Mid-term outcomes of a male retro-urethral, transobturator synthetic sling for treatment of post-prostatectomy incontinence: Impact of radiotherapy and storage dysfunction.

PURPOSE: To determine mid-term durability of the AdVance sling for post-prostatectomy incontinence (PPI) and impact of prior radiotherapy and storage dysfunction. METHOD: Eighty men undergoing AdVance sling for PPI during 2008-2013 were reviewed. Pre-op urodynamics, pre and post-op pad usage, prior radiotherapy, and PGI-I scores were recorded. RESULT: Mean follow-up was 36 months (range 14-72). Twelve men had radiotherapy pre-op, 10 had detrusor overactivity (DO), and 20 reduced compliance. Pre-op mean 24-hr pad weight was 264 g and mean pads-per-day (PPD) 2.60 ± 0.29. In the early post-op period (3-6 months), mean PPD was 0.40 (SD 0.16); at mid-term follow-up mean PPD was 1.02 ± 0.31. Radiotherapy and DO were independently predictive of poor mid-term outcome. Men with DO or radiotherapy were using 1.03 ± 0.42 (P = 0.019) and 1.17 ± 0.41 (P = 0.02) more PPD, respectively than men without these factors. At mid-term follow-up, men without radiotherapy or DO were using 1.98 ± 0.28 less PPD compared to pre-operatively (P < 0.0001); with radiotherapy or DO men were using 0.73 ± 0.38 (P = 0.057) and 0.72 ± 0.43 (P = 0.092) less PPD, respectively. PGI-I score for men without radiotherapy or DO was 1.98 ± 0.40 ("much better"); with radiotherapy or DO PGI-I score was 3.80 ± 0.49 ("no difference"). CONCLUSION: The AdVance sling provides mid-term improvement in men with PPI. However, men with radiotherapy or DO have significantly poorer outcomes with mid-term results indicating a return to baseline degree of incontinence. Caution should be taken when considering the AdVance sling in these men. Pre-op urodynamics in men with radiotherapy and/or overactive bladder may be important when considering men for AdVance sling. Neurourol. Urodynam. 36:1147-1150, 2017. © 2016 Wiley Periodicals, Inc.

New insights into the molecular mechanism of the Rab GTPase Sec4p activation.

BACKGROUND: Sec4p is a small monomeric Ras-related GTP-binding protein (23 kDa) that regulates polarized exocytosis in S. cerevisiae. In this study we examine the structural effects of a conserved serine residue in the P-loop corresponding to G12 in Ras. RESULTS: We show that the Sec4p residue serine 29 forms a hydrogen bond with the nucleotide. Mutations of this residue have a different impact than equivalent mutations in Ras and can form stable associations with the exchange factor allowing us to elucidate the structure of a complex of Sec4p bound to the exchange factor Sec2p representing an early stage of the exchange reaction. CONCLUSIONS: Our structural investigation of the Sec4p-Sec2p complex reveals the role of the Sec2p coiled-coil domain in facilitating the fast kinetics of the exchange reaction. For Ras-family GTPases, single point mutations that impact the signaling state of the molecule have been well described however less structural information is available for equivalent mutations in the case of Rab proteins. Understanding the structural properties of mutants such as the one described here, provides useful insights into unique aspects of Rab GTPase function.

Botulinum toxin (OnabotulinumtoxinA) in the male non-neurogenic overactive bladder: clinical and quality of life outcomes.

