Showing papers in "Journal of Clinical Investigation in 1967"

Brain Metabolism during Fasting

Abstract: Catheterization of cerebral vessels in three obese patients undergoing 5-6 wk of starvation demonstrated that beta-hydroxybutyrate and acetoacetate replaced glucose as the predominant fuel for brain metabolism. A strikingly low respiratory quotient was also observed, suggesting a carboxylation mechanism as a means of disposing of some of the carbon of the consumed substrates.

Plasma Insulin Responses to Oral and Intravenous Glucose: Studies in Normal and Diabetic Subjects*

Abstract: The plasma insulin responses of normal weight and obese, diabetic, and nondiabetic subjects to intravenous glucose was only 30-40% of that seen after oral glucose, indicating that alimentary mechanism(s) in addition to the arterial blood sugar concentration regulate insulin secretion. Observations made in subjects with diverted portal circulation indicate that the alimentary insulinogenic mechanism is located in the intestinal tract. The insulinogenic potency of the alimentary and glycemic stimuli expressed in terms of insulin secretion per gram of glucose were remarkably similar within each group of individuals. Between these groups, however, there were considerable differences. Obesity, with or without associated diabetes, was associated with a true hypersecretory responsiveness, whereas diabetes was characterized, with or without obesity, by a marked impairment in insulin secretion. The experimental design used in these studies permitted quantitation of the magnitude of the glycemic component of an oral glucose load. As a consequence of impaired insulin secretion, a greater than normal proportion of the oral glucose load escapes initial hepatic extraction in the maturity-onset diabetic and enters the peripheral circulation. Therefore, in the noninsulin-requiring maturity-onset diabetic, the glycemic insulinogenic stimulus for a given oral glucose load is significantly greater than in normal subjects and accounts for the excessive plasma insulin responses observed late in the course of an oral glucose tolerance test.

In Vitro Bactericidal Capacity of Human Polymorphonuclear Leukocytes: Diminished Activity in Chronic Granulomatous Disease of Childhood

Abstract: Diminished bactericidal capacity was found to be characteristic of polymorphonuclear leukocytes (PMN) from five children with the clinical syndrome of granulomatous disease of childhood. The PMN from these children demonstrated nearly normal phagocytic capacity, and the majority of viable bacteria, after 2 hours of incubation in the phagocytosis system, were found associated with leukocytes. The morphology of the unstimulated polymorphonuclear leukocytes from patients with chronic granulomatous disease was similar to those from normal persons of similar ages by light and electron microscopy. In addition, the total lysozyme and phagocytin activity of leukocyte extracts from these patients was similar to those from equal numbers of leukocytes from controls.A striking difference in the cytoplasmic response after phagocytosis characterized the PMN of the patients with granulomatous disease. Whereas degranulation, vacuole formation, and rapid bacterial digestion were the rule in the PMN from controls, little degranulation and persistence of intact bacteria in the cytoplasm characterized disease. The deficiency of bactericidal capacity and the minimal degranulation after active phagocytosis by the PMN of these children with an inherited syndrome suggest that separate metabolic processes are involved in phagocytosis and in intracellular digestion. Continuing study of the metabolic function of leukocytes from these children should provide an opportunity for increased understanding of the metabolic basis for degranulation and intracellular digestion in phagocytic cells.

Insulin Secretion in Response to Glycemic Stimulus: Relation of Delayed Initial Release to Carbohydrate intolerance in Mild Diabetes Mellitus*

Abstract: Insulin secretory responses to paired intravenous and oral glucose loads were determined in 38 nonobese individuals classified as normal (nondiabetic) subjects, "mild" diabetics (fasting blood glucose below 105 mg per 100 ml), or "moderate" diabetics (fasting glucose below 192 mg per 100 ml). Studies were also performed in 29 obese persons who were similarly grouped. The intravenous load was given to assess the alacrity of hormonal release after glycemic stimulus, and the oral glucose to determine how the speed of initial insulinogenesis modifies the disposition of ingested carbohydrate. In the nonobese group, normal subjects responded to massive hyperglycemia after rapid injection of glucose with immediate and maximal outpouring of insulin, in contrast to a desultory insulinogenic response in patients with mild diabetes, and no initial response at all in moderate diabetics. During oral glucose tolerance tests, the much faster clearance of blood sugar in nondiabetic subjects was actually associated with lower absolute insulin output than was found in mildly diabetic patients, since the latter exhibited delayed hyperinsulinemia in concert with prolonged hyperglycemia. Moderate diabetics never showed excessive insulin release despite even greater hyperglycemia. An empirical "insulinogenic index," the ratio relating enhancement of circulating insulin to magnitude of corresponding glycemic stimulus, was used to compare the secretory capacities of respective groups. Despite the higher absolute hormonal output after oral glucose in mild diabetics, the index revealed that insulin release in normal subjects was proportionally more than twice as great. This relatively greater normal secretory response declared itself shortly after the administration of glucose by either route, and was maintained throughout both tests. In the 29 obese individuals, differences among groups were essentially the same as in persons of normal weight. Obese nondiabetics did show much larger absolute insulinogenic responses during both tests than did nonobese controls. Since corresponding glucose tolerance curves were also higher, the mean insulinogenic indexes for obese subjects were not statistically greater. Moreover, when comparable glucose curves of obese and nonobese controls

