Urothelial Senescence in the Pathophysiology of Diabetic Bladder Dysfunction—A Novel Hypothesis

Diabetic bladder dysfunction (DBD) is a well-recognized and common symptom affecting up to 50% of all diabetic patients. DBD has a broad range of clinical presentations ranging from overactive to underactive bladder symptoms that develops in middle-aged to elderly patients with long standing and poorly controlled diabetes. Low efficacy of current therapeutics and lifestyle interventions combined with high national healthcare costs highlight the need for more research into bladder dysfunction pathophysiology and novel treatment options. Cellular senescence is an age-related physiologic process in which cells undergo irreversible growth arrest induced by replicative exhaustion and damaging insults. While controlled senescence negatively regulates cell proliferation and promotes tissue regeneration, uncontrolled senescence is known to result in tissue dysfunction through enhanced secretion of inflammatory factors. This review presents previous scientific findings and current hypotheses that characterize diabetic bladder dysfunction. Further, we propose the novel hypothesis that cellular senescence within the urothelial layer of the bladder contributes to the pro-inflammatory/pro-oxidant environment and symptoms of diabetic bladder dysfunction. Our results show increased cellular senescence in the urothelial layer of the bladder; however, whether this phenomenon is the cause or effect of DBD is unknown. The urothelial layer of the bladder is made up of transitional epithelia specialized to contract and expand with demand and plays an active role in transmission by modulating afferent activity. Transition from normal functioning urothelial cells to secretory senescence cells would not only disrupt the barrier function of this layer but may result in altered signaling and sensation of bladder fullness; dysfunction of this layer is known to result in symptoms of frequency and urgency. Future DBD therapeutics may benefit from targeting and preventing early transition of urothelial cells to senescent cells

Validity of Robot-based Assessments of Upper Extremity Function

Objective To examine the validity of 5 robot-based assessments of arm motor function post-stroke. Design Cross sectional. Setting Outpatient clinical research center. Participants Volunteer sample of 40 participants, age \u3e18 years, 3-6 months post-stroke, with arm motor deficits that had plateaued. Intervention None. Main Outcome Measures Clinical standards included the Fugl-Meyer Arm Motor Scale (FMA), and 5 secondary motor outcomes: hand/wrist subsection of the FMA; Action Research Arm Test (ART); Box & Blocks test (B/B); hand subscale of Stroke Impact Scale-2 (SIS); and the Barthel Index (BI). Robot-based assessments included: wrist targeting; finger targeting; finger movement speed; reaction time; and a robotic version of the (B/B) test. Anatomical measures included percentage injury to the corticospinal tract (CST) and primary motor cortex (M1, hand region) obtained from MRI . Results Subjects had moderate-severe impairment (arm FMA scores = 35.6±14.4, range 13.5-60). Performance on the robot-based tests, including speed (r=0.82, p\u3c0.0001), wrist targeting (r=0.72, p\u3c0.0001), and finger targeting (r=0.67, p\u3c0.0001) correlated significantly with the FMA scores. Wrist targeting (r=0.57 - 0.82) and finger targeting (r=0.49 - 0.68) correlated significantly with all 5 secondary motor outcomes and with percent CST injury. The robotic version of the B/B correlated significantly with the clinical B/B test but was less prone to floor effect. Robot-based assessments were comparable to FMA score in relation to percent CST injury and superior in relation to M1 hand injury. Conclusions The current findings support using a battery of robot-based methods for assessing the upper extremity motor function in subjects with chronic stroke

Chronic mercury exposure in Late Neolithic/Chalcolithic populations in Portugal from the cultural use of cinnabar

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/155748/1/Emslie_et_al_2015_Chronic_mercury.pd

Impact of Polymorphisms in PTK2 on Intrinsic Muscle Strength

Abstract Title: Impact of Polymorphisms in PTK2 on Intrinsic Muscle Strength Primary Presenter Full Name: Zachary Zeller Co-presenter Full Name(s): Click here to enter text. Co-author Full Name(s): Mohamed Al-Amoodi, Whitney Jones, Danny Lee, Steven Mckenzie, Helen Miller, Seth Stubblefied, Susan Knoblach, Heather Gordish-Dressman, Dustin Hittel, Laura L. Tosi Abstract Text (should not exceed 400 words): Recent studies have begun to search for correlations between genetic variations and muscle strength. One such study by Stebbings et al.1 examined two single nucleotide polymorphisms (SNPs)—rs7843014 and rs7460—on the PTK2 gene. The study found that genetic variation in the PTK2 gene impacts muscle-specific force, which is the force generated per unit of cross-sectional area of muscle. Muscle-specific force ultimately represents the intrinsic strength of a muscle and is a key determinant of functional capacity and mobility. This study sought to expand on prior research by looking for associations between genetic variants of PTK2 and measures of grip strength, as well as general anthropomorphic measures, in a cohort of healthy young adults. Our study assessed phenotypes for height, weight, VO2 max, max grip strength, and body mass index (BMI) using the Assessing Inherited Markers of Metabolic Syndrome in the Young (AIMMY) University of Calgary subset of 190 healthy, primarily Caucasian, individuals between the ages of 18 and 35. DNA samples were genotyped using ThermoFisher Taqman SNP genotype assays, and underwent the Applied Biosystems 7900HT real-time polymerase chain reaction (PCR) process. Analysis of covariance (ANCOVA) models were used to perform statistical analysis to look for genotype-phenotype associations. Unlike the findings by Stebbings et al.1 an association between the PTK2 genotypes and grip strength was not found. This could be due to the lower statistical power in the grip strength test, thus potentially indicating that grip strength and muscle-specific force do not measure similar parameters of muscle strength. Genetic variation in PTK2 has also been previously associated with VO2 max, but no association was found in the current study. Positive associations were found between genetic variants rs7843014 and rs7460 in PTK2 and BMI, and between genetic variant rs7843014 and height. High levels of functioning PTK2 have been found to have increased strength due to increased costamere density, resulting in more muscle myofibrils, and therein larger, presumably heavier muscles. However, this finding was only observed in males, and could be attributed to differential acquisition and maintenance of muscle mass based on sex. We identified a potentially novel association between genetic variants in PTK2 and anthropomorphic phenotypes. However, we were unable to confirm the effects of genetic variants on measures of intrinsic muscle strength, namely max grip strength or VO2 max in terms of functional capacity. Further research is needed to confirm this newly identified role for PTK2

