Comparative measurements of glucose, beta-hydroxybutyrate, acetoacetate, and insulin in blood and cerebrospinal fluid during starvation

The possibility that altered central nervous system (CNS) metabolism is reflected by changes in the constituents of the cerebrospinal fluid (CSF) was investigated. From eight obese subjects undergoing total starvation for weight reduction, overnight and 21-day fasting specimens of venous blood and lumbar CSF were obtained nearly simultaneously to determine the concentrations of glucose, beta-hydroxybutyrate (β-OHB), acetoacetate (AcAc), and immunoreactive insulin (IRI). After 21 days of starvation, the glucose concentration fell in both blood and CSF. The decrease in blood glucose was greater than the decline in CSF glucose, resulting in a diminished blood-CSF difference. Concentrations of β-OHB and AcAc in blood and CSF were elevated after prolonged fasting, but blood levels exceeded those in CSF, producing an increased blood-CSF ketone body difference. After an overnight and 21-day fast, the IRI levels in CSF were about one-half of the serum levels. These data suggest that metabolic alterations in CNS metabolism during prolonged starvation are reflected in substrate concentrations observed in CSF, and demonstrate that insulin is presented in the CSF of man.     

Substrate,hormone, and temperature responses in males and females to a common breakfast

To evaluate the response to a mixed meal we studied oral temperature, metabolite, and hormonal responses to a common American breakfast containing 11 kcal/kg body weight (carbohydrate 43%, fat 42%, and protein 15%) in 12 normal volunteers (6 males and 6 females). There was a significant rise in oral temperature during the postcibal period. This change in oral temperature did not depend upon food consumption in males but was meal-dependent in females. Food ingestion caused increases in the peripheral circulating concentrations of glucose, lactate, pyruvate, and amino acids and reciprocal decreases in the concentrations of free fatty acids, glycerol, and urea nitrogen. Acetoacetate and beta-hydroxybutyrate decreased during the postcibal period but the changes were not statistically significant. Although peripheral venous serum insulin and plasma glucagon concentrations were indistinguishable between the sexes, males had higher concentrations of plasma triglycerides, plasma amino acids, and serum urea nitrogen. Peripheral venous plasma somatostatin and secretin remained unchanged, but pancreatic polypeptide hormone showed a large biphasic response to the meal. After breakfast the blood glucose concentration tended to be greater in males than in females and this difference was significant at 60 and 120 min postcibal. Furthermore, every female had a 120 min postcibal glucose concentration that was lower than her basal fasting glucose concentration. This suggests that postcibal glucose concentrations should be related to gender in making the diagnosis of carbohydrate intolerance or reactive hypoglycemia.     

Mebendazole and insulin secretion from isolated rat islets

In a preliminary communication we reported that mebendazole, a vermicide, decreased plasma glucose and free fatty acid concentrations and increased plasma C peptide concentrations in both type II diabetic patients. Therefore, we suggested that mebendazole was an insulin secretagogue. However, these were uncontrolled studies, and improved metabolic control in these patients due to spontaneous remission rather than drug-induced insulin secretion was a possibility. To investigate the direct effect of mebendazole on insulin secretion we used intact islets isolated from normal rat pancreata. Mebendazole in concentrations as low as 10 to 20 mumol/L caused a twofold to threefold increase in acute-phase insulin release from isolated perifused rat islets. This heightened insulin release occurred in the presence of glucose-stimulated insulin secretion.     

Pseudomalfunction of a Beall mitral valve prosthesis in the presence of paravalvular aortic regurgitation.

Premature closure of a Beall mitral valve prosthesis is described in a patient with aortic prosthetic paravalvular regurgitation. Differentiation from valvular malfunction and diagnostic confirmation by means of cinefluoroscopy and simultaneous electrocardiography are discussed.     