OBJECTIVE: To assess the efficacy of OnabotulinumtoxinA (BTXA) injections in men with drug-refractory non-neurogenic overactive bladder (NNOAB). PATIENTS AND METHODS: A total of 43 men received BTXA injections for NNOAB from 2004 to 2012. Patient Global Impression of Improvement (PGI-I) score was obtained. For men with wet NNOAB, change in number of pads per day was also assessed. RESULTS: Forty-three men with a mean age of 69 (range 37-85) received at least one injection. Of the 43 men, 20 (47%) had prior prostate surgery: 11 had radical prostatectomy (RP) and nine had transurethral resection of prostate (TURP). Overall, average PGI-I score was 2.7. Comparing PGI-I score in men who had prior prostate surgery with men who have not: 2.6 ± 0.5 vs 2.8 ± 0.5 respectively (average ± 95% CI), P = 0.6. Comparing PGI-I score in men who had previous TURP with men who had previous RP: PGI-I score: 3.3 ± 0.8 vs 2.0 ± 0.5 respectively, P < 0.05. Men who had RP experienced a reduction in pad use (from 3.5 ± 1.7 to 1.6 ± 0.9 pads/day, P < 0.05) while this was not the case amongst men who had TURP (from 1.7 ± 1.5 to 1.4 ± 1.5 pads/day, P = 0.4). CONCLUSION: Overall, BTXA injection in men with drug-refractory NNOAB does provide a symptomatic benefit. Amongst men who have had prior prostate surgery, men who have had RP experience a greater benefit than men who have had TURP, both in regards to PGI-I score and pad use.

Olanzapine-induced acute necrotising pancreatitis leading to recurrent multiple organ dysfunction syndrome.

A married mother in her 50s acutely developed vomiting, diarrhoea and severe epigastric pain 2 weeks following discharge from an acute psychiatric inpatient unit. She presented to the emergency department complaining of a 2-day history of the above symptoms. Blood tests revealed neutrophilia, grossly raised inflammatory markers and amylase levels triple the normal range. Based on radiological investigations, she was treated for necrotising pancreatitis that quickly escalated to multi-system organ failure and a lengthy intensive care unit admission. Common causes of pancreatitis, including cholelithiasis, alcohol and other drugs, were ruled out. Despite this, she suffered recurrent episodes of pancreatitis with significant morbidity. Olanzapine, started during her psychiatric admission, was determined to be the offending agent. Two years following the discontinuation of olanzapine, the patient has had no further episodes of acute pancreatitis.

The HEV Ventilator: at the interface between particle physics and biomedical engineering.

A high-quality, low-cost ventilator, dubbed HEV, has been developed by the particle physics community working together with biomedical engineers and physicians around the world. The HEV design is suitable for use both in and out of hospital intensive care units, provides a variety of modes and is capable of supporting spontaneous breathing and supplying oxygen-enriched air. An external air supply can be combined with the unit for use in situations where compressed air is not readily available. HEV supports remote training and post market surveillance via a Web interface and data logging to complement standard touch screen operation, making it suitable for a wide range of geographical deployment. The HEV design places emphasis on the ventilation performance, especially the quality and accuracy of the pressure curves, reactivity of the trigger, measurement of delivered volume and control of oxygen mixing, delivering a global performance which will be applicable to ventilator needs beyond the COVID-19 pandemic. This article describes the conceptual design and presents the prototype units together with a performance evaluation.

Impact of communicating personalized genetic risk information on perceived control over the risk: a systematic review.

PURPOSE: Much concern has been expressed that feedback of personalized genetic risk information may lead to fatalism, i.e., a lack of perceived control over the risk. This review aimed to assess the strength of evidence for such a view. METHOD: Electronic databases were searched to find eligible studies, which comprised randomized, controlled trials and analog studies, in which participants in one arm received either real or imagined personalized genetic risk information and assessed perceived control in relation to the treatability or preventability of the health problem. RESULTS: Inspection of 1340 abstracts resulted in 5 studies meeting the inclusion criteria, involving the prediction of obesity, heart disease, depression, and diabetes. Meta-analyses of the clinical studies revealed no impact of personalized genetic risk information on perceived control in either the short term (pooled standardized mean difference 0.09, 95% confidence interval, -0.51 to 0.70) or longer term (pooled standardized mean difference 0.00, confidence interval, -0.20 to 0.21). Similarly, no impact on perceived control was evident in the three analog studies (pooled standardized mean difference 0.02, confidence interval, -0.17 to 0.20). CONCLUSION: Few studies have assessed empirically the impact of personalized genetic risk information on fatalism, assessed using perceptions of control over the risk. Limited evidence suggests feedback of genetic risk information may have little impact on such beliefs.

