Associations between the measures of physical function, risk of falls and the quality of life in haemodialysis patients : a cross-sectional study

Background Impaired physical function due to muscle weakness and exercise intolerance reduces the ability to perform activities of daily living in patients with end-stage kidney disease, and by consequence, Health-Related Quality of Life (HRQoL). Furthermore, the risk of falls is an aggregate of physical function and, therefore, could be associated with HRQoL as well. The present study examined the associations between objective and subjective measures of physical function, risk of falls and HRQoL in haemodialysis patients. Methods This cross-sectional multicentre study included patients on maintenance haemodialysis. Physical function (quadriceps force, handgrip force, Sit-to-Stand, and six-minute walking test), the risk of falls (Tinetti, FICSIT-4, and dialysis fall index) and HRQoL (PROMIS-29 and EQ-5D-3 L) were measured and analysed descriptively, by general linear models and logistic regression. Results Of the 113 haemodialysis patients (mean age 67.5 +/- 16.1, 57.5% male) enrolled, a majority had impaired quadriceps force (86.7%) and six-minute walking test (92%), and an increased risk of falls (73.5%). Whereas muscle strength and exercise capacity were associated with global HRQoL (R-2 = 0.32) and the risk of falls, the risk of falls itself was related to psycho-social domains (R-2 = 0.11) such as depression and social participation, rather than to the physical domains of HRQoL. Objective measures of physical function were not associated with subjective fatigue, nor with subjective appreciation of health status. Conclusions More than muscle strength, lack of coordination and balance as witnessed by the risk of falls contribute to social isolation and HRQoL of haemodialysis patients. Mental fatigue was less common than expected, whereas, subjective and objective physical function were decreased

The relationship between glycaemic variability and cardiovascular autonomic dysfunction in patients with type 1 diabetes : a systematic review

Rigorous glycaemic control-reflected by low HbA1c goals-is of the utmost importance in the prevention and management of complications in patients with type 1 diabetes mellitus (T1DM). However, previous studies suggested that short-term glycaemic variability (GV) is also important to consider as excessive glucose fluctuations may have an additional impact on the development of diabetic complications. The potential relationship between GV and the risk of cardiovascular autonomic neuropathy (CAN), a clinical expression of cardiovascular autonomic dysfunction, is of increasing interest. This systematic review aimed to summarize existing evidence concerning the relationship between GV and cardiovascular autonomic dysfunction in T1DM. An electronic database search of Medline (PubMed), Web of Science and Embase was performed up to October 2019. There were no limits concerning year of publication. Methodological quality was evaluated using the Newcastle Ottawa Scale for observational studies. Six studies (four cross-sectional and two prospective cohorts) were included. Methodological quality of the studies varied from level C to A2. Two studies examined the association between GV and heart rate variability (HRV), and both found significant negative correlations. Regarding cardiovascular autonomic reflex tests (CARTs), two studies did not, while two other studies did find significant associations between GV parameters and CART scores. However, associations were attenuated after adjusting for covariates such as HbA1c, age and disease duration. In conclusion, this systematic review found some preliminary evidence supporting an association between GV and cardiovascular autonomic dysfunction in T1DM. Hence, uncertainty remains whether high GV can independently contribute to the onset or progression of CAN. The heterogeneity in the methodological approach made it difficult to compare different studies. Future studies should therefore use uniformly evaluated continuous glucose monitoring-derived parameters of GV, while standardized assessment of HRV, CARTs and other potential cardiac autonomic function parameters is needed for an unambiguous definition of CAN

The influence of clinically diagnosed neuropathy on respiratory muscle strength in type 2 diabetes mellitus

Objectives: This cross-sectional study investigated the influence of clinically diagnosed neuropathy (cdNP) on respiratory muscle strength in patients with type 2 diabetes mellitus (T2DM). Methods: 110 T2DM patients and 35 nondiabetic healthy controls (>= 60 years) were allocated to one of three groups depending on the presence of cdNP: T2DM without cdNP (D-; n = 28), T2DM with cdNP (D+; n = 82), and controls without cdNP (C; n = 35). Clinical neurological diagnostic examination consisted of Vibration Perception Threshold and Diabetic Neuropathy Symptom score. Respiratory muscle strength was registered by maximal Inspiratory and Expiratory Pressures (PImax and PEmax), and respiratory function by Peak Expiratory Flow (PEF). Isometric Handgrip Strength and Short Physical Performance Battery were used to evaluate peripheral skeletal muscle strength and physical performance. Univariate analysis of covariance was used with age, level of physical activity, and body mass index as covariates. Results: PImax, PEmax, and PEF were higher in C compared to D- and D+. Exploring more in detail, PImax, PEmax, and PEF were significantly lower in D+ compared to C. PEmax and PEF were also significantly lower in D-versus C. Measures of peripheral muscle strength and physical performance showed less associations with cdNP and T2DM. Conclusions: The presence of cdNP affects respiratory muscle strength in T2DM patients compared to healthy controls. Both cdNP and diabetes in themselves showed a distinctive impact on respiratory muscle strength and function; however, an accumulating effect could not be ascertained in this study. As commonly used measures of peripheral muscle strength and physical performance seemed to be less affected at the given time, the integration of PImax, PEmax, and PEF measurements in the assessment of respiratory muscle weakness could be of added value in the (early) screening for neuropathy in patients with T2DM