Acquired "storage pool disease" of platelets associated with circulating antiplatelet antibodies

This study reports the first example of acquired “storage pool disease” in a patient with nephritis, polyarthralgia, chondritis, thrombophlebitis, Raynaud's phenomenon and circulating antiplatelet antibodies. Studies of platelet function showed a long bleeding time, decreased aggregation to collagen, thrombin and adenosine diphosphate (ADP), and depleted platelet stores of ADP and serotonin. These findings are similar to those found in a congenital disorder of platelets characterized by a deficiency of the storage pool of adenine nucleotides and serotonin. It is suggested that in this patient the circulating antibodies induced a release of the storage pools of adenine nucleotides and serotonin of the circulating platelets, leading to a state of defective hemostasis. The patient responded well to steroid therapy, and platelet function returned to normal concomitant with the disappearance of the antiplatelet antibodies. It is possible that “storage pool disease” with or without a thrombotic tendency may occur in other acquired disorders, especially the myeloproliferative disorders and those associated with circulating antibody.     

Relapsing polychondritis with insulin resistance and antibodies to cartilage

Described here is a patient with typical relapsing polychondritis in whom insulin-resistant diabetes mellitus was associated with high titers of insulin antibody. Widespread immunologic dysfunction was demonstrated including the presence of antinuclear antibody and a probably biologic false-positive fluorescent treponemal antibody absorbed (FTA-ABS) test. In addition, anticartilage antibody activity was found by indirect immunofluorescence. The substructure and antigenicity of cartilage in animal models and in our patient are discussed.     

Left ventricular performance in patients with coexistent mitral stenosis and aortic insufficiency

Isolated mitral stenosis and isolated aortic insufficiency impose unique and opposite loading conditions on the left ventricle. To assess these combined effects, hemodynamic and angiographic factors were compared among normal subjects and patients with isolated mitral stenosis, isolated aortic insufficiency or combined mitral stenosis and aortic insufficiency. Left ventricular end-diastolic volume index was lower in patients with combined lesions and severe or moderate aortic insufficiency than in patients with isolated severe or moderate aortic insufficiency (138 +/- 19 versus 206 +/- 20 cc/m2 and 87 +/- 5 versus 145 +/- 22 cc/m2, respectively) (p less than 0.05 for both). Left ventricular end-diastolic and end-systolic volume indexes were normal in two-thirds of patients with combined lesions and moderate or severe aortic insufficiency, whereas these indexes were high in all but one patient with isolated moderate or severe aortic insufficiency. Among patients with moderate or severe aortic insufficiency, 8 of 14 with isolated insufficiency had a reduced ejection fraction or circumferential fiber shortening rate compared with 5 of the 9 patients with combined lesions. Among patients with isolated aortic insufficiency, left ventricular end-systolic wall stress and end-diastolic and end-systolic volume indexes were higher (p less than 0.05) in those with reduced ejection performance than in those with normal ejection performance. These variables did not differ between patients with reduced or normal ejection performance in the group with combined lesions. The contractile index (ratio of end-systolic wall stress to end-systolic volume index) was significantly depressed in patients with severe aortic insufficiency in the groups with isolated aortic insufficiency or combined lesions.(ABSTRACT TRUNCATED AT 250 WORDS)     

Repeated hospitalization for diabetic ketoacidosis. The game of "Sartoris"

Repeated hospital admission is a serious problem for both the patient and the health care system. The life story of a patient repeatedly admitted for treatment of exacerbations of a chronic disease, such as diabetic ketoacidosis, can often be compared to Faulkner's family Sartoris. The Sartoris characters were wholly occupied in the pursuit of their painful decline and eventual demise. At the Johns Hopkins Hospital, 45 persons were identified who were repeatedly admitted to the medical service for diabetic ketoacidosis. Forty-two charts of "recidivist" patients and "non-recidivist" control patients matched for age and severity of disease were reviewed to determine factors that, if corrected, would prevent repeated admission. Case reports of three patients who were admitted an average of 11 times annually for several years are presented. Implications of the "Game of Sartoris" for the American teaching hospital are discussed.     

