Anergy in patients with leukocytosis

To confirm and clarify a previously found association between anergy and leukocytosis, patients with leukocyte counts above 15,000/mm³ were tested with five intradermal antigens, challenged with dinitrochlorobenzene (DNCB) and croton oil, and their lymphocytes studied in vitro. Of 32 patients with leukocytosis, 8 were unresponsive to all antigens; none of these 8 could be sensitized to DNCB, and only 3 had lymphocytes responsive to phytohemagglutinin. Only one was lymphopenic, and croton oil elicited weak or negative responses in five. Concurrent disease included pancreatitis, pneumonia, sepsis, urinary tract infection, abscess and endocarditis. Although quite ill, none had uremia, known malignancy or miliary tuberculosis, and none was taking immunosuppressive medications. Our evidence suggests that the anergy associated with leukocytosis may be an acute defect in lymphocyte function rather than a transient depression of the inflammatory response, and that leukocytosis may be a common clinically significant cause for depressed delay hypersensitivity in acutely ill patients.     

The role of glucagon in the regulation of plasma lipids.

The role of glucagon in regulating plasma lipid concentrations (nonesterified fatty acids, ketone bodies, and triglycerides) is reviewed. The effects of glucagon-induced insulin secretion upon this lipid regulation are discussed that may resolve conflicting reports in the literature are resolved. In addition, the unresolved problem concerning the pharmacologic versus physiologic effects of glucagon is stressed. Glucagon's role in stimulating lipolysis at the adipocyte serves two important functions. First, it provides plasma nonesterified fatty acids for energy metabolism and secondly, it ensures substrate for hepatic ketogenesis. In vitro, glucagon's lipolytic activity has been consistently observed, but in vivo, this activity has sometimes been obscured by the effects of glucagon-induced insulin secretion. Frequently, a biphasic response has been reported in which a direct lipolytic response is followed by a glucagon-induced insulin suppression of plasma nonesterified fatty acid concentration. When the glucagon-induced insulin secretion has been controlled by various in vivo techniques, glucagon's lipolytic activity in vivo has frequently been demonstrable. In the 1960s, in vitro liver perfusion experiments demonstrated that glucagon enhanced hepatic ketogenesis independent of glucagon's lipolytic activity. However, this direct effect of glucagon on the hepatocyte was not universally accepted because of conflicting reports in the literature. Failure to observe an in vitro ketogenic effect of the hormone in some studies may have been due to suboptimal experimental conditions. Certain factors are now known to influence the ketogenic response, such as the concentration of fatty acids in the media and the nutritional status of the animal. Under optimal in vitro conditions with liver preparations from fed animals, the ketogenic response to physiologic concentrations of glucagon has been demonstrated. However, further study is necessary to define the quantitative ketogenic role of the hormone. In spite of this early in vitro work, glucagon was not definitely shown to be ketogenic in vivo (independent of fatty acid availability) both in the rat and in diabetic man until 1975. Since these observations, several reports have confirmed the ketogenic action of glucagon in vivo by direct hepatic catheterization experiments. Glucagon's role in decreasing hepatic triglyceride synthesis and secretion in vitro has been repeatedly shown but the mechanism is unresolved. This lipid regulatory action of glucagon has been more difficult to demonstrate in vivo because of the many variables that affect triglyceride synthesis. Under specific experimental conditions, however, glucagon has been shown to decrease plasma triglyceride concentration in man at both physiologic and pharmacologic concentrations. Hepatic catheterization experiments have also confirmed this effect in man. The regulation of lipids by glucagon fits well into its role as a stress hormone...     

Leukocyte intracellular cations in hypertension: Effect of antihypertensive drugs

Leukocyte (WBC) cations were determined in 32 normotensive control subjects and in 47 agematched patients with uncomplicated hypertension. The intracellular concentration of sodium (Na⁺) which averaged 25.5 mEq./Kg. wet cell weight (wcw) in the hypertensive patients was significantly higher (P <.01) than in the control subjects (average 19.7 mEq./Kg. wcw). Elevated WBC Na⁺ was observed only in the hypertensive patients under age 50 years. WBC potassium, magnesium, and percentage water content were not significantly different in hypertensive patients as compared to the control subjects. The finding of an increased intracellular Na⁺ content in hypertensive patients is consistent with recent observations relating the extracellular/intracellular Na⁺ gradient to vascular smooth muscle tension and to the control of the peripheral vascular resistance.WBC cations also were determined after treatment with hydrochlorothiazide, hydralazine, reserpine, or alpha methyldopa. Hydrochlorothiazide was associated with a reduction in WBC sodium content (P < .01). Reserpine also was associated with a lesser fall in WBC sodium (P < .05). Cell water content decreased slightly after hydrochlorothiazide (P < .05), but increased slightly following reserpine (P < .05). Changes in WBC, sodium, or water were not significant following alpha methyldopa or hydralazine. None of the drugs were associated with changes in WBC potassium or magnesium, although serum potassium concentration decreased significantly (P < .05) with hydrochlorothiazide.     

Short-term influences of dichloroacetate on genetically hyperlipemic rats

The effects of short-term (7 days) administration of dichloroacetate (DCA) on carbohydrate and lipid metabolism in the Zucker obese and lean rat were investigated. Metabolic effects of the drug were more pronounced in the obese than in the lean rat. DCA decreased fasting blood glucose concentrations in both lean and obese rats, but more so in the fat animals, probably because of higher initial levels. The hypoglycemic action of DCA is likely attributable to a direct effect on liver and peripheral tissues and not to an indirect action caused by a decrease in the glucagon-to-insulin ratio because the drug induced just the opposite effect. DCA decreased plasma triglycerides (TG) and free fatty acids (FFA) in the hyperlipemic rats but not in lean rats. Intrahepatic triglyceride content diminished after drug treatment in fat rats, suggesting decreased hepatic TG synthesis. Hyperketonemia, induced in both lean and fat rats by DCA treatment, was also greater in the obese animal. This response was probably caused by accelerated hepatic ketone body production due to increased β-oxidation, and not to enhance FFA substrate supply. These data demonstrate that DCA is capable of correcting many of the underlying abnormalities in carbohydrate and fat metabolism in the obese Zucker rat.     

