Muscimol-induced death of GABAergic neurons in rat brain aggregating cell cultures.

During brain development, spontaneous neuronal activity has been shown to play a crucial role in the maturation of neuronal circuitries. Activity-related signals may cause selective neuronal cell death and/or rearrangement of neuronal connectivity. To study the effects of sustained inhibitory activity on developing inhibitory (GABAergic) neurons, three-dimensional primary cell cultures of fetal rat telencephalon were used. In relatively immature cultures, muscimol (10 microns), a GABAA receptor agonist, induced a transient increase in apoptotic cell death, as evidenced by a cycloheximide-sensitive increase of free nucleosomes and an increased frequency of DNA double strand breaks (TUNEL labeling). Furthermore, muscimol caused an irreversible reduction of glutamic acid decarboxylase activity, indicating a loss of GABAergic neurons. The muscimol-induced death of GABAergic neurons was attenuated by the GABAA receptor blockers bicuculline (100 microns) and picrotoxin (100 microns), by depolarizing potassium concentrations (30 mM KCl) and by the L-type calcium channel activator BAY K8644 (2 microns). As compared to the cholinergic marker (choline acetyltransferase activity), glutamic acid decarboxylase activity was significantly more affected by various agents known to inhibit neuronal activity, including tetrodotoxin (1 micron), flunarizine (5 microns), MK 801 (50 microns) and propofol (40 microns). The present results suggest that the survival of a subpopulation of immature GABAergic neurons is dependent on sustained neuronal activity and that these neurons may undergo apoptotic cell death in response to GABAA autoreceptor activation.

A human MYBPC3 mutation appearing about 10 centuries ago results in a hypertrophic cardiomyopathy with delayed onset, moderate evolution but with a risk of sudden death.

BACKGROUND: Hypertrophic Cardiomyopathy (HCM) is a genetically heterogeneous disease. One specific mutation in the MYBPC3 gene is highly prevalent in center east of France giving an opportunity to define the clinical profile of this specific mutation. METHODS: HCM probands were screened for mutation in the MYH7, MYBPC3, TNNT2 and TNNI3 genes. Carriers of the MYBPC3 IVS20-2A>G mutation were genotyped with 8 microsatellites flanking this gene. The age of this MYBPC3 mutation was inferred with the software ESTIAGE. The age at first symptom, diagnosis, first complication, first severe complication and the rate of sudden death were compared between carriers of the IVS20-2 mutation (group A) and carriers of all other mutations (group B) using time to event curves and log rank test. RESULTS: Out of 107 HCM probands, 45 had a single heterozygous mutation in one of the 4 tested sarcomeric genes including 9 patients with the MYBPC3 IVS20-2A>G mutation. The IVS20-2 mutation in these 9 patients and their 25 mutation carrier relatives was embedded in a common haplotype defined after genotyping 4 polymorphic markers on each side of the MYBPC3 gene. This result supports the hypothesis of a common ancestor. Furthermore, we evaluated that the mutation occurred about 47 generations ago, approximately at the 10th century.We then compared the clinical profile of the IVS20-2 mutation carriers (group A) and the carriers of all other mutations (group B). Age at onset of symptoms was similar in the 34 group A cases and the 73 group B cases but group A cases were diagnosed on average 15 years later (log rank test p = 0.022). Age of first complication and first severe complication was delayed in group A vs group B cases but the prevalence of sudden death and age at death was similar in both groups. CONCLUSION: A founder mutation arising at about the 10th century in the MYBPC3 gene accounts for 8.4% of all HCM in center east France and results in a cardiomyopathy starting late and evolving slowly but with an apparent risk of sudden death similar to other sarcomeric mutations.

Evaluation of postmortem MDCT and MDCT-angiography for the investigation of sudden cardiac death related to atherosclerotic coronary artery disease.

