Molecular dysfunction and phenotypic derangement in diabetic cardiomyopathy

The high incidence and poor prognosis of heart failure (HF) patients affected with diabetes (DM) is in part related to a specific cardiac remodeling currently recognized as diabetic cardiomyopathy (DCM). This cardiac frame occurs regardless of the presence of coronary artery diseases (CAD) and it can account for 15-20% of the total diabetic population. The pathogenesis of DCM remains controversial, and several molecular and cellular alterations including myocardial hypertrophy, interstitial fibrosis, oxidative stress and vascular inflammation, have been postulated. The main cardio-vascular alterations associated with hyperglycemia comprise endothelial dysfunction, adverse effects of circulating free fatty acids (FFA) and increased systemic inflammation. High glucose concentrations lead to a loss of mitochondrial networks, increased reactive oxygen species (ROS), endothelial nitric oxide synthase (eNOS) activation and a reduction in cGMP production related to protein kinase G (PKG) activity. Current mechanisms enhance the collagen deposition with subsequent increased myocardial stiffness. Several concerns regarding the exact role of DCM in HF development such as having an appearance as either dilated or as a concentric phenotype and whether diabetes could be considered a causal factor or a comorbidity in HF, remain to be clarified. In this review, we sought to explain the different DCM subtypes and the underlying pathophysiological mechanisms. Therefore, the traditional and new molecular and signal alterations and their relationship with macroscopic structural abnormalities are described

Recyclability of Photoinduced Cross-Linked EPM Rubber with Anthracene-Grafted Groups:Problems and Their Solutions

In this paper, we present the formation of reversible covalently cross-linked networks in ethylene propylene rubber with grafted anthracene groups (EPM-g-AN) based on the principles of photoinduced anthracene dimerization. First, an industrial-grade EPM rubber grafted with maleic anhydride functional groups (EPM-g-MA) was modified with 9-anthracenemethanol. By irradiating EPM-g-AN with UV light (365 nm), the anthracene moieties dimerize via [4 + 4]cycloaddition, forming a covalent network. The network cleavage proceeds at high temperatures (>170 °C), even if with considerable (chemical) degradation. Furthermore, one of the degradation routes has been identified by 1H NMR to occur via the ester bond cleavage releasing 9-anthracenemethanol. Nevertheless, the reversibility of cross-linking has been achieved by performing the reverse reaction in decalin. The UV-vis spectroscopy clearly shows that the de-cross-linking process in these conditions is due to the anthracene dimer cleavage. Although the recovery in mechanical properties upon recycling is yet to be optimized, the disclosed results pave the way toward the use of anthracene chemistry in thermally reversible networks with possible industrial perspective applications

Synthesis and solution properties of poly(p,α dimethylstyrene-co-maleic anhydride):The use of a monomer potentially obtained from renewable sources as a substitute of styrene in amphiphilic copolymers

The use of p,α-dimethylstyrene, potentially obtainable from renewable sources, as a substitute for styrene in the synthesis of amphiphilic copolymers is reported in this work. A series of novel poly(p,α-dimethylstyrene-co-maleic anhydride) (SMA) copolymers was synthesized, characterized, and studied as potential polymeric surfactants. After hydrolysis, the copolymers solution properties were compared to the similar and very well-known styrene-maleic acid copolymers. Both series of copolymers were synthesized using reversible addition-fragmentation chain transfer-mediated polymerization (RAFT), and a sample of poly(p,α-dimethylstyrene-co-maleic anhydride) was synthesized via classical free radical polymerization. The synthesized copolymers were studied from the point of view of their solution properties, with particular attention to the influence of the macromolecular and chemical structure on the surface tension of their aqueous solutions. Our results suggest that p,α-dimethylstyrene can be employed in copolymers with maleic anhydride, the resulting material being a valid alternative to SMA copolymers for various applications, such as emulsifiers and dispersants. Furthermore, the DMSMA series seems to be slightly more surface active than SMA