The Significance of Basal Insulin Levels in the Evaluation of the Insulin Response to Glucose in Diabetic and Nondiabetic Subjects

Abstract: The level of insulin after an overnight fast (basal) in 37 obese and nonobese male subjects with normal and abnormal carbohydrate tolerance was directly related to the increase in insulin concentration during a 3 hr 100 g oral glucose tolerance test. Obesity, but not diabetes, was associated with an elevation of this basal insulin level. Thus obesity predicted with the magnitude of the insulin response to glucose ingestion. When the individual insulin values were expressed as per cent change from the basal level, this effect of obesity was excluded. The insulin levels of all subjects with normal carbohydrate tolerance promptly rose 5-7-fold, and reached peak values 1 hr after oral glucose. In contrast, the diabetic response (as per cent increase) was markedly reduced during the 1st hr, and maximal (but still subnormal) insulin levels were not attained until 2 hr. In all subjects the insulin response (quantitated by calculation of the area circumscribed by a plot of the per cent change in insulin with time) showed a significant inverse correlation with the glucose response. Thus increasing degrees of carbohydrate intolerance were associated with decreasing insulin responses. Elevated levels of insulin, in both the basal state and in response to glucose, were related to obesity.

Studies of the Metabolic Activity of Leukocytes from Patients with a Genetic Abnormality of Phagocytic Function

Abstract: Polymorphonuclear leukocytes from patients with chronic granulomatous disease respond to the phagocytosis of latex particles with normal increments in glucose consumption, lactate production, Krebs' cycle activity, and lipid turnover. The leukocytes of these patients fail to show normal increments in respiration, direct oxidation of glucose, and hydrogen peroxide formation during particle uptake. It appears that the stimulation of respiration with the formation of hydrogen peroxide and stimulation of the direct oxidative pathway of glucose metabolism are closely linked to degranulation and intracellular killing of bacteria by polymorphonuclear leukocytes.

Role of Insulin in Endogenous Hypertriglyceridemia

Abstract: Dietary carbohydrate accentuation of endogenous triglyceride production has been studied in 33 patients. A broad and relatively continuous spectrum of steady-state plasma triglyceride concentrations was produced in 31 of the 33 subjects during 3 wk of a high carbohydrate (fat-free) liquid formula diet. Two patients developed plasma triglyceride concentrations in excess of 2000 mg/100 ml, and these were the only patients we have studied in which carbohydrate induction of hypertriglyceridemia seemed to be associated with a defect in endogenous plasma triglyceride removal mechanisms. In the remaining 31 patients the degree of hypertriglyceridemia was highly correlated with the insulin response elicited by the ingestion of the high carbohydrate formula (P < 0.005). No significant correlation existed between fasting plasma triglyceride concentration and either plasma glucose or free fatty acid concentrations after the high carbohydrate diet, nor was the degree of hypertriglyceridemia related to degree of obesity. It is suggested that hypertriglyceridemia in most subjects results from an increase in hepatic triglyceride secretion rate secondary to exaggerated postprandial increases in plasma insulin concentration.