The goal of this study was to evaluate the diagnostic value of postmortem multi-computed tomography (MDCT) and MDCT-angiography for sudden cardiac deaths related to ischemic heart disease. Twenty three cases were selected based on clinical history and the results of native MDCT, multiphase post-mortem CT-angiography and conventional autopsy were compared. Radiological examination showed calcification of coronary arteries in 78% of the cases, most of which were not detailed at autopsy. MDCT-angiography allowed better visualization of the coronary arteries than MDCT and permitted the evaluation of stenoses and occlusions. Of the 14 cases of coronary thrombosis detected at conventional autopsy, 11 were visible as stop of perfusion with CT-angiography and three were found to be partly perfused. One case had an old thrombosis with collateral circulation. One case had a coronary artery postmortem clot found with MDCT-angiography. Coronary artery calcifications are more easily detected and documented with radiological examination than with conventional autopsy. MDCT is of limited diagnostic value for ischemic heart disease. MDCT-angiography, when correctly interpreted, is a reasonable tool to view the morphology of coronary arteries, rule out significant coronary artery stenoses, identify occlusions and direct sampling for histological examination.

Risk of death due to chronic chagasic cardiopathy

In this longitudinal study 5,710 people were included. The inclusion criteria were two positive serological results for Trypanosoma cruzi infection, 15 and 50 years old and no other demostrable diesease at the time of study. In the five year follow up 1,117 patients were lost. The follow up involved yearly evaluation of serology, clinical examination, X-ray of torax, and ECG, for 4,593 patients and 263 were contacted at home because they did not assist for their clinical consultant. Time average of follow up was 5.3 years. Eighty nine (1.5%) of the 4,593 patients died during the follow-up period, 63 (71%) by cardiac insufiency (CI) and 26 (29%) by severe ventricular arrithmias. Diagnosis of cardiomegaly was present in all the patients with diagnosis of CI and in 15 (5%) of the patients with diagnosis of arrithmias.The ECG alterations of these pacients show 61 right bundle brunch block (RBBB), associated or not with left anterior hemiblock (LAHB), 47 pathological Q wave and 70 primary repolarization alterations; 61 had polyfocal ventricular arrithmia. The death rate was similar in the sexes and was more frequent between 40 and 50 years of age. Information on 1,380 recuperated patients shows that 15 died with no previous symptoms and without medical assistance and were interpretate as sudden death. The latest ECG in three follow-up of these pacients indicates (before death) that only one had normal study and 14 presented 12 RBBB; 9 LAHB; 7 isolated ventricular arrithmia; 10 repolariz alterations; 2 patological Q wave, 10 patients of them with RBBB and repolariz alterations. In all the cases we had people between 35 and 43 years old, 9 men and 6 women. This study shows that in Chagas disease is possible to differenciate two risk groups. A low risk death group that have normal ECG and clinical evaluation during the follow up, and a high risk group associate ECG with RBBB and primary alterations of repolarization and/or inactivation zones with not anual clinical evaluation.

Nineteenth century research on cell death.

This paper reviews research on cell death in the 19th C. The first report of cell death was by Vogt in 1842, which was remarkably soon after the establishment of the cell theory by Schleiden and Schwann between 1838 and 1842. Initial studies on cell death, including that of Vogt, focused on its occurrence in metamorphosis (Vogt, 1842; Prévost and Lebert, 1844; Weismann, 1863-1866) or in blatant pathology (Virchow, 1858), but as histological techniques improved it was found to be involved in more subtle roles in numerous situations including endochondral ossification (Stieda, 1872), ovarian follicle atresia (Flemming, 1885), cell turnover (Nissen, 1886), the wholesale loss of a population of sensory neurons in fish (Beard, 1889), and the naturally occurring histogenetic death of myocytes (Felix, 1889) and neurons (Collin, 1906). The current categorization of cell death into about three main morphological types has 19th century roots in that apoptosis was well described by Flemming (1885), who called it chromatolysis, and various authors including Noetzel (1895) proposed a threefold classification. This article is part of a Special Issue entitled "Apoptosis: Four Decades Later".

Flow cytometry in the study of cell death

In this report we present a concise review concerning the use of flow cytometric methods to characterize and differentiate between two different mechanisms of cell death, apoptosis and necrosis. The applications of these techniques to clinical and basic research are also considered. The following cell features are useful to characterize the mode of cell death: (1) activation of an endonuclease in apoptotic cells results in extraction of the low molecular weight DNA following cell permeabilization, which, in turn, leads to their decreased stainability with DNA-specific fluorochromes. Measurements of DNA content make it possible to identify apoptotic cells and to recognize the cell cycle phase specificity of apoptotic process; (2) plasma membrane integrity, which is lost in necrotic but not in apoptotic cells; (3) the decrease in forward light scatter, paralleled either by no change or an increase in side scatter, represent early changes during apoptosis. The data presented indicate that flow cytometry can be applied to basic research of the molecular and biochemical mechanisms of apoptosis, as well as in the clinical situations, where the ability to monitor early signs of apoptosis in some systems may be predictive for the outcome of some treatment protocols.