Acute and long-term hemodynamic effects of oral pirbuterol in patients with chronic severe congestive heart failure: randomized double-blind trial

In 20 patients with severe congestive heart failure (CHF), we studied the effects of the beta-adrenergic agonist pirbuterol compared to placebo in both an acute double-blind randomized trial and after long-term treatment. Acutely, pirbuterol patients (n = 10) demonstrated a significant rise in cardiac index (2.2 +/- 0.14 to 3.2 +/- 0.32 L/min/m2), stroke index (26 +/- 2.6 to 35 +/- 2.9 ml/beat/m2), stroke work index (22 +/- 2.4 to 30 +/- 2.7 gm X m/m2), and ejection fraction (22 +/- 4 to 30 +/- 5%). These hemodynamic variables did not significantly change in placebo patients (n = 10). After 3 weeks of pirbuterol therapy, 14 patients (70%) were symptomatically improved and were continued on the drug for another 3 weeks; 13 of 14 patients who were symptomatically improved underwent restudy. Compared to pretreatment baseline, there was continued improvement in cardiac index (2.5 +/- 0.16 to 3.2 +/- 0.24 L/min/m2), stroke index (30 +/- 2.5 to 38 +/- 2.9 ml/beat/m2), stroke work index (26 +/- 2.3 to 35 +/- 3.1 gm X m/m2), and ejection fraction (24 +/- 1 to 28 +/- 4%). Patients more frequently improved were those with nonischemic cardiomyopathy and those with higher initial ejection fractions. These results demonstrate the acute beneficial effects of oral pirbuterol versus placebo in a double-blind randomized trial. Improvement was maintained during long-term therapy in the majority of CHF patients.     

Quinidine pharmacokinetics in patients with cirrhosis or receiving propranolol.

Quinidine pharmacokinetics (half-life, volume of distribution, and clearance) as well as protein binding were evaluated following a single 200 mg. oral dose of quinidine sulfate in eight control patients, in eight patients with moderate to severe cirrhosis, and in seven patients receiving 40 to 400 mg./day of propranolol. Patients with cirrhosis had a significantly longer quinidine half-life (9 +/- 1 hr; p less than .01) when compared to control patients (6 +/- 0.5h). This was not related to a reduced quinidine clearance rate but rather to an increase in quinidine volume of distribution (4.1 +/- .4 L./Kg. in cirrhotic patients vs 2.6 +/- 1 L./Kg. in control patients; p less than .01). Abnormal quinidine binding (greater than 25 per cent unbound fraction) was noted in seven of the eight cirrhotic patients. In contrast, patients receiving propranolol had a normal quinidine half-life of 6 +/- 0.5 hr. However, these patients had a significantly reduced quinidine clearance (3.3 +/- .7 ml./min./Kg. vs. 5.3 +/- .5 ml./min./Kg. in controls; p less than .05) and higher peak concentrations (1.25 +/- .20 micrograms/ml. vs. .80 +/- .5 micrograms/ml. in controls; p less than .05). Therefore in patients receiving propranolol, quinidine levels may be higher than expected shortly after dosage, and therefore a potential for transient toxicity exists in these patients. Maintenance quinidine dosage may have to be reduced in patients with moderate to severe hepatic cirrhosis, but not in patients receiving propranolol. Total quinidine concentration measurement underestimate free quinidine concentrations in most cirrhotic patients.     

Alkalemia in diabetic ketoacidosis

A patient with a history of diabetes mellitus and congestive heart failure was taking furosemide and metolazone as diuretics. Diabetic ketoacidosis developed, and the patient became lethargic and confused. Initial biochemical determinations showed an alkalemic pH, serum and urine ketones with an anion gap, and hyperventilation. The hyperventilation was appropriate for the degree of ketoacidosis but it was grossly inappropriate for the alkalemia. This could be explained by a direct effect of ketones on the respiratory center or a sudden increase in hydrogen ion concentration superimposed on previously chronic alkalemic pH due to the potent combination of furosemide and metolazone.     