The association of polymorphism rs3736228 within the LRP5 gene with Bone Mineral Density in a Cohort of Caucasian Young Adults

INTRODUCTION: Osteoporosis is a significant burden for our aging population. Developing a better understanding of the genetic underpinnings of poor bone quality may assist in the future development of prevention strategies. Correa-Rodriguez et al. have identified a group of single nucleotide polymorphisms (SNPs) that were associated with bone mineral density (BMD) in a population of Spanish Caucasians. In particular, they found that SNP rs3736228 in the low-density lipoprotein receptor related protein 5 (LRP5) gene had an influence on BMD. While the role of LRP5 in the Wnt canonical pathway has been fairly well characterized, its association with phenotypic BMD and osteoporosis has only been explored in a limited fashion. The aim of this study is to expand on this, and to replicate the findings of previous studies in a cohort of healthy young adults. METHODS: Cohort: The University of Calgary cohort from the Assessing Inherited Metabolic Syndrome Markers in the Young (UC AIMMY) study. Participants included consist of 168 healthy, predominantly Caucasian young adults. Phenotypes: height, weight, BMI, and total BMD. Genotyping: Allelic discrimination was determined. Statistical Analysis: After being tested for Hardy-Weinberg equilibrium (HWE), the data was run through analysis of covariance (ANCOVA). RESULTS: Using a dominant model, we found that females with one or more copies of the risk T allele of SNP rs3736228 had a significant negative association with total BMD (p = 0.0347). However, a similar association was not seen in males in this cohort. We did not find a significant association for this polymorphism and height, weight, or BMI. DISCUSSION: Polymorphisms in rs3736228 alter the codon in position 1330, downregulating the LRP5 cell surface receptor function. The LRP5 gene has now been shown in multiple studies to be associated with bone quality measures like calcaneal Qualitative Ultrasound (QUS) and BMD. Our study suggests that SNP rs3736228 also influences BMD in healthy young females. This supports the work of Correa-Rodriguez et al that found that when stratifying by sex, females only showed a trend towards significance (p = 0.092) in QUS measures. SIGNIFICANCE: This study expands our understanding of the importance of LRP5 rs3736228 polymorphisms in BMD by extending its relationship to a cohort of predominantly Caucasian college students. While the development of BMD is polygenic, this work broadened the role of SNP rs3736228 across the age span, and the sexual dimorphism seen in musculoskeletal traits

Inhibition of NADPH oxidase blocks NETosis and reduces thrombosis in heparin-induced thrombocytopenia

Heparin-induced thrombocytopenia (HIT) is associated with severe and potentially lethal thrombotic complications. NETosis was recently shown to be an important driver of thrombosis in HIT. We investigated the role of reactive oxygen species (ROS) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2) and their contributions to thrombus development in HIT. We showed that neutrophil activation by HIT immune complexes induced ROS-dependent NETosis. Analysis of thrombi formed in a microfluidics system showed ROS production in both platelets and neutrophils, and abundant neutrophil extracellular traps (NETs) and ROS distributed throughout the clot. Neutrophil-targeted ROS inhibition was sufficient to block HIT-induced NETosis and thrombosis using human blood. Inhibition of NOX2 with diphenyleneiodonium chloride or GSK2795039 abrogated HIT-induced thrombi in vivo using FcγRIIa+/hPF4+-transgenic mice. Thrombocytopenia in mice remained unaffected by ROS inhibition. Increased ROS production in activated neutrophils was also confirmed using fresh blood from patients with active HIT. Our findings show that ROS and NOX2 play a crucial role in NETosis and thrombosis in HIT. This enhances our understanding of the processes driving thrombosis in HIT and identifies NOX2 as a potential new therapeutic target for antithrombotic treatment of HIT

Vectorial capacity and vector control: reconsidering sensitivity to parameters for malaria elimination

Background: Major gains have been made in reducing malaria transmission in many parts of the world, principally by scaling-up coverage with long-lasting insecticidal nets and indoor residual spraying. Historically, choice of vector control intervention has been largely guided by a parameter sensitivity analysis of George Macdonald's theory of vectorial capacity that suggested prioritizing methods that kill adult mosquitoes. While this advice has been highly successful for transmission suppression, there is a need to revisit these arguments as policymakers in certain areas consider which combinations of interventions are required to eliminate malaria.Methods and Results: Using analytical solutions to updated equations for vectorial capacity we build on previous work to show that, while adult killing methods can be highly effective under many circumstances, other vector control methods are frequently required to fill effective coverage gaps. These can arise due to pre-existing or developing mosquito physiological and behavioral refractoriness but also due to additive changes in the relative importance of different vector species for transmission. Furthermore, the optimal combination of interventions will depend on the operational constraints and costs associated with reaching high coverage levels with each intervention.Conclusions: Reaching specific policy goals, such as elimination, in defined contexts requires increasingly non-generic advice from modelling. Our results emphasize the importance of measuring baseline epidemiology, intervention coverage, vector ecology and program operational constraints in predicting expected outcomes with different combinations of interventions.<br/