Emotional impact of screening: a systematic review and meta-analysis.

BACKGROUND: There is a widely held expectation that screening for disease has adverse emotional impacts. The aim of the current review is to estimate the short (< 4 weeks) and longer term (> 4 weeks) emotional impact of such screening. METHODS: Studies selected for inclusion were (a) randomised controlled trials in which (b) participants in one arm underwent screening and received test results, and those in a control arm did not, and (c) emotional outcomes were assessed in both arms. MEDLINE via PubMed (1950 to present), EMBASE (1980 to present), PsycINFO (1985 to present) using OVID SP, and CINAHL (1982 to present) via EBSCO were searched, using strategies developed with keywords and medical subject headings. Data were extracted on emotional outcomes, type of screening test and test results. RESULTS: Of the 12 studies that met the inclusion criteria, six involved screening for cancer, two for diabetes, and one each for abdominal aortic aneurysms, peptic ulcer, coronary heart disease and osteoporosis. Five studies reported data on anxiety, five [corrected] on depression, two on general distress and eight on quality of life assessed between one week and 13 years after screening (median = 1.3 years).Meta-analyses revealed no significant impact of screening on longer term anxiety (pooled SMD 0.01, 95% CI -0.10, 0.11), depression (pooled SMD -0.04, 95% CI -.12, 0.20), or quality of life subscales (mental and self-assessed health pooled SMDs, respectively: 0.03; -0.01, (95% CI -.02, 0.04; 0.00, 95% CI -.04, 0.03). CONCLUSION: Screening does not appear to have adverse emotional impacts in the longer term (> 4 weeks). Too few studies assessed outcomes before four weeks to comment on the shorter term emotional impact of screening.

Secretory vesicle transport velocity in living cells depends on the myosin-V lever arm length.

Myosins are molecular motors that exert force against actin filaments. One widely conserved myosin class, the myosin-Vs, recruits organelles to polarized sites in animal and fungal cells. However, it has been unclear whether myosin-Vs actively transport organelles, and whether the recently challenged lever arm model developed for muscle myosin applies to myosin-Vs. Here we demonstrate in living, intact yeast that secretory vesicles move rapidly toward their site of exocytosis. The maximal speed varies linearly over a wide range of lever arm lengths genetically engineered into the myosin-V heavy chain encoded by the MYO2 gene. Thus, secretory vesicle polarization is achieved through active transport by a myosin-V, and the motor mechanism is consistent with the lever arm model.

A role for Yip1p in COPII vesicle biogenesis.

Yeast Ypt1p-interacting protein (Yip1p) belongs to a conserved family of transmembrane proteins that interact with Rab GTPases. We encountered Yip1p as a constituent of ER-derived transport vesicles, leading us to hypothesize a direct role for this protein in transport through the early secretory pathway. Using a cell-free assay that recapitulates protein transport from the ER to the Golgi complex, we find that affinity-purified antibodies directed against the hydrophilic amino terminus of Yip1p potently inhibit transport. Surprisingly, inhibition is specific to the COPII-dependent budding stage. In support of this in vitro observation, strains bearing the temperature-sensitive yip1-4 allele accumulate ER membranes at a nonpermissive temperature, with no apparent accumulation of vesicle intermediates. Genetic interaction analyses of the yip1-4 mutation corroborate a function in ER budding. Finally, ordering experiments show that preincubation of ER membranes with COPII proteins decreases sensitivity to anti-Yip1p antibodies, indicating an early requirement for Yip1p in vesicle formation. We propose that Yip1p has a previously unappreciated role in COPII vesicle biogenesis.

Bioinformatic and comparative localization of Rab proteins reveals functional insights into the uncharacterized GTPases Ypt10p and Ypt11p.

