Altered circadian relationship between serum nitric oxide, carbon dioxide, and uric acid in multiple sclerosis.

The free radical nitric oxide (NO*) is involved in a variety of diverse biological processes from acting as a vasodilator in the cardiovascular system to being the rate-limiting component in the production of peroxynitrite (ONOO-), a contributor to neurodegenerative disorders such as multiple sclerosis (MS). Uric acid (UA), the end product of purine metabolism in humans and a selective inhibitor of toxic reactions attributed to radicals formed by the interaction of ONOO- and CO2, is generally low in MS patients. We investigated the relationship between serum ONOO-, CO2, and UA in MS patients and normal controls by comparing the circadian characteristics of the NO* metabolites nitrite/ nitrate (NO), CO2, and UA. In this preliminary study, we found the functional relationship ascribed to the circadian timing of the peak and trough levels of NO, CO2, and UA in healthy subjects to be clearly altered in MS patients. These findings suggest that alterations in the temporal relationship between the 24h pattern in serum ONOO- formation and UA may either contribute to or reflect the disease processes in MS.

Circadian rhythm of serum total homocysteine in men.

Serum homocysteine levels were examined in a 24-hour study of 7 healthy and 5 diabetic men, revealing a statistically significant circadian rhythm (p = 0.030), normal concentrations of 11.83 +/- 1.2 vs 12.99 +/- 1.2 micromol/L, with peak values occurring during the evening (10:37 P.M.) and lowest levels occurring during the morning. These findings imply that increased atherosclerotic risk in insulin-resistant diabetics during morning hours does not appear to be explained by differences in homocysteine levels in the normal population.

Relation between circadian patterns in levels of circulating lipoprotein(a), fibrinogen, platelets, and related lipid variables in men.

BACKGROUND: A correlation has been reported between lipoprotein(a) [Lp(a)] concentration and risk for coronary artery disease. High concentrations of Lp(a) might be markers for vascular or tissue injury or might be associated with other genetic or environmental factors that can cause acute myocardial infarction. METHODS: We measured the circadian characteristics of circulating Lp(a), fibrinogen, platelets, cholesterol, triglycerides, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol for a group of adult male volunteers who had no clinical symptoms. We obtained samples every 3 hours around the clock to assess the normal degree of variation within a 24-hour period and to test for similarities in circadian patterns and correlations with level of Lp(a). RESULTS: Each variable displayed a highly significant circadian rhythm. Lp(a), fibrinogen, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol peaked in the morning. Cholesterol and platelets peaked in the late afternoon, and triglycerides peaked in the evening. CONCLUSIONS: Although peak levels of Lp(a) and fibrinogen coincide with reported morning peak frequencies of myocardial infarction and stroke, the platelet peak appears to coincide with late afternoon peak frequencies of sudden cardiac death and fatal stroke. The data suggest that proper timing of single samples may improve the usefulness and accuracy of diagnosis, risk assessment, and therapy.

Weekly and yearly rhythms in plasma fibrinogen in hospitalized male military veterans.

The variation in plasma fibrinogen level demonstrating prominent circaseptan and circannual cycles is clinically relevant. There is a correlation between increasing level of fibrinogen and other hemostatic factors and risk of myocardial infarction and sudden death. The circaseptan and circannual cycles in fibrinogen concentration described in this study may help to explain further the variation in frequency of coronary events. Furthermore, the recent demonstration of a circadian pattern in the efficacy of tissue plasminogen activator, with peak efficacy occurring at 2000 hours--10 hours after the peak incidence of myocardial infarction--implies that further patterns to coronary artery syndromes may be predicted and the treatment efficacy may rely on demonstrated circaseptan and circannual cycles of these events.

A quest for the relief of atherosclerosis: potential role of intrapulmonary heparin--a hypothesis.

Recent progress in the treatment of coronary artery disease is reviewed from the standpoint of changes in lifestyle, surgical techniques to revascularize the myocardium and a variety of medical interventions. Among the medical modalities, heparin appears to have a greater potential than any other agent tested to neutralize the atherogenic process at most of its stages. This potential is supported by success in clinical trials of heparin administered by intravenous, subcutaneous, pulmonary, sublingual and topical routes. The suggested self-administration of low-dose heparin by inhalation appears to be well justified and easily adaptable to home therapy. The summarized evidence suggests the need for further clinical trials to test the use of heparin in the prophylaxis of atherosclerotic disease.

Heparin as a therapy for atherosclerosis: preliminary observations on the intrapulmonary administration of low-dose heparin in the morning versus evening gauged by its effect on blood variables.