Cardiac function in sickle cell anemia

Although ventricular dysfunction is suspected to underlie congestive heart failure in sickle cell anemia (SCA), ejection indexes of left ventricular (LV) pump performance have been found to be normal. The increased preload and decreased afterload of SCA increases the ejection phase indexes and might obscure true LV dysfunction. Therefore, the preload and afterload independent end-systolic stress-volume index was compared in 11 patients with SCA and in 11 normal volunteers. End-systolic pressure and echocardiographic LV dimensions were determined during rest, leg raise, hand-grip and amyl nitrite inhalation. Systemic vascular resistance (afterload) was decreased to 1,033 ± 314 dynes s cm⁻⁵ (mean ± standard deviation) in SCA from 1,701 ± 314 dynes s cm⁻⁵ in normal subjects. End-diastolic volume index (preload) was increased to 102 ± 24 ml/m² in SCA from 66 ± 10 ml/m² in normal subjects. Cardiac index was increased to 4.7 ± 1.1 liters/min/m² in SCA from 2.8 ± 0.8 liters/ min/m² in normal subjects. Ejection fractions were similar: 0.59 ± 0.09 in SCA versus 0.62 ± 0.07 in normal subjects. However, in patients with SCA, the ratio of resting end-systolic stress-volume index was decreased (1.5 ± 0.5 in SCA versus 2.8 ± 0.6 in normal subjects) and the slope of the end-systolic stress versus end-systolic volume index relation was decreased (2.7 ± 1.3 in SCA versus 4.4 ± 1.8 in normal subjects), suggesting LV dysfunction in those patients. Thus, LV muscle contractile performance is depressed in SCA. Increased preload and decreased afterload compensate for the LV dysfunction and maintain a normal ejection fraction and high cardiac output.     

Hyperglucagonemia in diabetic ketoacidosis. Its prevalence and significance

The prevalence of hyperglucagonemia was studied in twenty-six consecutive patients admitted to Dallas hospitals in diabetic ketoacidosis. Plasma glucagon averaged 390 pg/ml, ranging from 120 to 1,290 pg/ml, significantly greater than the fasting level of 118 pg/ml in diabetic subjects without ketoacidosis. Absolute hyperglucagonemia, i.e., levels over 240 pg/ml, was present in sixteen; all had “relative hyperglucagonemia.” Glucagon levels declined after four hours of therapy and were normal at discharge. The plasma glucagon level was significantly correlated with the blood glucose level, respiratory rate and hours of insulin therapy required to correct the ketonemia. Patients with absolute hyperglucagonemia required significantly more insulin than patients without absolute hyperglucagonemia.The results indicate that glucagon excess is present in most patients hospitalized with diabetic ketoacidosis and are compatible with the view that glucagon, an insulin-opposing hormone, may increase the severity of the disease and its insulin requirements.     

Galactose metabolism and its regulation

Galactose, a constituent of milk sugar, is a major source of calories in the young as well as an important component of glycolipids and glycoproteins. The conversion of galactose to glucose is mediated by a series of four enzymes. Deficiency of the first two enzymes of the Leloir pathway are associated with two clinical entities: galactokinase deficiency galactosemia and uridyl transferase deficiency galactosemia. The latter condition in which phosphorylation by the galactokinase takes place is the more severe clinical state. Regulation of galactose metabolism in the higher organism has been examined from the point of view of genetic, developmental, and enzymatic considerations. The genetic heterogeneity encountered with both the galactokinase and unridyl transferase is explored. The developmental pattern of the enzymes involved in galactose metabolism are reviewed along with studies involving excretion of ¹⁴C-galactose, which negate the impression that patients with transferase deficiency demonstrate increasing ability to dispose a galactose with advancing age. Four alternate pathways of galactose utilization are discussed, with particular emphasis on explaining the ability of Caucasion galactosemics, who have no detectable transferase activity to excrete small amounts of CO₂ after galactose administration. The control characteristics of the enzymes of the Leloir pathway are examined, with reference to the relationship of substrate and cofactor levels acting as constraints on this pathway. Finally, animal models of galactosemia are discussed and their heuristic value is considered.