Radioimmunoassay for Luteinizing Hormone in Human plasma Or Serum: Physiological Studies*

Abstract: It is not practical to quantitate gonadotropin in the blood of normal men and women by utilizing bioassays. We have developed a method for sensitive, precise, and specific radioimmunoassay of luteinizing hormone (LH) in human serum or plasma. Antisera were developed against human chorionic gonadotropin, and one of these was selected for extensive cross-reaction with human LH. Highly purified LH was radioiodinated by the method of Greenwood, Hunter, and Glover. Separation of antibody-bound from free LH-131I was accomplished by a double antibody technique. Dose-response curves for the purifed LH, an impure urinary LH preparation, pituitary powder, and LH in plasma were all identical. Immunoassay and bioassay of impure urinary and pituitary gonadotropin preparations in terms of a common standard resulted in an index of discrimination of close to unity. LH levels in plasma from 32 adult men and 30 women outside the midcycle ranged from 0.6 to 3.2 mμg per ml (1 mμg of our laboratory LH standard is equivalent to 8 mU of the Second International Reference Preparation of Human Menopausal Gonadotropin). Levels were remarkably constant in men from day to day and in women except at midcycle, when a sharp peak occurred lasting less than 24 hours. In all women studied who had a midcycle LH peak, mean plasma LH levels during the follicular phase of the menstrual cycle were higher than mean values obtained during the luteal phase. Prepubertal children had detectable plasma LH, and mean values were only slightly less than in adults. Plasma from castrate men or women or postmenopausal women contained 4.5 to 10.5 mμg per ml. Clomiphene treatment of four men resulted in a doubling of plasma LH in 5 days.

A Receptor Mechanism for the Inhibition Of Insulin Release by Epinephrine in Man

Abstract: Normal adult men and women have been infused with epinephrine, 6 mug per minute, during lipolytic blockade with nicotinic acid, beta-adrenergic blockade with propranolol and Butoxamine, and alpha-adrenergic blockade with phentolamine. Epinephrine infusion was associated with low serum levels of immunoreactive insulin (IRI) except when phentolamine was given simultaneously. These findings are compatible with an alpha receptor mechanism for the epinephrine inhibition of insulin release. Phentolamine had no blocking effects on the tachycardia and widened pulse pressure or lipolytic stimulation by epinephrine, whereas both propranolol and Butoxamine blocked lipolysis, tachycardia, and widened pulse pressure. These findings are consistent with an alpha receptor blocking action for phentolamine and beta receptor blocking action for propranolol and Butoxamine. Inhibition of lipolysis by nicotinic acid did not alter IRI or glucose responses to epinephrine. It is concluded that the lipolytic effect of epinephrine is unrelated to its effects on IRI release. Lipolytic blockade by nicotinic acid also did not change IRI or glucose in fasting subjects or their responses to a glucose infusion, 300 mg per minute. These observations appear to conflict with the Randle hypothesis (the glucose-fatty acid cycle) and raise some doubt as to whether plasma FFA concentrations are direct determinants of glucose or IRI concentrations in normal man.

Influence of the Thyroid State on the Intrinsic Contractile Properties and Energy Stores of the Myocardium

Abstract: The intrinsic contractile properties of isolated cat papillary muscles and myocardial high energy phosphate stores were examined at three levels of thyroid activity and correlated with hemodynamic measurements in the intact animal. In addition, the relationship of thyroid state to endogenous norepinephrine stores and myocardial responsiveness to certain inotropic interventions were studied. In muscles from hyperthyroid cats, the velocity of shortening and the rate of tension development were markedly augmented, while duration of active state was decreased, compared to euthyroid muscles. These findings occurred in the presence and absence of intact norepinephrine stores and over a wide range of temperature and contraction frequency. The opposite changes occurred in muscles from hypothyroid cats. Isometric tension was slightly higher in muscles from hyperthyroid and lower in muscles from hypothyroid cats. The inotropic response to both norepinephrine and strophanthidin varied inversely with the level of thyroid state and allowed all three groups of muscles to reach a common ceiling of isometric tension regardless of thyroid state. Creatine phosphate and adenosine triphosphate stores were intact at all three levels of thyroid state. Thus, the level of thyroid activity profoundly affects the intrinsic contractile state of cardiac muscle, independent of both norepinephrine stores and alterations in high energy phosphate stores, and, in addition, modifies the responsiveness of cardiac muscle to inotropic agents.

Role of autonomic nervous system and the cough reflex in the increased responsiveness of airways in patients with obstructive airway disease.