A striking characteristic of a Rab protein is its steady-state localization to the cytosolic surface of a particular subcellular membrane. In this study, we have undertaken a combined bioinformatic and experimental approach to examine the evolutionary conservation of Rab protein localization. A comprehensive primary sequence classification shows that 10 out of the 11 Rab proteins identified in the yeast (Saccharomyces cerevisiae) genome can be grouped within a major subclass, each comprising multiple Rab orthologs from diverse species. We compared the locations of individual yeast Rab proteins with their localizations following ectopic expression in mammalian cells. Our results suggest that green fluorescent protein-tagged Rab proteins maintain localizations across large evolutionary distances and that the major known player in the Rab localization pathway, mammalian Rab-GDI, is able to function in yeast. These findings enable us to provide insight into novel gene functions and classify the uncharacterized Rab proteins Ypt10p (YBR264C) as being involved in endocytic function and Ypt11p (YNL304W) as being localized to the endoplasmic reticulum, where we demonstrate it is required for organelle inheritance.

Efficacy of treatment in an opioid -dependent population group using the Maudsley Addiction Profile (MAP) tool.

A pilot study was performed to assess the effectiveness of treatment in an opioid dependent population using the Maudsley Addiction Profile (MAP) tool1.The primary outcome of the study was to assess if treatment had an effect on 1. Substance use (quantity and frequency of use), 2. Health risk behaviour (injecting and sharing injecting equipment), 3. Health symptoms (physical and psychological) and 4. Personal /Social functioning (relationships, employment and crime). A secondary outcome was also sought.The study took place in 2007 in an inner city Belfast hospital specialising in the treatment of addiction, over a two month period. Fifteen patients, all opioid dependent and receiving outpatient community treatment, were interviewed at baseline (prior to the commencement of treatment) and at eight weeks follow up.Three patients were lost to follow up. Two patients stopped using altogether. Of the remaining patients, improvements were seen in most areas. There was a decrease in the use of heroin (71.28%), cocaine (99.72%), crack cocaine (100%), cannabis (99.94%) and alcohol (33.17%). There was a reduction in injecting behaviour (60.93%). Improvements were observed in health with a reduction in physical (41.35%) and psychological (35%) symptoms. Overall personal and social functioning improved regarding interactions with family and friends. A reduction in crime was also observed (75%).Opinions and views of staff involved in the study were generally positive.This patient population presents with multiple and complex needs. Effective treatment needs to address these needs and not just drug addiction alone. The Maudsley Addiction Profile tool highlights this.

School Nursing Protocol for the Management of Human Bites.

Human biting is considered a common stage in pediatric infant growth and development. However, this stage is not considered appropriate once children enter group daycare and school settings, and such behavior can lead to injury, stress, and trauma for other students and staff. When biting occurs in the school setting, staff are often unprepared to respond appropriately, and may seek delayed care, if at all. The school nurse may also be ill-equipped to provide first aid and education if there are no standardized guidelines to follow. Having a protocol in place for human bite incidents in the school setting helps school nurses provide information to students, parents, and staff in a timely manner and assists them with following evidence-based practice. Accurate documentation of the incidents also allows school nurses to identify triggers and knowledge deficits, which can assist them in planning educational interventions and training in the school setting.

Mutational analysis of betaCOP (Sec26p) identifies an appendage domain critical for function.

BACKGROUND: The appendage domain of the gammaCOP subunit of the COPI vesicle coat bears a striking structural resemblance to adaptin-family appendages despite limited primary sequence homology. Both the gammaCOP appendage domain and an equivalent region on betaCOP contain the FxxxW motif; the conservation of this motif suggested the existence of a functional appendage domain in betaCOP. RESULTS: Sequence comparisons in combination with structural prediction tools show that the fold of the COOH-terminus of Sec26p is strongly predicted to closely mimic that of adaptin-family appendages. Deletion of the appendage domain of Sec26p results in inviability in yeast, over-expression of the deletion construct is dominant negative and mutagenesis of this region identifies residues critical for function. The ArfGAP Glo3p was identified via suppression screening as a potential downstream modulator of Sec26p in a manner that is independent of the GAP activity of Glo3p but requires the presence of the COOH-terminal ISS motifs. CONCLUSION: Together, these results indicate an essential function for the predicted betaCOP appendage and suggest that both COPI appendages perform a biologically active regulatory role with a structure related to adaptin-family appendage domains.

Analysis of the Elp complex and its role in regulating exocytosis.