IQ, the urban environment, and their impact on future schizophrenia risk in men

Exposure to an urban environment during early life and low IQ are 2 well-established risk factors for schizophrenia. It is not known, however, how these factors might relate to one another. Data were pooled from the North Jutland regional draft board IQ assessments and the Danish Conscription Registry for men born between 1955 and 1993. Excluding those who were followed up for less than 1 year after the assessment yielded a final cohort of 153 170 men of whom 578 later developed a schizophrenia spectrum disorder. We found significant effects of having an urban birth, and also experiencing an increase in urbanicity before the age of 10 years, on adult schizophrenia risk. The effect of urban birth was independent of IQ. However, there was a significant interaction between childhood changes in urbanization in the first 10 years and IQ level on the future adult schizophrenia risk. In short, those subjects who moved to more or less urban areas before their 10th birthday lost the protective effect of IQ. When thinking about adult schizophrenia risk, the critical time window of childhood sensitivity to changes in urbanization seems to be linked to IQ. Given the prediction that by 2050, over 80% of the developed world's population will live in an urban environment, this represents a major future public health issue. © The Author 2017

Working memory in unaffected relatives of patients with schizophrenia: A meta-analysis of functional magnetic resonance imaging studies

Working memory deficits, a core cognitive feature of schizophrenia may arise from dysfunction in the frontal and parietal cortices. Numerous studies have also found abnormal neural activation during working memory tasks in patients' unaffected relatives. The aim of this study was to systematically identify and anatomically localize the evidence for those activation differences across all eligible studies. Fifteen functional magnetic resonance imaging (fMRI) manuscripts, containing 16 samples of 289 unaffected relatives of patients with schizophrenia, and 358 healthy controls were identified that met our inclusion criteria: (1) used a working memory task; and (2) reported standard space coordinates. Activation likelihood estimation (ALE) identified convergence across studies. Compared to healthy controls, patients' unaffected relatives showed decreases in neural activation in the right middle frontal gyrus (BA9), as well as right inferior frontal gyrus (BA44). Increased activation was seen in relatives in the right frontopolar (BA10), left inferior parietal lobe (BA40), and thalamus bilaterally. These results suggest that the familial risk of schizophrenia is expressed in changes in neural activation in the unaffected relatives in the cortical-subcortical working memory network that includes, but is not restricted to the middle prefrontal cortex. © The Author 2014. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved

The impact of CACNA1C gene, and its epistasis with ZNF804A, on white matter microstructure in health, schizophrenia and bipolar disorder

Genome-wide studies have identified allele A (adenine) of single nucleotide polymorphism (SNP) rs1006737 of the calcium-channel CACNA1C gene as a risk factor for both schizophrenia (SZ) and bipolar disorder (BD) as well as allele A for rs1344706 in the zinc-finger ZNF804A gene. These illnesses have also been associated with white matter abnormalities, reflected by reductions in fractional anisotropy (FA), measured using diffusion tensor imaging (DTI). We assessed the impact of the CACNA1C psychosis risk variant on FA in SZ, BD and health. 230 individuals (with existing ZNF804A rs1344706 genotype data) were genotyped for CACNA1C rs1006737 and underwent DTI. FA data was analysed with tract-based spatial statistics and threshold-free cluster enhancement significance correction (p < 0.05) to detect effects of CACNA1C genotype on FA, and its potential interaction with ZNF804A genotype and with diagnosis, on FA. There was no significant main effect of the CACNA1C genotype on FA, nor diagnosis by genotype(s) interactions. Nevertheless, when inspecting SZ in particular, risk allele carriers had significantly lower FA than the protective genotype individuals, in portions of the left middle occipital and parahippocampal gyri, right cerebelleum, left optic radiation and left inferior and superior temporal gyri. Our data suggests a minor involvement of CACNA1C rs1006737 in psychosis via conferring susceptibility to white matter microstructural abnormalities in SZ. Put in perspective, ZNF804A rs1344706, not only had a significant main effect, but its SZ-specific effects were two orders of magnitude more widespread than that of CACNA1C rs1006737

Electroactive Self-Healing Shape Memory Polymer Composites Based on Diels–Alder Chemistry