Effect of clofibrate on arginine-stimulated glucagon and insulin secretion in man

Insulin and glucagon have been reported to have opposing effects upon the mechanisms regulating serum triglyceride concentration. Glucagon in excess of insulin will lower serum lipids in man. In the present studies, we have examined the possibility that a change in glucagon and insulin regulation might contribute to the hypolipemic action of the drug clofibrate. Control insulin and glucagon secretion were evaluated in 24 normal subjects by intravenous arginine infusion, which resulted in a prompt rise in both serum immunoreactive insulin and glucagon concentration. During the maximum rise in concentration of these hormones, plasma triglyceride concentration was acutely reduced from basal levels of $\text{104 ± 6}\text{mg}\text{100}\text{ml}$ to $\text{75 ± 5}\text{mg}\text{100}\text{ml}$ (p ≤ 0.001). Following 7 days of clofibrate therapy, basal plasma triglyceride concentration attained a new mean level of $\text{78 ± 5}\text{mg}\text{100}\text{ml}$, while basal insulin and glucagon concentrations remained unchanged. However, arginine infusion now resulted in a reduction of the insulin secretory response to 56% of the preclofibrate studies with an associated normal glucagon secretory response. Serum triglyceride concentration was further reduced during arginine infusion to $\text{46 ± 3}\text{mg}\text{100}\text{ml}$, demonstrating this minimum level as maximum plasma glucagon levels were attained, representing an excess of this hormone relative to the reduced insulin concentration. These observations are consistent with an effect of clofibrate on the hormonal regulation of triglyceride physiology in man. Glucose tolerance was unimpaired by clofibrate therapy in these normal subjects, in spite of an apparent reduction in glucose-stimulated insulin secretion.     

Artifacts in portable electrocardiographic monitoring.

The development of portable ECG monitoring techniques has brought with it new insights into the electrical activity of the heart, and new problems in interpretation of artifacts. This article summarizes and classifies 15 different types of artifacts observed from dynamic electrocardiography. The artifacts appear partly as pseudo-arrhythmias mimicking supraventricular, ventricular, junctional, and dissociative rhythms. There are also non-arrhythmic artifacts which can be misleading in the interpretation of Q-waves, S-T-segments, and T-waves. Eight of the 15 artifacts have potentially serious consequences if not understood, and in 2 instances an artifact almost led to the unnecessary implantation of an artificial cardiac pacemaker.     

Electrophysiologic effects of propranolol on sinus node function in children

Little is known regarding the effects of propranolol (P) on sinus node function in children. In this study, corrected sinus node recovery time (CSNRT) and estimated sinoartial conduction time (SACT) were measured in 10 children (ages 3 to 16 years; mean 8.3 years) without clinical evidence of sinus node dysfunction before and after intravenous P. The spontaneous sinus cycle length (SCL) increased after P(0.1 mg/kg) in all patients. Mean SCL increased 13.4% from 635 ± 200 msec (± SD) to 720 ± 202 msec (p < 0.01). Maximum CSNRT increased in nine patients after P and mean CSNRT increased 63% from 203 ± 61 msec to 330 ± 190 msec (p < 0.05). SACT changed in a random fashion after P. Mean SACT did not change significantly. We conclude that P significantly suppresses sinus node automaticity in children with normal sinus node function but has little or no effect on sinoatrial conduction.     

Open clinical studies at a referral center: Chronic maintenance tocainide therapy in patients with recurrent sustained ventricular tachycardia refractory to conventional antiarrhythmic agents

Chronic maintenance tocainide therapy was effective in controlling symptomatic, recurrent ventricular tachycardia in 11 of 15 patients. Patients were selected for tocainide therapy on the basis of refractoriness to conventional antiarrhythmic agents and responsiveness to the intravenous administration of lidocaine. Side effects were frequent but could usually be managed by taking the drug with meals or by more frequent administration of smaller doses. Survival, frequency of symptomatic tachycardia, frequency of asymptomatic ventricular tachycardia, and tolerance of the therapeutically effective dosage were the criteria used to assess therapeutic effectiveness. Factors common to the response group included primary and secondary Q-T prolongation before therapy, a paradoxical increase in ventricular ectopic activity with quinidine-like medications, and shortening of the Q-T interval with maintenance tocainide therapy. These factors may prove to be useful in identifying the patients who are most likely to benefit from chronic maintenance tocainide therapy.     

New nitrate delivery systems: Buccal nitroglycerin

BN, a new nitrate formulation, has recently been made available. The main advantages of this medication is the combination of prompt onset of action, comparable to that of sublingual NTG, and sustained activity that persists for many hours. The tablet remains pharmacologically effective as long as it remains in the buccal pouch. A variety of studies indicate that BN is well tolerated by patients, acts promptly to provide protection against anginal pain, and has sustained efficacy that persists for 2 to 6 hours. Clinical investigations using serial treadmill testing in patients with angina demonstrate clinical effectiveness and bioactivity of BN beginning within minutes and lasting over 4 hours. The potential advantages of this preparation are discussed, and the formulation is compared to other available longacting nitrates. BN is an effective new addition to the nitrate armamentarium.