Attenuation of exercise conditioning by low dose beta-adrenergic receptor blockade

Because it has been shown that high doses of propranolol (40 to 80 mg orally, four times daily) markedly attenuate cardiovascular response to exercise training in healthy subjects, the effects of lower doses of this nonselective beta-adrenergic receptor antagonist on the conditioning response were investigated. Twelve normal men underwent maximal treadmill testing before and after a 6 week intensive exercise program. After an initial test, six men were randomized in a paired fashion to receive low dose propranolol and the others received no drug. The average propranolol dose +/- standard error was 22 +/- 4 mg four times daily, and the average decrease in maximal heart rate due to propranolol was 32 +/- 4 beats/min. Both groups trained at comparable intensities. At the end of the training period, propranolol was stopped and testing was repeated so that the effect of beta-receptor blockade was no longer present but the training effects still persisted. Maximal oxygen consumption increased in control subjects from 47.5 +/- 1.1 to 51.4 +/- 0.4 ml/kg per min (p less than 0.05) but was unchanged in those receiving propranolol (47.2 +/- 1.9 versus 47.4 +/- 1.5). Exercise duration increased in both groups but the increment was greater in the control group (+2.4 versus +1.1 min, p less than 0.05). It is concluded that low level beta-receptor blockade attenuates cardiovascular conditioning in normal subjects in exercise training programs. High levels of sympathetic stimulation during training appear to be important, if not essential, to the conditioning process.     

Balloon embolization to occlude a Blalock-Taussig shunt

Balloon embolization was used to successfully occlude a large residual Blalock-Taussig shunt. The use of an "upstream" nondetachable balloon catheter to reduce flow and turbulence during final positioning of the detachable balloon may have made the technique safer and more precise.     

Effect of beta-adrenergic blockade on circulating catecholamines and dopamine-beta-hydroxylase activity during exercise in normal subjects

We investigated the effects of beta-adrenergic blockade with propranolol (P) on circulating catecholamines at rest and during isometric and dynamic exercise. By means of a radioenzymatic assay, we measured plasma norepinephrine (NE) and epinephrine (E) concentrations in nine normal, sedentary men, aged 22 to 34 years. Measurements were made during resting conditions, at 3 minutes of 30% maximal isometric handgrip exercise (IHE), and during submaximal and maximal dynamic treadmill exercise. Measurements were repeated one week later after the subjects received P in doses ranging from 40 to 80 mg four times a day (plasma P levels at the time of exercise ranged from 96 to 303 ng/ml with a mean of 178 ng/ml). We also measured serum dopamine-beta-hydroxylase (DBH) activity to detect changes in chronic sympathetic tone. Changes in NE from rest to exercise were significant (p less than 0.01) at all exercise loads with or without P. Changes in E from rest to exercise were significant (p less than 0.01) at all exercise loads with or without P except for submaximal dynamic exercise during the control study (p greater than 0.05). For NE, there were no significant differences between the control and P values either at rest or during any form of exercise. For E, there were no significant changes between the control and p values at rest or at maximal dynamic exercise, although there were mild increases (p less than 0.05) with IHE and submaximal dynamic exercise. DBH activity increased significantly (p less than 0.01) from rest to exercise for all exercise points with and without P, but there were no significant differences between the control and p values either at rest or during any form of exercise. In conclusion, we have demonstrated that competitive blockade of beta-adrenergic receptors at the tissue level does not alter neural release of NE or DBH and has little effect on adrenal release of E.     

Efficacy,safety, and pharmacokinetics of a concentration-maintaining regimen of intravenous pirmenol

A 3-stage, concentration-maintaining intravenous infusion regimen of pirmenol, a new antiarrhythmic agent, was tested for efficacy and safety in 8 subjects with chronic, stable premature ventricular beats. The regimen, which consisted of (1) a priming bolus of 50 mg over 2 minutes, followed by (2) a rapid loading infusion of 2.5 mg/min for 1 hour, and (3) a maintenance infusion of 0.25 mg/min, rapidly achieved and maintained stable plasma pirmenol levels from 0.94 to 2.75 μg/ml, during infusions lasting up to 48 hours. Therapeutic efficacy was evaluated during 4-hour infusions in 5 patients utilizing a randomized, double-blind, placebo-controlled study design. Pirmenol suppressed average premature ventricular beat frequency 93 ± 6% compared with control values (p = 0.03). Pirmenol infusions were unassociated with toxicity. There were slight but significant increases in diastolic blood pressure, QRS duration, and corrected Q-T interval. No significant changes occurred in systolic blood pressure, heart rate, P-R interval, or laboratory variables. Pirmenol is a promising therapeutic agent that warrants further evaluation. The 3-stage infusion satisfactorily achieves and maintains therapeutic plasma pirmenol levels.     