Both shape memory and self-healing polymers have received significant attention from the materials science community. The former, for their application as actuators, self-deployable structures, and medical devices; and the latter, for extending the lifetime of polymeric products. Both effects can be stimulated by heat, which makes resistive heating a practical approach to trigger these effects. Here we show a conductive polyketone polymer and carbon nanotube composite with cross-links based on the thermo-reversible furan/maleimide Diels–Alder chemistry. This approach resulted in products with efficient electroactive shape memory effect, shape reprogrammability, and self-healing. They exhibit electroactive shape memory behavior with recovery ratios of about 0.9; requiring less than a minute for shape recovery; electroactive self-healing behavior able to repair microcracks and almost fully recover their mechanical properties; requiring a voltage in the order of tens of volts for both shape memory and self-healing effects. To the best of our knowledge, this is the first report of electroactive self-healing shape memory polymer composites that use covalent reversible Diels–Alder linkages, which yield robust solvent-resistant polymer networks without jeopardizing their reprocessability. These responsive polymers may be ideal for soft robotics and actuators. They are also a step toward sustainable materials by allowing an increased lifetime of use and reprocessability

Effects of Bisphosphonate Treatment on Circulating Lipid and Glucose Levels in Patients with Metabolic Bone Disorders

Bisphosphonates are the first-choice treatment of osteoporosis and Paget’s disease of bone. Among the bisphosphonates, the non-amino-bisphosphonates, such as clodronic acid, are intracellular converted into toxic analogues of ATP and induce cellular apoptosis whereas the amino-bisphosphonates, such as zoledronic acid, inhibit the farnesyl-diphosphate-synthase, an enzyme of the mevalonate pathway. This pathway regulates cholesterol and glucose homeostasis and is a target for statins. In this retrospective cohort study, we evaluated the effects of an intravenous infusion of zoledronic acid (5&nbsp;mg) or clodronic acid (1500&nbsp;mg) on blood lipid (i.e. total cholesterol, low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol and triglycerides) and glucose levels in patients with osteoporosis and Paget’s disease of bone. All patients were evaluated before, 1 and 6&nbsp;months after bisphosphonate treatment. Pagetic and osteoporotic patients treated with zoledronic acid showed a significant reduction in glucose and atherogenic lipids during follow-up whereas these phenomena were not observed after clodronic treatment. The effect on circulating lipid levels was similar in naïve and re-treated Pagetic patients. Zoledronic acid treatment was associated with a reduction in blood glucose and atherogenic lipids in patients with metabolic bone disorders. The extent of change was similar to that obtained with the regular assumption of a low-intensity statin. Further studies are warranted to better evaluate the clinical implications of these observations

The clinical effectiveness and cost effectiveness of clozapine for inpatients with severe borderline personality disorder (CALMED study): A randomised placebo-controlled trial.

Background: Data from case series suggest that clozapine may benefit inpatients with borderline personality disorder (BPD), but randomised trials have not been conducted. Methods: Multicentre, double-blind, placebo-controlled trial. We aimed to recruit 222 inpatients with severe BPD aged 18 or over, who had failed to respond to other antipsychotic medications. We randomly allocated participants on a 1:1 ratio to receive up to 400mg of clozapine per day or an inert placebo using a remote web-based randomisation service. The primary outcome was total score on the Zanarini Rating scale for Borderline Personality Disorder (ZAN-BPD) at six months. Secondary outcomes included self-harm, aggression, resource use and costs, side effects and adverse events. We used a modified intention to treat analysis (mITT) restricted to those who took one or more dose of trial medication, using a general linear model fitted at six months adjusted for baseline score, allocation group and site. Results: The study closed early due to poor recruitment and the impact of the COVID-19 pandemic. Of 29 study participants, 24 (83%) were followed up at six months, of whom 21 (72%) were included in the mITT analysis. At six months, 11 (73%) participants assigned to clozapine and 6 (43%) of those assigned to placebo were still taking trial medication. Adjusted difference in mean total ZAN-BPD score at six months was -3.86 (95% Confidence Intervals = -10.04 to 2.32, p=0.22). There were 14 serious adverse events; six in the clozapine arm and eight in the placebo arm of the trial. There was little difference in the cost of care between groups. Interpretation: We recruited insufficient participants to test the primary hypothesis. The study findings highlight problems in conducting placebo-controlled trials of clozapine and in using clozapine for people with BPD, outside specialist inpatient mental health units. Trial registration ISRCTN18352058. https://doi.org/10.1186/ISRCTN1835205

Nonlinear complexity analysis of brain fMRI signals in schizophrenia

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