Reports on clinical trials with subcutaneous and intrapulmonary administration of low-dose heparin suggest that it may be an attractive therapeutic modality for the treatment of coronary artery disease because of unprecedented reduction in mortality of treated subjects. As a preliminary to a clinical trial with low-dose intrapulmonary heparin, a pilot study was conducted on three subjects. It compares overall circadian responses of 37 blood variables following intrapulmonary administration of heparin (10,500-18,800 U) in the morning (0800 h) and in the evening (2000 h). After each of these times, blood samples, mostly at 3 h intervals for the ensuing 27 h, were analyzed for heparin, APTT, TT, functional fibrinogen, CBC, enzymes, lipids, electrolytes, and hormones. Each time series was analyzed for circadian rhythm by the least-squares fit of a 24 h cosine and circadian mesors were compared by the Bingham test of rhythm parameters. Following heparin in the evening, but not in the morning, a statistically significant increase in circulating heparin levels, as well as directional increases in APTT and TT and decreases in fibrinogen, were observed in all three subjects. Same direction changes in several other variables were also observed. It is concluded that inhalation of heparin in low-dose levels results in variable circadian effects on blood parameters measured, ranging from no changes in their levels to minimal within normal range changes, and that these effects are dependent upon the timing of dose administration. It is suggested that the timed self-administration of low-dose heparin by inhalation be seriously considered for long-term clinical trials in the treatment and prevention of atherosclerosis.

Cocaine-induced arrhythmia in human foetal myocardium in vitro: possible mechanism for foetal death in utero.

We examined the acute in vitro effects of cocaine on cell membrane potentials and contractility of 12-16 week old human foetal heart, to better assess the potential for the induction of serious arrhythmia, in utero, by this abused substance. Ventricular preparations were maintained in a tissue bath, and continuously provided with oxygen and glucose during the measurement of membrane potentials with microelectrodes, and developed force of contractions with microforce transducers. Cocaine (600 ng/ml) had a significant effect on the ability of the heart to produce action potentials of normal rising velocity, amplitude, and duration. Within 90 min., all electromechanical activity had ceased. Under the conditions of our study, the effects of cocaine were reversible, however, reversibility in vitro may have no counterpart in utero, and irreversible loss of cardiac function may result.

A moderate concentration of ethanol alters cellular membrane potentials and decreases contractile force of human fetal heart.

The effects of ethanol, although well studied in the adult myocardium, have been little studied in fetal tissue. Experiments in pregnant animals suggest that ethanol compromises fetal myocardial performance, in utero; however, the physiological mechanism(s) remains obscure. The present report examines, in vitro, the effects of a moderate concentration of ethanol (20 mM) directly on cell membrane potentials and contractility of human fetal left ventricle as determined using intracellular microelectrodes and microforce transducers. We observed significant decreases in action potential amplitude, upstroke velocity, duration of repolarization, and the force of contractions. These effects were reversible. As ethanol crosses the placenta, our findings suggest that moderate concentrations of ethanol, as occur during 'social drinking', may temporarily compromise fetal myocardial performance in utero.

Coronary risk factors and exercise test performance in asymptomatic hypercholesterolemic men: application of proportional hazards analysis.

The association of established coronary risk factors with submaximal graded treadmill exercise test performance was examined in 6,850 asymptomatic, white 34--59-year-old hypercholesterolemic men screened between 1973 and 1976 at 12 North American Lipid Research Clinics for participation in their Coronary Primary Prevention Trial. The prevalence of ischemic electrocardiographic responses (greater than or equal to 1 mm S-T segment depression) was 8.6%. The Cox proportional hazards method was adapted so as to take into account the level of exercise at which ischemic responses occurred and to which subjects without ischemic responses were exposed. The results were compared with those obtained by standard logistic regression. In both models, age, blood pressure, plasma cholesterol, and (inversely) plasma high-density lipoprotein cholesterol and alcohol consumption were significant independent predictors of an ischemic response to exercise. Surprisingly, ischemic responses were less frequent in smokers than in nonsmokers. However, when the proportional hazards method was used, cigarette smoking was weakly but significantly (p less than 0.01) predictive of an ischemic response on the treadmill. Results from this model differed from those of the logistic model because the former takes into account the reduced exercise capacity of smokers, which renders them less likely to reach workloads sufficient to induce myocardial ischemia. The proportional hazards model similarly demonstrated a possible beneficial effect of habitual physical activity which was not apparent in the logistic model. Quetelet index and plasma triglyceride were only weakly associated with the probability of an ischemic response, and did not contribute significantly to either model.

Treatment of life-threatening digitalis intoxication with digoxin-specific Fab antibody fragments: experience in 26 cases.