Hyperlipidemia in adult, pediatric and diabetic renal transplant recipients.

Serum cholesterol and triglyceride concentrations were measured and lipoprotein electrophoreses were performed on serum samples from 175 adult, 19 pediatric and 11 diabetic transplant recipients and from 102 healthy volunteer subjects. Serum lipids were also measured in 14 patients prior to and for 40 weeks following transplantation. p]The mean serum cholesterol and triglyceride concentrations were greater in all three groups of transplant recipients than in the healthy volunteer subjects but there were no differences in serum lipids between any two of the transplant recipient groups. Sixty-one per cent (125) of the patients had hyperlipidemia. Lipoprotein electrophoreses demonstrated that the hyperlipoproteinemia was heterogeneous, 26 per cent (46) of the patients had type IV hyperlipoproteinemla, 23 per cent (39) type 11b and 11 per cent (19) type 11 A. Serum lipid concentrations in patients receiving alternate-day corticosterold therapy were not different from those receiving daily corticosterold therapy. Positive correlations were found between serum triglyceride concentrations and the daily prednlsone dosage, relative body weight, serum creatinine and blood glucose concentrations. No correlation was found between prednlsone dosage and the latter three variables. A positive correlation was also found between serum triglycerides and relative body weight in the healthy volunteer subjects, but for any given body weight serum triglycerides were significantly greater in the transplant recipients. Transplant recipients with hypercholesterolemla were receiving a larger prednisone dosage than those with normal serum cholesterol levels. Serum cholesterol and triglyceride levels became abnormal within eight weeks of transplantation and remained abnormal throughout the remaining 32 weeks during which these patients were followed. Correlations were found between serum cholesterol and triglyceride levels and the cumulative dose of prednisone during this 40 week period.It is concluded that hyperllpidemla is very common in renal transplant recipients, is a mixture of types 11 A, 11B and IV hyperlipoprotelnemla, is equally prevalent in diabetic, pediatric and adult transplant recipients and is not diminished by the use of alternateday cortlcosteroids. Prednisone dosage, obesity and the degree of Impairment of graft function appear to be responsible for hypertriglycerldemia; prednlsone dosage appears to be responsible for hypercholesterolemla. Serum lipid abnormalities develop within eight weeks of transplantation and can be related to the cumulative dose of prednisone in the early post-transplant period.     

Arterial calcification and pathology in uremic patients undergoing dialysis.

Arterial samples obtained from uremic patients were compared with those obtained from nonuremic control subjects. Arteries from the uremic patients showed fibrous or fibroelastic intimai thickening, calcification of the internal elastic lamella, medial ground substance and medial elastic fibers, and disruption and reduplication of the internal elastic lamella. Lipid deposition was seen infrequently. The calcium concentrations of the arteries of the patients were greater than those of the control subjects. Correlations were found between the degree of intimai thickening and the duration of renal disease, and between arterial calcification and both the duration of hypertension and the duration of renal disease. In the control subjects, positive exponential correlations were found between age and arterial calcium concentrations, but at any age the calcium concentration was greater in the aorta than in the other arteries.This study has demonstrated that pathologic changes are extremely common in the arteries of uremic patients, that calcification is an integral part of this disease process and that, despite hyperlipidemia, lipid deposition is not an initiating factor. The changes seen probably represent an acceleration of the normal arterial aging process. This study has also shown that the disease seen may be, in part, related to the duration of uremia and to the duration of hypertension. It is likely that the arterial disease seen in uremia is a result of a summation of the many atherogenic risk factors present in these patients.     

Cimetidine-drug interactions

The use of cimetidine, the histamine H2 receptor antagonist, is associated with a relatively low incidence of adverse reactions. However, its liberal use has led to the identification of several clinically significant cimetidine-drug interactions that can lead to drug accumulation, toxicity, and life-threatening sequelae. A review of the literature and the clinical significance and physiologic basis of these interactions are presented. Recommended management of cimetidine-drug interactions is discussed.     

