The influence of glutathione S­-transferases M1 and M3 on the development of bladder cancer

Problem: Cigarette smoking is the most important risk factor of transitional cell carcinoma of the urinary bladder. The effect of the glutathione S­transferases M1 (GSTM1) and M3 (GSTM3) on the influence of this risk factor was investigated. Methods: A total of 293 bladder cancer patients from Dortmund and Wittenberg as well as 176 surgical patients without any malignancy from Dortmund were genotyped for GSTM1 und GSTM3 according to standard PCR/RFLP methods. Smoking habits were also qualified by a standardized interview. Results: The percentage of GSTM1 negative cases was 63 % in the entire bladder cancer patient group compared to 50 % in the control group. GSTM3*A/*A genotype was 76 % in the entire group of bladder cancer cases and 74 % in controls. Smokers and ex­smokers were overrepresented in the bladder cancer patient group. A significant association between smoking status and GSTM1 or GSTM3 genotype could not be revealed. Conclusion: The elevated percentage of GSTM1 negative bladder cancer cases shows the important effect of this polymorphic enzyme on the development of bladder cancer. In contrast to some other studies, an influence of GSTM1 on the risk due to cigarette smoking could not be observed

NEURAL MARKERS OF SELF-OTHER DIFFERENTIATION DURING DYNAMIC JOINT ACTION

Joint actions, in which two or more people coordinate their actions with each other to achieve a common goal, are ubiquitous in daily life. Examples range from moving furniture with a friend to musical ensemble performance. Despite the ubiquity of joint actions, researchers know relatively little about the underlying neural processes that operate during real-world, dynamic joint action. Furthermore, recent research emphasizes the importance of using one’s own sensorimotor system to represent and simulate others’ contributions to the joint action to facilitate coordination. However, the notion that people represent their own and others’ contributions to a joint action using the same neural resources raises the question of how people nevertheless maintain a distinction between each person’s individual contributions. This dissertation will focus on delineating neural markers of self-other differentiation during dynamic joint action. In four experiments, I employ a joint sequence production paradigm in which pairs of participants take turns producing tones to match a metronome pace. I use electroencephalography (EEG) to examine the time course of neural activity associated with each person’s actions (i.e., taps) and sensory consequences (i.e., tones) as the sequence unfolds. In Chapters 2 and 3 (Experiments 1 and 2), I investigate whether there is a perceptual differentiation in the processing of sensory consequences that result from one’s own vs. others’ actions by measuring auditory event-related potentials (ERPs) elicited by self- and partner-produced tones. Together, the findings from Experiments 1 and 2 indicate that self-specific attenuation of the auditory P2 provides a neural marker of self-other differentiation at a perceptual level. The findings from Experiment 2 also show that orienting processes associated with the coordination requirements of a joint action enhance P2 amplitude for partner-produced tones, suggesting that people direct their attention to their partner’s tone onsets to better coordinate with them. In Chapter 3 (Experiment 3 and 4), I investigate whether there is a differentiation in the motor activity that is associated with each person’s actions by conducting novel analyses of the data previously reported in Experiments 1 and 2 to examine motor-related cortical oscillations during self- and partner-produced taps. Together, the findings from Experiments 3 and 4 indicate that motor-related suppression provides a neural marker of self-other differentiation at a motor level. The findings from Experiment 3 and 4 also show that the coordination requirements of a joint action affect the degree of motor-related suppression for a partner’s actions, suggesting that people simulate their partners action timing to better coordinate with them. Overall, this research suggests that distinct neural activity for one’s own contributions to a joint action is dynamically coupled with periods of neural activity that reflect the integration of a partner’s actions based on the coordination demands of the joint action. Together, the experiments presented in this dissertation provide important and direct implications for theoretical accounts of joint action, as they further our understanding of how people maintain a distinction between their own and their partners’ contributions to a joint action, while also dynamically integrating information about the timing of their partners’ actions and sensory consequences to better coordinate with them. More broadly, these experiments contribute to our understanding of disorders associated with self-other processing deficits, such as schizophrenia, and provide valuable insight into the development of effective paradigms for motor training and rehabilitation

Practice Patterns Of Clinicians: Assessment Of Malnutrition In Ckd Dialysis And Interventions

With limited information on the practice patterns regarding clinician identification of malnutrition and the use of nutritional interventions in malnourished CKD-5 dialysis patients, a market research survey was conducted by NKF sponsored by Pentec Health to evaluate this amongst renal clinicians. For dialysis patients, results for the top four assessment markers were: decreased appetite; albumin level; decrease in dry weight, quality of life. Most commonly recommended oral supplements (OS) were nutritionally complete renal, diabetic and standard products with most common barriers: out of pocket cost; patient resistance; and reimbursement issues. Nutrition support and food during dialysis responses for outpatients in table below:Nutrition Intervention% of clinicians who would recommendBarriers to Use (Top 3 )Tube Feeding28.0 %Not available at unit; patient resistance; family resistanceIntradialytic Parenteral Nutrition (IDPN)48.7 %Reimbursement ; not available at unit; MD resistanceIntraperitoneal Nutrition (IPN)22.0 %Not available at unit; reimbursement; MD resistanceTotal Parenteral Nutrition (TPN)16.9 %Not available at unit; reimbursement, MD resistanceFood During Hemodialysis83.3 % OS 63.3% FoodDrop in blood pressure, risk of aspiration; hygieneFindings: A clinician gap seems to exist around nutrition support interventions in CKD-5 dialysis patients. Meal provision during dialysis could be expanded. These interventions may improve the nutritional status of dialysis patients