Abstract: Inhalation of aerosols of citric acid, histamine phosphate, or carbon dust, or air cooled to - 20 degrees C or rapid respiratory maneuvers (inspiration or expiration) results in an increase in airway resistance in some patients with asthma or bronchitis It has been shown previously in animals that stimulation of cough receptors results in bronchoconstriction through efferent cholinergic pathways In the patients studied, the administration of atropine sulfate, which would block such pathways, abolished the bronchoconstrictor effects of all the stimuli except large doses of histamine, which may exert a direct effect on airway smooth muscle These data suggest that sensitized cough receptors may be involved in triggering reflex airway constriction in such patients

The Effects of Secretin, Pancreozymin, and Gastrin on Insulin and Glucagon Secretion in Anesthetized Dogs *

Abstract: The effects upon islet hormone secretion of highly purified preparations of secretin and of pancreozymin-cholecystokinin and of a crude gastrin-containing extract of hog antrum have been studied in acutely operated dogs. All three preparations were shown to cause a striking increase in insulin concentration in the pancreaticoduodenal venous plasma after their rapid endoportal injection in anesthetized dogs. With each hormone preparation, the peak in insulin secretion occurred 1 minute after injection, and a rapid decline was observed immediately thereafter. Whereas secretin and gastrin failed to alter significantly the pancreaticoduodenal venous glucagon or arterial glucose concentration, pancreozymin caused a dramatic rise in pancreaticoduodenal venous glucagon concentration, which reached a peak 3 minutes after injection, and hyperglycemia was noted to occur soon thereafter. Endoportal infusion of secretin and pancreozymin for 20 minutes caused responses that were sustained but qualitatively identical to the responses noted after rapid injection of the hormones. The beta-cytotropic effect of secretin was abolished by the infusion of epinephrine. These results could not be attributed to the small degree of contamination of the enteric hormone preparations with insulin or glucagon, and it would appear that secretin, pancreozymin, and probably gastrin have insulin-releasing activity and that pancreozymin has, in addition, glucagon-releasing activity. The demonstration that these three hormones possess insulin-releasing activity suggests that there is in the gastrointestinal tract a chain of betacytotropic hormones from antrum to ileum that is capable of augmenting insulin secretion as required for disposal of substrate loads. It is suggested that the existence of this “entero-insular axis” prevents high substrate concentrations that would otherwise follow ingestion of large meals were the insular response entirely a function of arterial substrate concentration.

A Possible Role for the Adenylcyclase System in Insulin Secretion

Abstract: A possible role for adenylcyclase in insulin secretion was investigated. Isoproterenol, a predominantly beta-adrenergic agent, when mixed with an alpha-adrenergic blocking agent (phenoxybenzamine), stimulated insulin secretion from pieces of the rat's pancreas in vitro. Theophylline, caffeine, 3'5'-cyclic AMP, glucagon, adrenocorticotropin (ACTH), and thyrotropin (TSH), all of which are thought to act through the adenylcyclase systems in the liver and adipose tissue, also stimulated insulin secretion in vitro; oxytocin and vasopressin, which do not stimulate lipolysis in adipose tissue, were inactive. In all cases, stimulation of insulin secretion could not be detected when glucose was absent or present in only low concentrations (less than 100 mg/100 ml) and was maximal at high levels of glucose (300 mg/100 ml). When pancreatic tissue was obtained from normoglycemic rats and contained no detectable glycogen in the Islets, the stimulant effects of glucose and of theophylline were reduced or abolished by mannoheptulose and 2-deoxyglucose. When tissue was derived from rats infused for 8-10 hr with glucose and contained glycogen, theophylline, even in the absence of glucose, stimulated secretion and this effect was reduced by 2-deoxyglucose but not by mannoheptulose. It is suggested that the beta-cell contains an adenylcyclase system through which phosphorylase and possibly phosphofructokinase could be activated; and that insulin secretion could depend upon and be regulated by hormones and other substances which influence the rate at which glycolysis proceeds within the beta-cell.

Studies of the Mechanism by Which Chronic Metabolic Acidosis Augments Urinary Calcium Excretion in Man

Abstract: Summary. We carried out clearance studies in nine healthy adults and four patients with hypoparathyroidism before and after inducing stable metabolic acidosis with either NHCl or acetazolamide. Clearances were repeated in seven normal subjects and three of the patients 3 days after stopping these agents. During acidosis in the normal subjects, serum ultrafilterable calcium concentration rose significantly, but inulin clearance fell to a greater extent, so that the calculated filtered load of calcium fell significantly. Despite this, urinary calcium excretion rose. Urinary calcium excretion remained elevated in the recovery studies when the serum ultrafilterable calcium concentration and filtered load of calcium had returned to control levels. Evidence is presented indicating that the increased calcium excretion which occurred during acidosis and recovery clearances was not due to natriuresis or to increased excretion of complexing anions. The comparable results in the four patients with hypoparathyroidism, two of whom also had hypothyroidism, suggest that the capacity to alter secretion rates of parathyroid hormone, thyrocalcitonin or both is not a critical determinant of the augmented rates of calcium excretion during acidosis. We conclude that metabolic acidosis produces increased urinary calcium excretion by causing decreased renal tubular calcium reabsorption. Evidence is presented which suggests that this is a direct effect of metabolic acidosis on metabolic processes within renal tubular cells.