Purified Fab fragments of digoxin-specific antibodies obtained from sheep were used to treat 26 patients with advanced, life-threatening digoxin (23 cases) or digitoxin (3 cases) toxicity. These patients had advanced cardiac arrhythmias, and in some cases hyperkalemia, which were resistant to conventional treatment. All patients had an initial favorable response to doses of Fab fragments calculated (in most cases) to be equivalent, on a molar basis, to the amount of cardiac glycoside in the patient's body. In four patients treated after prolonged hypotension and low cardiac output, death ensued from cerebral or myocardial hypoperfusion. In one case the available Fab fragment supply was inadequate to reverse a massive suicidal ingestion of digoxin, and the patient died after recurrent ventricular arrhythmias. In the remaining 21 patients, cardiac rhythm disturbances and hyperkalemia were rapidly reversed, and full recovery ensued. There were no adverse reactions to the treatment. We conclude that the use of purified digoxin-specific Fab fragments is a safe and effective means to reverse advanced, life-threatening digitalis intoxication.

Increased plasma fibrinogen and platelet-aggregates in type II hyperlipoproteinaemia.

Plasma fibrinogen and platelet-aggregates (method of Wu and Hoak) were measured in 21 patients with familial Type II hyperlipoproteinemia and 21 matched control subjects. Patients with hyperlipoproteinaemia had increased levels of fibrinogen and platelet-aggregates (p less than 0.01). Young patients with hyperlipoproteinaemia had prematurely high fibrinogen levels, and the normal rise in fibrinogen during adult life was abolished. There were no statistically significant correlations within the patient group between fibrinogen, platelet-aggregates, and plasma lipids. High fibrinogen and platelet-aggregate levels may play a part in the development of the premature arterial disease associated with Type II hyperlipoproteinaemia, or may be markers of arterial injury.

Radiation effects of iodine-125 and iodine-131 on the overactive rat thyroid.

The effects of graded doses of iodine-125 and iodine-131 on rat thyroid glands under prolonged stimulation with oral thyrotropin-releasing hormone were assessed by histological and autoradiographic studies. No evidence for a difference in effect between iodine-125 and iodine-131 was found. The reason for this is suggested.

Regulation of cholesterol synthesis in the hyperlipoproteinaemias. Polymorphonuclear leucocyte abnormality specific to familial type II hypercholesterolaemia.

A simple procedure has been devised to give virtually pure preparations of polymorphonuclear leucocytes. This has permitted study of the regulation of cholesterol biosynthesis at cell level. Freshly isolated cells from donors with various forms of hyperlipoproteinaemia have been shown to have very low levels of cholesterol synthesis, presumably due to high circulating levels of apoprotein-B in donor plasma [1]. The activity of the rate-limiting enzyme for cholesterol biosynthesis, 3-hydroxy-3-methylglutaryl coenzyme A reductase, rapidly increases as the cells are incubated in lipoprotein-deficient medium, until, by 12 h, cells from patients heterozygous for familial type IIa hypercholesterolaemia are clearly distinguished from other hyperlipoproteinaemias. The possible significance of this finding is discussed in relation to the causation and treatment of atherosclerotic disease.

Hypothalamo-pituitary-thyroid axis function during cardiopulmonary bypass.

Marked alterations in levels of circulating thyroid hormone were found in patients undergoing cardiopulmonary bypass with a rise in the free thyroxine and a fall in the free triiodothyronine levels. Studies using thyrotropin-releasing hormone during bypass demonstrated a blunted response to this stimulus. This reduced response is related to changes in thyroid hormone levels and it is suggested that bypass surgery may have a direct inhibitory action on thyroid-stimulating hormone release at the hypothalamo-pituitary level. The potential significance of these hormonal changes is discussed.

Anterior pituitary response to thyrotrophin-releasing hormone during open-heart surgery.

The anterior pituitary response to thyrotrophin-releasing hormone has been studied in 20 patients submitted to elective open-heart surgical procedures, and in six control patients submitted to closed mitral valvotomy. Standard non-pulsatile normothermic perfusion was used in all the open-heart cases. 400 microgram thyrotropin-releasing hormone was administered by intravenous injection during bypass, at 30 min post-bypass, and at 60 min post-bypass. The same dose (400 microgram) was given during closed mitral valvotomy (Control Group). Thyrotrophin-releasing hormone administration during bypass failed to produce a normal response from the anterior pituitary, in contrast to the normal response pattern seen in the control group (P less than 0.01). Thyrotrophin-releasing hormone given after the period of bypass produced responses within the normal range in the majority of patients. These results suggest that anterior pituitary hypofunction may exist during the period of extracorporeal circulation using non-pulsatile perfusion and that recovery of pituitary function is evident within the first hour post-extracorporeal circulation.

Massive digoxin ingestion. Report of a case and review of currently available therapies.

Recent reports of treatment of massive digoxin overdosage have emphasized the success of medical therapy. This report describes a fatal outcome to this problem despite aggressive medical management, including pervenous cardiac pacing and draws attention to deficiencies in current treatment of a serious problem.