Donation after Circulatory Death Legal-Guidance March 2011 (PDF 333 KB)

Donation after Circulatory Death. Legal Guidance

Review of the Lessons Arising from the Death of the Late Janine Murtagh (PDF 1.04 Mb)

Regulation and Quality Improvement Authority - Independent Review

Subclinical hypothyroidism and the risk of heart failure, other cardiovascular events, and death.

BACKGROUND: Subclinical hypothyroidism has been associated with systolic and diastolic cardiac dysfunction and an elevated cholesterol level, but data on cardiovascular outcomes and death are limited. METHODS: We studied 2730 men and women, aged 70 to 79 years, with baseline thyrotropin (TSH) measurements and 4-year follow-up data to determine whether subclinical hypothyroidism was associated with congestive heart failure (CHF), coronary heart disease, stroke, peripheral arterial disease, and cardiovascular-related and total mortality. After the exclusion of participants with abnormal thyroxine levels, subclinical hypothyroidism was defined as a TSH level of 4.5 mIU/L or greater, and was further classified according to TSH levels (4.5-6.9, 7.0-9.9, and > or = 10.0 mIU/L). RESULTS: Subclinical hypothyroidism was present in 338 (12.4%) of the participants. Compared with euthyroid participants, CHF events occurred more frequently among those with a TSH level of 7.0 mIU/L or greater (35.0 vs 16.5 per 1000 person-years; P = .006), but not among those with TSH levels between 4.5 and 6.9 mIU/L. In multivariate analyses, the risk of CHF was higher among those with high TSH levels (TSH of 7.0-9.9 mIU/L: hazard ratio, 2.58 [95% confidence interval, 1.19-5.60]; and TSH of > or = 10.0 mIU/L: hazard ratio, 3.26 [95% confidence interval, 1.37-7.77]). Among the 2555 participants without CHF at baseline, the hazard ratio for incident CHF events was 2.33 (95% confidence interval, 1.10-4.96; P = .03) in those with a TSH of 7.0 mIU/L or greater. Subclinical hypothyroidism was not associated with increased risk for coronary heart disease, stroke, peripheral arterial disease, or cardiovascular-related or total mortality. CONCLUSIONS: Subclinical hypothyroidism is associated with an increased risk of CHF among older adults with a TSH level of 7.0 mIU/L or greater, but not with other cardiovascular events and mortality. Further investigation is warranted to assess whether subclinical hypothyroidism causes or worsens preexisting heart failure.

Publication of Report into the death of baby Bronagh Livingstone

The Minister for Health and Children convened a Panel and requested an independent evaluation be carried out of the report of the North Eastern Health Board into the handling of an obstetrical emergency at the Cavan Monaghan Hospital Group on 11 December 2002.   Report of the Independent Review Panel North Eastern Health Board Report

Report of the Panel established to conduct an independent review of the events surrounding the death of Roisin Ruddle - February 2005

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Reducing the Risk: A Strategic Approach - The Report of the Task Force on Sudden Cardiac Death

The Minister for Health and Children established the Task Force on Sudden Cardiac Death (SCD) in the Autumn of 2004, with the following terms of reference:1) Define SCD and describe its incidence and underlying causes in Ireland.2) Advise on the detection and assessment of those at high risk of SCD and their relatives.3) Advise on the systematic assessment of those engaged in sports and exercise for risk of SCD.4) Advise on maximizing access to basic life support (BLS) and automated external defibrillators (AEDs) and on:- appropriate levels of training in BLS and use of AEDs, and on the maintenance of that training- priority individuals and priority groups for such training- geographic areas and functional locations of greatest need- best practice models of first responder scheme and public access defibrillation, and- integration of such training services.5) Advise on the establishment and maintenance of surveillance systems, including a registry of SCD and information systems to monitor risk assessment, and training and equipment programmes.6) Advise and make recommendations on other priority issues relevant to SCD in Ireland.7) Outline a plan for implementation and advise on monitoring the implementation of recommendations made in the Task Force’s report. In undertaking its work the Task Force was mindful of national health policy, relevant national strategies and of the recently reformed structures for health service delivery in Ireland. Read the Report (PDF, 1.66mb)