The regulation of membrane trafficking events in the secretory and endocytic pathways by Rab GTPases requires the cycling and activation of a Rab protein. The cycle of nucleotide binding and hydrolysis of Rab proteins is accompanied by a physical cycle of membrane translocation. An open question in membrane traffic remains how the cycle of Rab GTPase function is coupled to regulatory inputs from other cellular processes. This chapter describes the principles and methodologies used to identify the physiological regulators that influence Rab-mediated membrane traffic.

Yos1p is a novel subunit of the Yip1p-Yif1p complex and is required for transport between the endoplasmic reticulum and the Golgi complex.

Yeast Yip1p is a member of a conserved family of transmembrane proteins that interact with Rab GTPases. Previous studies also have indicated a role for Yip1p in the biogenesis of endoplasmic reticulum (ER)-derived COPII transport vesicles. In this report, we describe the identification and characterization of the uncharacterized open reading frame YER074W-A as a novel multicopy suppressor of the thermosensitive yip1-4 strain. We have termed this gene Yip One Suppressor 1 (YOS1). Yos1p is essential for growth and for function of the secretory pathway; depletion or inactivation of Yos1p blocks transport between the ER and the Golgi complex. YOS1 encodes an integral membrane protein of 87 amino acids that is conserved in eukaryotes. Yos1p localizes to ER and Golgi membranes and is efficiently packaged into ER-derived COPII transport vesicles. Yos1p associates with Yip1p and Yif1p, indicating Yos1p is a novel subunit of the Yip1p-Yif1p complex.

Dual prenylation is required for Rab protein localization and function.

The majority of Rab proteins are posttranslationally modified with two geranylgeranyl lipid moieties that enable their stable association with membranes. In this study, we present evidence to demonstrate that there is a specific lipid requirement for Rab protein localization and function. Substitution of different prenyl anchors on Rab GTPases does not lead to correct function. In the case of YPT1 and SEC4, two essential Rab genes in Saccharomyces cerevisiae, alternative lipid tails cannot support life when present as the sole source of YPT1 and SEC4. Furthermore, our data suggest that double geranyl-geranyl groups are required for Rab proteins to correctly localize to their characteristic organelle membrane. We have identified a factor, Yip1p that specifically binds the di-geranylgeranylated Rab and does not interact with mono-prenylated Rab proteins. This is the first demonstration that the double prenylation modification of Rab proteins is an important feature in the function of this small GTPase family and adds specific prenylation to the already known determinants of Rab localization.

Comparative measurements of hypoxia in human brain tumors using needle electrodes and EF5 binding.

Hypoxia is known to be an important prognostic marker in many human cancers. We report the use of two oxygen measurement techniques in human brain tumors and compare these data with semiquantitative histological end points. Oxygenation was measured using the Eppendorf needle electrode and/or EF5 binding in 28 brain tumors. These data were compared with necrosis, mitosis, and endothelial proliferation. In some tumors, absolute EF5 binding was converted to tissue pO(2) based on in vitro calibrations. Eppendorf electrode readings could not be used to identify WHO grade 1/2 versus WHO grade 3/4 tumors, they could not differentiate grade 3 versus grade 4 glial-derived neoplasms, nor did they correlate with necrosis or endothelial proliferation scores. EF5 binding increased as the tumor grade increased and was significantly associated with necrosis and endothelial proliferation. There was no statistically significant correlation between the two hypoxia detection techniques, although both methods indicated similar absolute ranges of tissue pO(2). There was substantial inter- and intratumoral heterogeneity of EF5 binding in WHO grade 4 glial neoplasms. The majority of cells in glial-derived tumor had levels of hypoxia that were mild to moderate (defined herein as 10% to 0.5% pO(2)) rather than severe (defined as approximately 0.1% pO(2)). Immunohistochemical detection of EF5 binding tracks histological parameters in adult brain tumors, with increased binding associated with increasing necrosis and endothelial proliferation. The proportion of moderately to severely hypoxic cells is relatively low, even in the high-grade tumors. Human brain tumors are dominated by oxic to moderately hypoxic cells.