Impact of exercise-nutritional state interactions in patients with type 2 diabetes

Introduction This study examines the role of nutritional status during exercise training in patients with type 2 diabetes mellitus by investigating the effect of endurance-type exercise training in the fasted versus the fed state on clinical outcome measures, glycemic control, and skeletal muscle characteristics in male type 2 diabetes patients. Methods Twenty-five male patients (glycated hemoglobin (HbA1c), 57 ± 3 mmol·mol−1 (7.4% ± 0.3%)) participated in a randomized 12-wk supervised endurance-type exercise intervention, with exercise being performed in an overnight-fasted state (n = 13) or after consuming breakfast (n = 12). Patients were evaluated for glycemic control, blood lipid profiles, body composition and physical fitness, and skeletal muscle gene expression. Results Exercise training was well tolerated without any incident of hypoglycemia. Exercise training significantly decreased whole-body fat mass (−1.6 kg) and increased high-density lipoprotein concentrations (+2 mg·dL−1), physical fitness (+1.7 mL·min−1·kg−1), and fat oxidation during exercise in both groups (PTIME 0.05). HbA1c concentrations significantly decreased after exercise training (PTIME < 0.001), with a significant greater reduction after consuming breakfast (−0.30% ± 0.06%) compared with fasted state (−0.08% ± 0.06%; mean difference, 0.21%; PTIME × GROUP = 0.016). No interaction effects were observed for skeletal muscle genes related to lipid metabolism or oxidative capacity. Conclusions Endurance-type exercise training in the fasted or fed state do not differ in their efficacy to reduce fat mass, increase fat oxidation capacity, and increase cardiorespiratory fitness and high-density lipoprotein concentrations or their risk of hypoglycemia in male patients with type 2 diabetes. HbA1c seems to be improved more with exercise performed in the postprandial compared with the postabsorptive state

Crystal structure of the EphA4 protein tyrosine kinase domain in the apo- and dasatinib-bound state

AbstractThe Eph family of receptor tyrosine kinases regulates diverse cellular processes while the over-expression of a member of this family, EphA4, has been reported in a variety of malignant carcinomas. To gain insight into molecular mechanisms and to facilitate structure-based inhibitor design, we solved the crystal structure of the native EphA4 kinase domain in both the apo and dasatinib bound forms. Analysis of the two structures provides insight into structural features of inhibitor binding and revealed a hydrophobic back-pocket in the ATP- binding site of EphA4 which was previously unidentified. The structures suggest a route towards development of novel and specific inhibitors

Cohesin Releases DNA through Asymmetric ATPase-Driven Ring Opening

Cohesin stably holds together the sister chromatids from S phase until mitosis. To do so, cohesin must be protected against its cellular antagonist Wapl. Eco1 acetylates cohesin's Smc3 subunit, which locks together the sister DNAs. We used yeast genetics to dissect how Wapl drives cohesin from chromatin and identified mutants of cohesin that are impaired in ATPase activity but remarkably confer robust cohesion that bypasses the need for the cohesin protectors Eco1 in yeast and Sororin in human cells. We uncover a functional asymmetry within the heart of cohesin's highly conserved ABC-like ATPase machinery and find that both ATPase sites contribute to DNA loading, whereas DNA release is controlled specifically by one site. We propose that Smc3 acetylation locks cohesin rings around the sister chromatids by counteracting an activity associated with one of cohesin's two ATPase sites. Tight regulation of DNA entrapment and release by the cohesin complex is crucial for its multiple cellular functions. Elbatsh et al. find that cohesin's release from DNA requires an activity associated with one of its ATPase sites, whereas both sites control cohesin's loading onto DNA

Caskin2 is a novel talin- and Abi1-binding protein that promotes cell motility.

Talin (herein referring collectively to talin 1 and 2) couples the actomyosin cytoskeleton to integrins and transmits tension to the extracellular matrix. Talin also interacts with numerous additional proteins capable of modulating the actin-integrin linkage and thus downstream mechanosignaling cascades. Here, we demonstrate that the scaffold protein Caskin2 interacts directly with the R8 domain of talin through its C-terminal LD motif. Caskin2 also associates with the WAVE regulatory complex to promote cell migration in an Abi1-dependent manner. Furthermore, we demonstrate that the Caskin2-Abi1 interaction is regulated by growth factor-induced phosphorylation of Caskin2 on serine 878. In MCF7 and UACC893 cells, which contain an amplification of CASKIN2, Caskin2 localizes in plasma membrane-associated plaques and around focal adhesions in cortical microtubule stabilization complexes. Taken together, our results identify Caskin2 as a novel talin-binding protein that might not only connect integrin-mediated adhesion to actin polymerization but could also play a role in crosstalk between integrins and microtubules