawing process did not affect the rates of water or urea transport or the inhibitory potency of p-chloromercuribenzenesulfonate (pCMBS) on water transport and of phloretin on urea transport. Red cell urea transport inactivated with radiation (0-4 Mrad) with a single target size of 469 +/- 36 kDa. 40 microM phloretin inhibited urea flux by approx. 50% at each radiation dose, indicating that urea transporters surviving radiation were inhibitable. Water transport did not inactivate with radiation; however, the inhibitory potency of 2.5 mM pCMBS decreased from 86 +/- 1% to 4 +/- 9% over a 0-2 Mrad dose range. These studies suggest that red cell water transport either required one or more low-molecular-weight proteins, or is lipid-mediated, and that the pCMBS-binding site which regulates water flow inactivates with radiation. These results also suggest that red cell urea transport is mediated by a specific, high-molecular-weight protein. These results do not support the hypothesis that a band 3 dimer (190 kDa) mediates red cell osmotic water and urea transport.

Interaction of phloretin with the anion transport protein of the red blood cell membrane.

Phloretin is an inhibitor of anion exchange and glucose and urea transport in human red cells. Equilibrium binding the kinetic studies indicate that phloretin binds to band 3, a major integral protein of the red cell membrane. Equilibrium phloretin binding has been found to be competitive with the binding of the anion transport inhibitor, 4,4'-dibenzamido-2,2'-disulfonic stilbene (DBDS), which binds specifically to band 3. The apparent binding (dissociation) constant of phloretin to red cell ghost band 3 in 28.5 mM citrate buffer, pH 7.4, 25 degree C, determined from equilibrium binding competition, is 1.8 +/- 0.1 microM. Stopped-flow kinetic studies show that phloretin decreases the rate of DBDS binding to band 3 in a purely competitive manner, with an apparent phloretin constant of 1.6 +/- 0.4 microM. The pH dependence of equilibrium binding studies show that it is the charged, anionic form of phloretin that competes with DBDS binding, with an apparent phloretin inhibition constant of 1.4 microM. The phloretin binding and inhibition constants determined by equilibrium binding, kinetic and pH studies are all similar to the inhibition constant of phloretin for anion exchange. These studies suggest that phloretin inhibits anion exchange in red cells by a specific interaction between phloretin and band 3.

Anion transport inhibitor binding to band 3 in red blood cell membranes.

The inhibitor of anion exchange 4,4'-dibenzoamido-2,2'-disulfonic stilbene (DBDS) binds to band 3, the anion transport protein in human red cell ghost membranes, and undergoes a large increase in fluorescence intensity when bound to band 3. Equilibrium binding studies performed in the absence of transportable anions show that DBDS binds to both a class of high-affinity (65 nM) and low-affinity (820 nM) sites with stoichiometry equivalent to 1.6 nmol/mg ghost protein for each site, which is consistent with one DBDS site on each band 3 monomer. The kinetics of DBDS binding were studied both by stopped-flow and temperature-jump experiments. The stopped-flow data indicate that DBDS binding to the apparent high-affinity site involves association with a low-affinity site (3 microM) followed by a slow (4 s-1) conformational change that locks the DBDS molecule in place. A detailed, quantitative fit of the temperature-jump data to several binding mechanisms supports a sequential-binding model, in which a first DBDS molecule binds to one monomer and induces a conformational change. A second DBDS molecule then binds to the second monomer. If the two monomers are assumed to be initially identical, thermodynamic characterization of the binding sites shows that the conformational change induces an interaction between the two monomers that modifies the characteristics of the second DBDS binding site.

Proton (or hydroxide) fluxes and the biphasic osmotic response of human red blood cells.

Upon exposure of human red blood cells to hypertonic sucrose, the fluorescence of the potentiometric indicator 3,3'-dipropylthiadicarbocyanine iodide, denoted diS-C3(5), displays a biphasic time course indicating the rapid development of an inside-positive transmembrane voltage, followed by a slow DIDS (4,4'-diisothiocyano-2,2'-disulfonic acid stilbene)-sensitive decline of the voltage. In addition to monitoring membrane potential, proton (or hydroxide) fluxes were measured by a pH stat method, cell volume was monitored by light scattering, and cell electrolytes were measured directly when red cells were shrunken either with hypertonic NaCl or sucrose. Shrinkage by sucrose induced an initial proton efflux (or OH- influx) of 5.5 mu eq/g Hb.min and a Cl shift of 21-31 mu eq/g Hb in 15 min. Upon shrinkage with hypertonic NaCl, the cells are initially close to Donnan equilibrium and exhibit no detectable shift of Cl or protons. Experiments with the carbonic anhydrase inhibitor ethoxzolamide demonstrate that for red cell suspensions exposed to air and shrunken with sucrose, proton fluxes mediated by the Jacobs-Stewart cycle contribute to dissipation of the increased outward Cl concentration gradient. With maximally inhibitory concentrations of ethoxzolamide, a residual proton efflux of 2 mu eq/g Hb.min is insensitive to manipulation of the membrane potential with valinomycin, but is completely inhibited by DIDS. The ethoxzolamide-insensitive apparent proton efflux may be driven against the electrochemical gradient, and is thus consistent with HCl cotransport (or Cl/OH exchange). The data are consistent with predictions of equations describing nonideal osmotic and ionic equilibria of human red blood cells. Thus osmotic equilibration after shrinkage of human red blood cells by hypertonic sucrose occurs in two time-resolved steps: rapid equilibration of water followed by slower equilibration of chloride and protons (or hydroxide). Under our experimental conditions, about two-thirds of the osmotically induced apparent proton efflux is mediated by the Jacobs-Stewart cycle, with the remainder being consistent with mediation via DIDS-sensitive HCl cotransport (or Cl/OH exchange).

[Structure of biobanks for urological research]. / Struktur von Biobanken für die urologische Forschung.

Biomedical research plays an important role in the development of novel diagnostic procedures, drugs and treatment strategies with regard to cancerous and chronic inflammatory diseases. Biobanks are essential tools in this process. The complex structures and benefits of biobanks are presented in this article.

[Intratumoral heterogeneity in renal cell carcinoma. Molecular basis and translational implications]. / Intratumorale Heterogenität des Nierenzellkarzinoms. Molekulare Grundlagen und translationale Implikationen.

Advanced clear cell renal cell carcinoma is characterized by extensive intratumoral genomic heterogeneity and branched as well as convergent evolutionary traits with genomically different subclones evolving in parallel in the same tumor. Distinct driver mutations can be found in spatially separated subclones, which may hinder the development of novel targeted therapies. However, truncal mutations of the VHL tumor suppressor gene and chromosome 3p loss were ubiquitously detected and will hence continue to be a focus of future drug development. Nevertheless, genomic instability, enhanced tumor genome plasticity and intratumoral heterogeneity are likely to represent major challenges towards biomarker development and personalized patient care.