Anticytoplasmic antibodies in antinuclear antibody-negative lupus erythematosus. Correlation with clinical course

A patient with clinical manifestations of systemic lupus erythematosus (SLE) and without antinuclear antibodies was found to have anticytoplasmic antibodies. These anticytoplasmic antibodies were directed against ribosomal ribonucleoprotein, and the titer of anticytoplasmic and anti-ribosomal ribonucleoprotein antibodies correlated with the clinical course of the patient's illness. The importance of detecting anticytoplasmic antibodies and their role in producing disease in patients with SLE is discussed.     

Carpal tunnel syndrome as the initial manifestation of tuberculosis.

Two patients presenting with carpal tunnel syndrome as the initial manifestations of tuberculosis were seen during a recent four month period at a larg city-county hospital. Although the clinical picture of the carpal tunnel syndrome was typical, a definite diagnosis could not be made until the time of surgery because of the many other causes of the carpal tunnel syndrome. A review of the experience with musculoskeletal tuberculosis and carpal tunnel syndrome at our hospital indicates that although this combination is not common, it is one of the treatable causes of the carpal tunnel syndrome. A review of the literature substantiates this impression.     

Central, renal and adrenal effects of lithium in man.

The effect of lithium on thirst and plasma vasopressin concentration was tested in seven subjects with affective psychiatric disorders. Mean ad libitum fluid intake was liberal but no different before (3,293 ml/day) and three to four weeks after treatment with lithium (3,443 ml/day). After fluid deprivation, plasma vasopressin was 1.5 ± 0.39 pg/ml before and 3.72 ± 0.55 pg/ml after treatment with lithium (p < 0.02) as plasma osmolalities and body weights were comparable. Urinary osmolalities were no different (735 versus 759 mOsm/kg) and did riot increase with exogenous vasopressin. With a water load, plasma vasopressin decreased 1.58 to 0.79 pg/ml (p < 0.05) before and from 2.68 to 0.91 pg/ml (p < 0.025) after treatment with lithium. The water load excreted in 4 hours was less during lithium therapy (66 versus 85 per cent, p < 0.05). Lithium therapy had no effect on plasma renin activity (PRA) or aldosterone. On standing, PRA increased from 2.27 to 5.28 ng/ml/hour (p < 0.05) before and from 2.19 to 7.59 ng/ ml/hour (p < 0.05) after lithium therapy. At the same time plasma aldosterone increased from 121 to 365 pg/ml (p < 0.05) before and from 76 to 436 pg/ml (p < 0.05) after treatment with lithium. Lithium had no effect on indices of proximal tubular function (HCO₃^?, HPO₄⁼, glucose, amino acid and uric acid excretion). A lower titratable acid excretion (21 ± 5 versus 32 ± 4 μeq/min, p < 0.05) and higher urine pH (5.40 versus 5.02, p < 0.05) was observed after NH₄Cl ingestion during lithium therapy as compared to control. In conclusion, three to four weeks of lithium therapy neither stimulates thirst nor suppresses vasopressin release; some of the polyuria in patients with affective disorders may be due to their liberal fluid intakes. Lithium does not alter base line or standing PRA, aldosterone or proximal tubular function. Lithium does, however, induce an incomplete renal tubular acidosis.     

Effect of a glucosidase inhibitor on the metabolic response of diabetic rats to a high carbohydrate diet,consisting of starch and sucrose,or glucose

The metabolic consequences of the addition of BAY-g-5421 to a diet whose caloric value included 67% carbohydrate, comprising wheat starch (diet A), equal quantities of wheat starch and sucrose (diet B) or glucose (diet C) were studied in lean diabetic and non-diabetic rats. BAY-g-5421 led to a significant (30%) reduction in daily food intake of diabetic and non-diabetic rats fed diets A and B, respectively. In diabetic rats fed diets A and B with BAY-g-5421, daily urinary glucose was diminished ten-fold, while the post-prandial plasma glucose excursions were almost halved. Serum cholesterol, but not triglyceride concentrations, were reduced after five days, by the addition of BAY-g-5421 to diets A or B in non-diabetic rats, and in diabetic rats when the animals fed diets A and B were combined. BAY-g-5421 did not significantly alter the food intake, urinary glucose excretion, post-prandial plasma glucose excursions nor serum lipids in diabetic and non-diabetic rats fed diet C. These findings illustrate the therapeutic potential of BAY-g-5421 as an adjunct to the dietary management of diabetes mellitus.     

