Abstract-Oxidative stress stimulates both growth and apoptosis in cardiac myocytes in vitro. We investigated whether oxidative stress mediates hypertrophy and apoptosis in cyclically stretched ventricular myocytes. Neonatal rat ventricular myocytes cultured on laminin-coated silastic membranes were stretched cyclically (1 Hz) at low (nominal 5%) and high (nominal 25%) amplitudes for 24 hours. Stretch caused a graded increase in superoxide anion production as assessed by superoxide dismutase (SOD)-inhibitable cytochrome c reduction or electron paramagnetic resonance spectroscopy. The role of reactive oxygen species (ROS) was assessed using the cell-permeable SOD/catalase mimetics Mn(II/III)tetrakis(1-methyl-4-peridyl) (MnTMPyP) and EUK-8. Stretch-induced increases in protein synthesis ( 3 Hleucine incorporation) and cellular protein content were completely inhibited by MnTMPyP (0.05 mmol/L) at both low and high amplitudes of stretch. In contrast, while MnTMPyP inhibited basal atrial natriuretic factor (ANF) mRNA expression, the stretch-induced increase in ANF mRNA expression was not inhibited by MnTMPyP. In contrast to hypertrophy, only high-amplitude stretch increased myocyte apoptosis, as reflected by increased DNA fragmentation on gel electrophoresis and an Ϸ3-fold increase in the number of TUNEL-positive myocytes. Similarly, only high-amplitude stretch increased the expression of bax mRNA. Myocyte apoptosis and bax expression stimulated by high-amplitude stretch were inhibited by MnTMPyP. Both low-and high-amplitude stretch caused rapid phosphorylation of ERK1/2, while high-, but not low-, amplitude stretch caused phosphorylation of JNKs. Activation of both ERK1/2 and JNKs was ROS-dependent. Thus, cyclic strain causes an amplitude-related increase in ROS, associated with differential activation of kinases and induction of hypertrophic and apoptotic phenotypes.

We tested the hypothesis that left ventricular (LV) remodeling late after myocardial infarction (MI) is associated with myocyte apoptosis in myocardium remote from the infarcted area and is related temporally to LV dilation and contractile dysfunction. One, four, and six months after MI caused by coronary artery ligation, LV volume and contractile function were determined using an isovolumic balloon-in-LV Langendorff technique. Apoptosis and nuclear morphology were determined by terminal deoxynucleotidyl transferase-mediated nick end-labeling (TUNEL) and Hoechst 33258 staining. Progressive LV dilation 1-6 mo post-MI was associated with reduced peak LV developed pressure (LVDP). In myocardium remote from the infarct, there was increased wall thickness and expression of atrial natriuretic peptide mRNA consistent with reactive hypertrophy. There was a progressive increase in the number of TUNEL-positive myocytes from 1 to 6 mo post-MI (2.9-fold increase at 6 mo; P < 0. 001 vs. sham). Thus LV remodeling late post-MI is associated with increased apoptosis in myocardium remote from the area of ischemic injury. The frequency of apoptosis is related to the severity of LV dysfunction.

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We performed a prospective, randomized, double-blind, crossover study to compare the efficacy and safety of vasodilation with the calcium entry blocker nifedipine with that of isosorbide dinitrate (ISDN)

Amyloid β peptide (Aβ) immunization of Alzheimer's disease (AD) patients has been reported to induce amyloid plaque removal, but with little impact on cognitive decline. We have explored the consequences of Aβ immunotherapy on neurons in post mortem brain tissue. Eleven immunized (AN1792, Elan Pharmaceuticals) AD patients were compared to 28 non-immunized AD cases. Immunohistochemistry on sections of neocortex was performed for neuron-specific nuclear antigen (NeuN), neurofilament protein (NFP) and phosphorylated-(p)PKR (pro-apoptotic kinase detected in degenerating neurons). Quantification was performed for pPKR and status spongiosis (neuropil degeneration), NeuN-positive neurons/field, curvature of the neuronal processes and interneuronal distance. Data were corrected for age, gender, duration of dementia and APOE genotype and also assessed in relation to Aβ42 and tau pathology and key features of AD. In non-immunized patients, the degree of neuritic curvature correlated with spongiosis and pPKR, and overall the neurodegenerative markers correlated better with tau pathology than Aβ42 load. Following immunization, spongiosis increased, interneuronal distance increased, while the number of NeuN-positive neurons decreased, consistent with enhanced neuronal loss. However, neuritic curvature was reduced and pPKR was associated with Aβ removal in immunized patients. In AD, associations of spongiosis status, curvature ratio and pPKR load with microglial markers Iba1, CD68 and CD32 suggest a role for microglia in neurodegeneration. After immunization, correlations were detected between the number of NeuN-positive neurons and pPKR with Iba1, CD68 and CD64, suggesting that microglia are involved in the neuronal loss. Our findings suggest that in established AD this form of active Aβ immunization may predominantly accelerate loss of damaged degenerating neurons. This interpretation is consistent with in vivo imaging indicating an increased rate of cerebral atrophy in immunized AD patients.

The inflammasome complex is part of the innate immune system, which serves to protect the host against harm from pathogens and damaged cells. It is a term first proposed by Tschopp's group in 2002, with numerous original research articles and reviews published on the topic since. There have been many types of inflammasome identified, but all result in the common pathway of activation of caspases and interleukin 1β along with possible cell death due to pyroptosis.Despite a growing body of research investigating the structure and function of the inflammasome in animal models, there is still limited evidence identifying inflammasome components in human physiology and disease. In this review, we explore the molecular structure and mechanism of activation of the inflammasome with a particular focus on inflammasome complexes expressed in humans. Inflammasome components have been identified in several human peripheral and brain tissues using both in-vivo and ex-vivo work, and the inflammasome complex has been shown to be associated with several genetic and acquired inflammatory disorders. We discuss the strengths and weaknesses of the information available on the inflammasome with an emphasis on the importance of prioritising work on human tissue.There is a huge demand for more effective treatments for a number of inflammatory and neurodegenerative diseases. Modulation of the inflammasome has been proposed as a novel treatment for several of these diseases and there are currently clinical trials ongoing to test this theory.

Background Specialist inpatient dementia units (SIDU) have been developed to address adverse outcomes often experienced by people living with dementia admitted to acute hospitals. However, the evidence base of their effectiveness remains limited. Aim To review the current literature to establish the comparative effectiveness of acute hospital SIDU vs. standard ward care (SWC). Methods We did an online search of 12 biomedical databases from inception to 31st October 2017. Studies of inpatients with any form of dementia in acute hospitals, published in English language peer-reviewed journals, using experimental, observational or qualitative study designs, comparing SIDU with SWC and which measured any qualitative or quantitative outcome of the patient or carer experience were included in the search criteria. We used a standardised data extraction and appraisal form. Results Three of 46 full-text studies evaluated were suitable for analysis. Due to study heterogeneity, pooled odds ratios were only possible for mortality [OR 1.06 (CI 1.0–1.4)]. Otherwise, a narrative synthesis was performed. Although quantitative measures of length of stay, mortality and behavioural and psychiatric symptoms of dementia are not significantly lower, SIDU are associated with greater patient and carer satisfaction, reduced readmission rates, more accurate and comprehensive assessment processes, documentation of resuscitation decisions, and increased rates of discharge to the patient’s own home. Conclusions Although SIDU may be associated with improved care outcomes, the current evidence of their effectiveness is markedly limited. Further research and service evaluation of SIDU as a method for providing high-quality dementia care in acute NHS Trusts is needed. PROSPERO: CRD42017078364.