Testosterone and Androstenedione Blood Production Rates in Normal Women and Women with Idiopathic Hirsutism or Polycystic Ovaries

Abstract: The average plasma testosterone concentration of women with either hirsutism or polycystic ovaries and hirsutism was higher (p < 0.01) than that of normal women although the ranges overlapped. Testosterone blood production rates averaged 830 +/- 120 SE and 1,180 +/- 310 SE mug per day in the two groups of hirsute women and 230 +/- 33 SE mug per day in normal women. The ranges did not overlap. The testosterone metabolic clearance rates of hirsute women (1,090 +/- 140 SE L per day) and of men (1,240 +/- 136 SE L per day) were significantly higher than those of normal women (590 +/- 44 SE L per day). These differences persisted when the metabolic clearance rates were corrected for surface area. We suggest that testosterone metabolic clearance rates vary directly with some function of testosterone production. The mean plasma androstenedione levels (2.8 +/- 0.35 SE and 2.8 +/- 0.30 SE mug per L) and production rates (6,060 +/- 450 SE and 7,360 +/- 345 SE mug per day) of the women with hirsutism or polycystic ovaries, respectively, were significantly higher than those of normal women (1.5 +/- 0.22 SE mug per L; 3,300 +/- 830 SE mug per day). The androstenedione metabolic clearance rates were the same in each group. Plasma androstenedione was the precursor of 49% of plasma testosterone in normal women and of 26% of plasma testosterone in hirsute women. Thus, 74% of the plasma testosterone in these subjects must have been either secreted or derived from a precursor that did not enter the plasma androstenedione pool.

Role of the Sympathetic Nervous System in Regulating Renin and Aldosterone Production in Man

Abstract: Several lines of evidence have been developed indicating that the sympathetic nervous system may play a role in mediating the renal and adrenocortical secretory responses to upright posture and sodium deprivation. Despite concurrent increases in arterial blood pressure, the plasma renin activity of normal subjects increased both in response to the infusion of catecholamines (norepinephrine: epinephrine, 10:1) and in response to stimulation of the sympathetic nervous system by cold. Aldosterone excretion was also increased by catecholamine infusion. In normal subjects the stimuli of upright posture and of sodium depletion both resulted in increases in urinary catecholamines, plasma renin activity, and urinary aldosterone. A patient with severe autonomic insufficiency did not experience normal elevations of urinary catecholamines, plasma renin activity, or urinary aldosterone in response to upright posture or sodium deprivation, despite a substantial fall in arterial blood pressure. When orthostatic hypotension was prevented by infusion of catecholamines, however, increases in plasma renin activity and in aldosterone excretion were observed. We suggest that both upright posture and sodium depletion lead to decreases in effective plasma volume and increases in sympathetic nervous system activity. This increase in sympathetic activity is then responsible for an increase in renal afferent arteriolar constriction, leading to an increase in renin secretion and, ultimately, an increase in aldosterone secretion.

Effects of Adrenergic Receptor Activation and Blockade on the Systolic Preejection Period, Heart Rate, and Arterial Pressure in Man