Pharmacokinetics of verapamil: Experience with a sustained intravenous infusion regimen

Disappearance kinetic characteristics of verapamil were determined in 9 patients after a single intravenous dose. From the pharmacokinetic variables determined, we designed an intravenous regimen to maintain a plasma verapamil concentration of 150 ng/ml consisting of (1) a loading bolus (10 mg over 2 minutes), followed by (2) a rapid loading infusion (0.375 mg/min) for 30 minutes, and finally (3) a maintenance infusion (0.125 mg/min). We tested this regimen in 7 patients for 2 to 12 hours, and found it to be safe and to produce stable prolongation of the P-R interval. Verapamil concentration was highest immediately after the bolus administration and was prevented from falling below 67 ng/ml by the rapid infusion. Maintenance concentration remained between 77 and 156 ng/ml for all patients, and averaged 122 ng/ml.Transient and slight decreases in brachial blood pressure and sinus cycle length occurred coincident with the maximum verapamil concentration. Maximum P-R prolongation lagged behind peak plasma concentration but was sustained for the duration of the infusion. Prolongation of the P-R interval was not significantly different at the end of the infusion from that 90 minutes after the start of the regimen. No patient demonstrated significant side effects, arrhythmia, or clinically important hypotension. Although the specified regimen produced a final concentration averaging 125 ng/ml, it is predicted that infusion regimens producing other plasma concentrations can be similarly devised by changing the bolus, rapid loading infusion, and maintenance infusion doses in proportion to the desired final plasma concentration.     

Familial leukemia and aplastic anemia associated with monosomy 7

A kindred is described in which eight of 14 patients in one generation had acute nonlymphocytic leukemia or aplastic anemia either alone or terminating in acute nonlymphocytic leukemia. The proband and two siblings in one branch of this kindred presented with aplastic anemia, whereas acute nonlymphocytic leukemia was the presenting feature in the other two branches. Karyotypic evolution from a normal karyotype to monosomy 7 was demonstrated in the proband, and group C monosomy was seen in two other patients. The proband's serum sample inhibited in vitro growth of normal bone marrow colonies. The occurrence of hematologic disease in this kindred appears to be the result of a maternally transmitted trait, and persons younger than 30 years of age appear to have the highest risk of hematologic disease.     

Successful treatment of brucella melitensis endocarditis

Brucella endocarditis is a rare, but often fatal, complication of brucellosis. A 32 year old man acquired brucellosis while on a visit to his former home in Greece and presented six months later with malaise, fever and aortic regurgitation. Blood cultures grew Brucella melitensis biotype 1. Combined chemotherapy with streptomycin, tetracycline and rifampin sterilized his blood; however, his aortic valve was replaced owing to recurrent emboli and cardiac failure. Over the next 18 months the patient's antibody titer to Brucella fell and his blood remained sterile. Cure was achieved by resection of the infected aortic valve and 10 weeks of bactericidal therapy for B. melitensis.     

Immune complexes in primary biliary cirrhosis: Higher prevalence of circulating immune complexes in patients with associated autoimmune features

A longitudinal study, examining the levels of immune complexes serially for three years, in serum from 88 patients with primary biliary cirrhosis was performed by the Raji cell radioimmunoassay. Studies of the association of autoimmune features in primary biliary cirrhosis and the effect of D-penicillamine therapy in relation to the levels of complexes were carried out. Twenty-two patients (25 percent) were found to have autoimmune features, such as Sjögren's syndrome, rheumatoid-like arthritis, scleroderma, Raynaud's disease, and Hashimoto's thyroiditis. In this subset of patients with primary biliary cirrhosis, a significantly higher prevalence (86 percent) of circulating immune complexes was detected compared with those patients showing no autoimmune features (60 percent). In addition, patients with associated autoimmune features had higher mean levels of immune complexes (259.7 μg AHG eq/ml) compared with those without autoimmune features (202.1 μg AHG eq/ml). The mean levels of complement C4, reflecting activation of classic complement pathway, were significantly lower in patients with elevated immune complexes and associated autoimmune features. The mean level of immune complexes in 13 patients receiving D-penicillamine, in contrast to the placebo group, decreased at one year but subsequently was greater than the initial level. Patients who had normal levels of immune complexes and received penicillamine therapy continued to have complex levels within the normal range for up to three years of follow-up study, but patients receiving placebo showed significantly elevated levels at subsequent intervals. Thus, levels of immune complexes in primary biliary cirrhosis may reflect the association with autoimmune features.     