Ions modulate stress-induced nano-texture in supported fluid lipid bilayers

Most plasma membranes comprise a large number of different molecules including lipids and proteins. In the standard fluid mosaic model, the membrane function is effected by proteins whereas lipids are largely passive and serve solely in the membrane cohesion. Here we show, using supported 1,2-dioleoyl-sn-glycero-3-phosphocholine lipid bilayers in different saline solutions, that ions can locally induce ordering of the lipid molecules within the otherwise fluid bilayer when the latter is supported. This nanoordering exhibits a characteristic length scale of ∼20 nm, and manifests itself clearly when mechanical stress is applied to the membrane. Atomic force microscopy (AFM) measurements in aqueous solutions containing NaCl, KCl, CaCl2, and Tris buffer show that the magnitude of the effect is strongly ion-specific, with Ca2+ and Tris, respectively, promoting and reducing stress-induced nanotexturing of the membrane. The AFM results are complemented by fluorescence recovery after photobleaching experiments, which reveal an inverse correlation between the tendency for molecular nanoordering and the diffusion coefficient within the bilayer. Control AFM experiments on other lipids and at different temperatures support the hypothesis that the nanotexturing is induced by reversible, localized gel-like solidification of the membrane. These results suggest that supported fluid phospholipid bilayers are not homogenous at the nanoscale, but specific ions are able to locally alter molecular organization and mobility, and spatially modulate the membrane’s properties on a length scale of ∼20 nm. To illustrate this point, AFM was used to follow the adsorption of the membrane-penetrating antimicrobial peptide Temporin L in different solutions. The results confirm that the peptides do not absorb randomly, but follow the ion-induced spatial modulation of the membrane. Our results suggest that ionic effects have a significant impact for passively modulating the local properties of biological membranes, when in contact with a support such as the cytoskeleton

Replication fork regression in vitro by the Werner syndrome protein (WRN): Holliday junction formation, the effect of leading arm structure and a potential role for WRN exonuclease activity

The premature aging and cancer-prone disease Werner syndrome stems from loss of WRN protein function. WRN deficiency causes replication abnormalities, sensitivity to certain genotoxic agents, genomic instability and early replicative senescence in primary fibroblasts. As a RecQ helicase family member, WRN is a DNA-dependent ATPase and unwinding enzyme, but also possesses strand annealing and exonuclease activities. RecQ helicases are postulated to participate in pathways responding to replication blockage, pathways possibly initiated by fork regression. In this study, a series of model replication fork substrates were used to examine the fork regression capability of WRN. Our results demonstrate that WRN catalyzes fork regression and Holliday junction formation. This process is an ATP-dependent reaction that is particularly efficient on forks containing single-stranded gaps of at least 11–13 nt on the leading arm at the fork junction. Importantly, WRN exonuclease activity, by digesting the leading daughter strand, enhances regression of forks with smaller gaps on the leading arm, thus creating an optimal structure for regression. Our results suggest that the multiple activities of WRN cooperate to promote replication fork regression. These findings, along with the established cellular consequences of WRN deficiency, strongly support a role for WRN in regression of blocked replication forks

Replication Fork Regression \u3cem\u3eIn Vitro\u3c/em\u3e by the Werner Syndrome Protein (WRN): Holliday Junction Formation, the Effect of Leading Arm Structure and a Potential Role for WRN Exonuclease Activity

The premature aging and cancer-prone disease Werner syndrome stems from loss of WRN protein function. WRN deficiency causes replication abnormalities, sensitivity to certain genotoxic agents, genomic instability and early replicative senescence in primary fibroblasts. As a RecQ helicase family member, WRN is a DNA-dependent ATPase and unwinding enzyme, but also possesses strand annealing and exonuclease activities. RecQ helicases are postulated to participate in pathways responding to replication blockage, pathways possibly initiated by fork regression. In this study, a series of model replication fork substrates were used to examine the fork regression capability of WRN. Our results demonstrate that WRN catalyzes fork regression and Holliday junction formation. This process is an ATP-dependent reaction that is particularly efficient on forks containing single-stranded gaps of at least 11–13 nt on the leading arm at the fork junction. Importantly, WRN exonuclease activity, by digesting the leading daughter strand, enhances regression of forks with smaller gaps on the leading arm, thus creating an optimal structure for regression. Our results suggest that the multiple activities of WRN cooperate to promote replication fork regression. These findings, along with the established cellular consequences of WRN deficiency, strongly support a role for WRN in regression of blocked replication forks

Enabling the classroom and the curriculum: higher education, literary studies and disability

In this article the tripartite model of disability is applied to the lived experience of twenty-first-century higher education. The tripartite model facilitates a complex understanding of disability that recognises assumptions and discrimination but not at the cost of valued identity. This being so, not only the normative positivisms and non-normative negativisms but also the non-normative positivisms of the classroom and the curriculum are explored. Inclusion is taken as the starting point and the argument progresses to a profound and innovational appreciation of disability. The problem addressed is that inclusion, as shown in The Biopolitics of Disability, constitutes little more than inclusion-ism until disability is recognised in the context of alternative lives and values that neither enforce nor reify normalcy. Informed by this understanding, the article adopts the disciplinary example of literary studies and refers to Brian Friel’s Molly Sweeney as a primary text. The conclusion is that, despite passive and active resistance, disability enters higher education in many ways, most of which are beneficial to students and educators alike