Alcohol and ischaemic heart disease in middle aged British men.

The relation between alcohol intake and ischaemic heart disease was examined in a large scale prospective study of middle aged men drawn from general practices in 24 British towns. After an average follow up of 6.2 years 335 of the 7729 men had experienced a myocardial infarction (fatal or non-fatal) or sudden cardiac death. No significant relation was found between reported alcohol intake and the incidence of such events. Though the group of light daily drinkers had the lowest incidence of ischaemic heart disease events, it also contained the lowest proportion of current smokers, had the lowest mean blood pressure, had the lowest mean body mass index, and contained the lowest proportion of manual workers. These characteristics are more likely to account for the apparent protective effect of alcohol against ischaemic heart disease than a direct effect of alcohol. Compared with the effects of established risk factors alcohol seems to be quite unimportant in the development of ischaemic heart disease.     

Dye permeability at phase transitions in single and binary component phospholipid bilayers

By encapsulating a pH-sensitive dye, phenol red, in multilamellar liposomes of DMPC, DPPC and DMPC/DPPC mixtures, the permeability of these phospholipid bilayers to dye as a function of temperature has been studied. For both DMPC and DPPC liposomes, dye release begins well below the main gel-to-liquid-crystalline phase transition (24°C and 42°C, respectively) at temperatures corresponding to the onset of the pretransition (about 14°C and 36°C, respectively) with DPPC liposomes exhibiting a permeability anomaly at the main phase transition (42°C). The perturbation occurring in the bilayer structure that allows the release of encapsulated phenol red (approx. 5 Å diameter) is not sufficient to permit the release of encapsulated haemoglobin (approx. 20 Å diameter, negatively charged). In liposomes composed of a range of DMPC/DPPC mixtures, dye release commences at the onset of the pretransition range (determined by optical absorbance measurements) and increases with increasing temperature until the first appearance of liquid crystalline phase after which no further dye release occurs. Interestingly, the dye retaining properties of DMPC and DPPC liposomes well below their respective pretransition temperature regions are very different: DMPC liposomes release much encapsulated dye at incubation temperatures of 5°C whilst DPPC liposomes do not.     

RADIOAUTOGRAPHY OF CHOLESTEROL IN LUNG : An Assessment of Different Tissue Processing Techniques

30 Swiss albino mice aged 8 days were injected intraperitoneally with 0.2 ml of a solution of 4% N,N-dimethyl-formamide in 5% dextrose in water containing cholesterol-1,2-³H (~1 mCi/ml). Lung tissue was embedded in an Epon mixture after either acetone and propylene oxide dehydration, partial ethanol and Epon 812 dehydration, or the precipitation of cholesterol by digitonin succeeded by partial dehydration. The distribution of cholesterol-1,2-³H in lung parenchyma in 1µ Epon section radioautograms was compared with that in frozen section radioautograms and was found to be independent of the manner of tissue processing. Grain distribution in the tissue was essentially the same whether 16, 63, 93, or 100% radioactivity was retained in the lung. However, grain distribution in the alveolar spaces differed, presumably due to displacement of pulmonary surfactant, which contains cholesterol. Intracellular distribution of cholesterol, in electron microscope radioautograms, was the same with either 51% or 93% retention of radioactivity in the lung. Loss of radioactivity into the various processing solutions was monitored. The various processing techniques have different drawbacks.     

Concentrations of high density lipoprotein cholesterol,triglycerides, and total cholesterol in ischaemic heart disease.

