Runs of Homozygosity: Association with Coronary Artery Disease and Gene Expression in Monocytes and Macrophages

Runs of homozygosity (ROHs) are recognized signature of recessive inheritance. Contributions of ROHs to the genetic architecture of coronary artery disease and regulation of gene expression in cells relevant to atherosclerosis are not known. Our combined analysis of 24,320 individuals from 11 populations of white European ethnicity showed an association between coronary artery disease and both the count and the size of ROHs. Individuals with coronary artery disease had approximately 0.63 (95% CI: 0.4–0.8) excess of ROHs when compared to coronary-artery-disease-free control subjects (p = 1.49 × 10⁻⁹). The average total length of ROHs was approximately 1,046.92 (95% CI: 634.4–1,459.5) kb greater in individuals with coronary artery disease than control subjects (p = 6.61 × 10⁻⁷). None of the identified individual ROHs was associated with coronary artery disease after correction for multiple testing. However, in aggregate burden analysis, ROHs favoring increased risk of coronary artery disease were much more common than those showing the opposite direction of association with coronary artery disease (p = 2.69 × 10⁻³³). Individual ROHs showed significant associations with monocyte and macrophage expression of genes in their close proximity—subjects with several individual ROHs showed significant differences in the expression of 44 mRNAs in monocytes and 17 mRNAs in macrophages when compared to subjects without those ROHs. This study provides evidence for an excess of homozygosity in coronary artery disease in outbred populations and suggest the potential biological relevance of ROHs in cells of importance to the pathogenesis of atherosclerosis.     

Babies with spina bifida treated without surgery: parents' views on home versus hospital care.

From 1971 to 1981, 98 babies born with meningomyelocoele at the North Staffordshire Hospital Centre''s district maternity hospital, were thought not suitable for surgery. Sixty three survived for more than one week. Over the period the hospital''s policy changed: initially all such babies were kept in hospital, but later parents were given the choice of taking their baby home for palliative and terminal care. In an attempt to determine parents'' views on the care of their baby the parents of 44 of the babies who survived to one week were traced in 1985-6, five to 14 years later; 80 of them were asked how they felt about the lives and deaths of their babies. Eighteen babies had been taken home, and they had lived longer than the 26 who had been cared for in hospital. Parents whose baby had remained in hospital were sadder than those who had taken their baby home when they looked back at their experiences, and they also considered that their baby''s life had been of poor quality. Most of those who had taken their baby home had a more positive view of their child''s life. The figures suggest that the bereavement process after a baby''s death is longer than has been thought, but despite residual sadness just over half of the parents interviewed thought that something positive had come out of their experience.     

Histological and immunohistochemical effects of Curcuma longa on activation of rat hepatic stellate cells after cadmium induced hepatotoxicity

The liver is a target for toxic chemicals such as cadmium (Cd). When the liver is damaged, hepatic stellate cells (HSC) are activated and transformed into myofibroblast-like cells, which are responsible for liver fibrosis. Curcuma longa has been reported to exert a hepato-protective effect under various pathological conditions. We investigated the effects of C. longa administration on HSC activation in response to Cd induced hepatotoxicity. Forty adult male albino rats were divided into: group 1 (control), group 2 (Cd treated), group 3 (C. longa treated) and group 4 (Cd and C. longa treated). After 6 weeks, liver specimens were prepared for light and electron microscopy examination of histological changes and immunohistochemical localization of alpha smooth muscle actin (αSMA) as a specific marker for activated HSC. Activated HSC with a positive αSMA immune reaction were not detected in groups 1 and 3. Large numbers of activated HSC with αSMA immune reactions were observed in group 2 in addition to Cd induced hepatotoxic changes including excess collagen deposition in thickened portal triads, interlobular septa with hepatic lobulation, inflammatory cell infiltration, a significant increase in Kupffer cells and degenerated hepatocytes. In group 4, we observed a significant decrease in HSC that expressed αSMA with amelioration of the hepatotoxic changes. C. longa administration decreased HSC activation and ameliorated hepatotoxic changes caused by Cd in adult rats.     

The acetylcholine receptor: Isolation of a brain nicotinic receptor and its preliminary characterization in lipid bilayer membranes

The technique of affinity chromatography with the curarizing neurotoxins of Naja naja venom has been employed to extract nicotinic acetylcholine receptors from the brain tissues of mouse and hog. Both carbochol and hexamethonium were used as linear or step gradients to elute the receptor and its properties were investigated in lipid bilayer membranes. Of particular interest is the observation that discrete quanta of conductance could be observed across an NaCl gradient of 1.0:0.1 M. By switching the voltage-clamp across the bilayer between a positive and negative 80 mV, the separate Na⁺ and Cl⁻ conductances of these quanta could be estimated and the following conductances of the smallest discrete quanta were observed: 3.7 · 10⁻¹¹ Ω⁻¹ (Na⁺) and 5.9 · 10⁻¹¹ Ω⁻¹ (Cl⁻) for mouse brain receptors; 3.8 · 10⁻¹¹ Ω⁻¹ (Na⁺) and 4.7 · 10⁻¹¹ Ω⁻¹ (Cl⁻) for hog brain receptors. Large aggregates of receptors appeared to activate and deactivate as multiples of a basic conductance size, although there is evidence that they may not represent the actual gating of ion channels. A “background noise” that is not within the temporal capability of the recording system is also present at an intensity that seems to parallel the number of activated receptors, and in view of recent electrophysiological evidence that the relaxation lifetime of the open channel state is of a millisecond duration, it may be that this “noise” actually represent the channel gating.     

The transmission of excitation from the membrane to actomyosin

The impressed field, “Window Field” (WF), due to a half-wave action potential on a muscle fiber, has been calculated on the basis of potential theory. It has been shown that in spite of the small intensity of the field, its integrated action can transfer the energy needed to induce, contraction from the membrane to the interior of the fiber. The energy of polarization has been found to be sufficient to exceed the energy of, thermal agitation on that length of fiber, which can be identified as the length of a sarcomere. The changes of ion concentration, caused by the WF, if calculated on the assumption of the semipermeability of theZ membranes, was found to be equal to the changes necessary to induce contraction of actomyosinin vitro.