Cardiac complications of wegener granulomatosis: A case report of complete heart block and review of the literature

Wegener granulomatosis is a necrotizing vasculitis whose target organs are classically the upper and lower respiratory tracts and the kidneys. There has been other end-organ involvement documentation, emphasizing the disseminated nature of this disease, but the literature concerning cardiac involvement is limited. The few case reports and general reviews show that the two most common histologic cardiac manifestations are pericarditis and coronary arteritis, each occurring in 50% of the reported cases. The most frequent clinical manifestation is cardiac arrhythmias that are manifested as supraventricular tachyarrhythmias. We report an unusual cardiac manifestation, a case of complete heart block, occurring during the active stage of Wegener granulomatosis. The problem this case presented and the management are reported. The literature dealing with the cardiac involvement in Wegener granulomatosis is reviewed, and the specific histopathologic findings and the pathophysiologic mechanisms of this involvement are discussed.     

Primary cutaneous inoculation drug-resistant tuberculosis

A laboratory technician with a previously negative tuberculin reaction punctured her thumb with a needle containing drug-resistant tuberculous organisms while performing guinea pig inoculation. Diagnosis was established 8 weeks after the initial injury by culture of the excised tissue. Complete resolution of the tuberculous process was accomplished with surgery and chemotherapy. The patient never had a positive tuberculin reaction, and this presumably was due to early chemotherapy.     

Mechanisms of insulin resistance in obesity and noninsulin-dependent (type II) diabetes

Insulin resistance is a characteristic feature of both obesity and noninsulin-dependent diabetes mellitus. In general, the causes of insulin resistance can be placed into three categories: (1) abnormal beta cell secretory products, (2) circulating insulin antagonists, and (3) target tissue defects in insulin action. In obesity and in noninsulin-dependent diabetes mellitus, the cause of the insulin resistance resides at the level of the target tissue. However, the specific mechanisms underlying these insulin-resistant states are heterogeneous. Mechanisms of insulin resistance can be evaluated by constructing in vivo dose-response curves using the euglycemic glucose clamp technique. If dose-response curves are shifted to the right with no impairment in maximal insulin action, then this is termed a decrease in “insulin sensitivity” and is consistent with a pure defect in insulin receptors. If a decrease in maximal insulin action exists, then this is termed a decrease in “insulin responsiveness” and is consistent with a postreceptor defect in insulin action. In obese patients, cellular insulin receptors are decreased and the magnitude of this decrease is inversely related to the degree of hyperinsulinemia. In those patients with only moderate hyperinsulinemia, the insulin resistance is not severe. In these patients, the in vivo dose-response curve between plasma insulin levels and glucose disposal demonstrates a rightward shift with no change in maximal insulin responsiveness. Thus, in this situation, insulin resistance is due to decreased insulin receptors only. In obese patients, with more severe insulin resistance, decreased maximal insulin responsiveness is also seen indicating a combined receptor and postreceptor defect. In patients with noninsulin-dependent diabetes mellitus, the same phenomenon is observed; i.e., those patients with mild insulin resistance have decreased insulin sensitivity due to decreased insulin receptors whereas those with severe insulin resistance have decreased insulin sensitivity and decreased insulin responsiveness due to a combined receptor and postreceptor defect. When the spectrum of patients is examined, a continuum of defects exists. In patients with mild insulin resistance, decreased insulin receptors are the only abnormality; in patients with severe insulin resistance, decreased numbers of insulin receptors and the postreceptor defect in insulin action coexist, but the postreceptor defect is the predominant abnormality. Between these extremes the relative roles of receptor defects and postreceptor defects vary, but the general trend is that as insulin resistance worsens, the postreceptor defect becomes more prominant.