OBJECTIVE--To assess the roles of serum concentrations of total cholesterol, high density lipoprotein cholesterol, and triglycerides in predicting major ischaemic heart disease. DESIGN--Men recruited for the British regional heart study followed up for a mean of 7.5 years. SETTING--General practices in 24 British towns. PATIENTS--7735 Middle aged men. END POINT--Predictive value of serum concentrations of lipids. MEASUREMENTS AND MAIN RESULTS--At initial screening serum concentrations of total cholesterol, high density lipoprotein cholesterol, and triglycerides were determined from non-fasting blood samples. Altogether 443 major ischaemic heart disease events (fatal and non-fatal) occurred during the study. Men in the highest fifth of the distribution of total cholesterol concentration (greater than or equal to 7.2 mmol/l) had 3.5 times the risk of ischaemic heart disease than did men in the lowest fifth (less than 5.5 mmol/l) after adjustment for high density lipoprotein cholesterol concentration and other risk factors. Men in the lowest fifth of high density lipoprotein cholesterol concentration (less than 0.93 mmol/l) had 2.0 times the risk of men in the highest fifth (greater than or equal to 1.33 mmol/l) after adjustment for total cholesterol concentration and other risk factors. Men in the highest fifth of triglyceride concentration (greater than or equal to 2.8 mmol/l) had only 1.3 times the risk of those in the lowest fifth (less than 1.08 mmol/l) after adjustment for total cholesterol concentration and other risk factors; additional adjustment for high density lipoprotein cholesterol concentration made the association with ischaemic heart disease disappear. CONCLUSIONS--Serum concentration of total cholesterol is the most important single blood lipid risk factor for ischaemic heart disease in men. High density lipoprotein cholesterol concentration is less important, and triglyceride concentrations do not have predictive importance once other risk factors have been taken into account.     

Flesinoxan Dose-Dependently Reduces Extracellular 5-Hydroxytryptamine (5-HT) in Rat Median Raphe and Dorsal Hippocampus Through Activation of 5-HT1A Receptors

Abstract: The effects of systemic administration of the serotonin (5-hydroxytryptamine) 5-HT_1A receptor agonists flesinoxan and 8-hydroxy-2-(di- n -propylamino)tetralin on extracellular 5-HT were measured using microdialysis probes in both median raphe nucleus and dorsal hippocampus. Both 5-HT_1A agonists dose-dependently decreased dialysate 5-HT levels from both brain regions. The effects of flesinoxan in the median raphe (0.3 mg/kg) and dorsal hippocampus (1.0 mg/kg) could be blocked by the 5-HT_1A receptor antagonist N -[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]- N -(2-pyridyl)cyclohexane carboxamide trihydrochloride (WAY 100,635) at a dose of 0.05 mg/kg s.c. The antagonist itself had no effect at this dosage. Local perfusion of flesinoxan for 30 min through the dialysis probe into the median raphe region at concentrations of 20, 100, and 1,000 n M resulted in a significant decrease in dialysate 5-HT content from both regions. The effect of 100 n M flesinoxan could be blocked by coperfusion of 1,000 n M WAY 100,635. The data indicate that flesinoxan is a potent 5-HT_1A receptor agonist and also support the notion that somatodendritic 5-HT_1A autoreceptors regulate both terminal and somatodendritic 5-HT release.     

Modulation of Ion Gradients and Glutamate Release in Cultured Cerebellar Granule Cells by Ouabain

Abstract: Upon addition of the cardiac glycoside ouabain to cultured cerebellar granule cells, an immediate increase in intracellular free sodium is evoked mediated by two pathways, a voltage-sensitive channel blocked by tetrodotoxin and a channel sensitive to flunarizine. Ouabain induces a steady plasma membrane depolarization in low Ca²⁺ medium; whereas in the presence of Ca²⁺, a distinct discontinuity is observed always preceded by a large increase in intracellular free Ca²⁺ ([Ca²⁺]_c). The plateau component of the increase can be inhibited additively by the L-type Ca²⁺ channel antagonist nifedipine, the spider toxin Aga-Gl, and the NMDA receptor antagonist MK-801. Single-cell imaging reveals that the [Ca²⁺]_c increase occurs asynchronously in the cell population and is not dependent on a critical level of extracellular glutamate or synaptic transmission between the cells. A prolonged release of glutamate is also observed that is predominantly Ca²⁺ dependent for the first 6–10 min after the evoked increase in [Ca²⁺]_c. This release is four times as large as that observed with 50 m M KCl and is predominantly exocytotic because release was inhibited by tetanus toxin, the V-type ATPase inhibitor bafilomycin, and Aga-Gl. It is proposed, therefore, that ouabain induces a period of membrane excitability culminating in a sustained exocytosis above that observed upon permanent depolarization with KCl.