Abstract: We have investigated the possibility that alterations in the duration of the systolic preejection period can be used to estimate adrenergic influences on the human left ventricle. The preejection period was determined from high speed, simultaneous recordings of the phonocardiogram, carotid pulse tracing, and electrocardiogram. The preejection period was shortened by isoproterenol, epinephrine, and moderate doses of norepinephrine-all of which activate beta adrenergic receptors-and by cedilanid-D. It was unaltered by changes in heart rate induced by atropine and right atrial electrical pacing. Beta adrenergic receptor blockade by propranolol abolished the shortening effects of the three catecholamines but did not inhibit that due to cedilanid-D. Vasoconstriction, both alpha adrenergic (epinephrine and norepinephrine after propranolol) and nonadrenergic (angiotensin), prolonged the preejection period. Most of the shortening of the preejection period by beta adrenergic receptor activating agents and cedilanid-D and all of the prolongation accompanying pharmacologic vasoconstriction occurred after the onset of the first heart sound, thereby excluding changes in electrical-mechanical delay as a major factor in the observed preejection period responses. Shortening of the preejection period by beta adrenergic activity induced with isoproterenol was dose-related. Increasing doses of propranolol produced parallel shifts to the right in the isoproterenol dose-response curve. In 37 normal resting subjects intravenous propranolol (10 mg) prolonged the preejection period an average of 10 (SE +/- 1) msec. In six patients with psychogenic sinus tachycardia and a patient with a pheochromocytoma the presence of excessive beta adrenergic influences on the left ventricle was demonstrated by the finding of an initially short preejection period which responded with an abnormally great prolongation to beta adrenergic receptor blockade.

Sites of serum alpha-fetoprotein synthesis in the human and in the rat.

Abstract: Selected tissues from human embryos of 6 to 9 weeks' gestation, from rat fetuses of 15 days' gestation, and from rats 2 days of age were incubated with (14)C-labeled amino acids. Immunoelectrophoresis of the culture fluid after incubation, using rabbit antisera against human and rat fetal serum proteins, followed by radioautography revealed that: 1) Radioactive alpha-fetoprotein was present in cultures of human liver, rat liver, and rat yolk sac, but not in cultures of human or rat brain, lung, heart, kidney, intestines, skeletal muscle, skin, or placenta; human yolk sac was not studied. 2) Radioactive transferrin was also present in rat yolk sac cultures, and the same protein was found in rat liver cultures as well. 3) Rat liver and rat placenta cultures both produced radioactive serum Ralpha(2)-globulin. Serum alpha-fetoprotein concentrations in the rat declined abruptly after birth to approximately half of the prenatal level by 2 to 3 days of age, in accord with the loss of the fetal membranes at delivery; the alpha-fetoprotein level then remained relatively constant until the rat was 6 to 8 days of age, after which synthesis of the protein was increasingly suppressed.

The Role of Sodium-Potassium—Activated Adenosine Triphosphatase in the Reabsorption of Sodium by the Kidney*

Abstract: Summary. In order to evaluate the possible role of sodium- and potassiumactivated adenosine triphosphatase in the active transport of sodium by the renal tubules, we examined the effect of large changes in the tubular reabsorptive load of sodium on the Na-K-ATPase activity of rat kidney homogenates. Glomerular filtration and tubular reabsorption of sodium per gram of kidney tissue increased progressively after contralateral uninephrectomy. This was paralleled by an increase in Na-K-ATPase per milligram of protein in a microsomal fraction of kidney cortex. The importance of this change is underlined by the absence of simultaneous increases in other microsomal enzymes such as glucose-6-phosphatase and Mg++-dependent ATPase, or in succinic dehydrogenase or glutaminase. Similar increases in Na-K-ATPase were observed when the net tubular reabsorption of sodium was increased by feeding the animals a high-protein diet or after injection of methylprednisolone. On the other hand,-Na-K-ATPase was lowered when tubular transport of sodium was reduced by bilateral adrenalectomy. The results of these experiments show that renal Na-K-ATPase changes in an adaptive way when renal reabsorption of sodium is chronically increased or diminished and support the hypothesis that this enzyme system is involved in the process by

Regional Distribution of Pulmonary Ventilation and Perfusion in Obesity

Abstract: Five women and three men, all obese and weighing 95 to 140 kg, were studied by routine pulmonary function tests and by a radioactive xenon technique, while seated upright at rest, to measure the regional ventilation and perfusion distribution in the lung. In four subjects in whom the expiratory reserve volume averaged 49% of predicted normal, the ventilation distribution as measured with (133)xenon was normal. In the remaining four subjects, in whom the expiratory reserve volume was reduced to less than 0.4 L and averaged only 21% of predicted values, the distribution of a normal tidal breath was predominantly to the upper zones. In all subjects the perfusion distribution was predominantly to the lower lung zones but was slightly more uniform than in normal nonobese subjects. During tidal-volume breathing, therefore, in four subjects the ventilation and perfusion distribution was substantially normal, whereas in the remaining four perfusion was maximal in the lower zones, to which ventilation was significantly reduced. These findings show that there may be significant ventilation/perfusion abnormality on a regional basis in obese subjects, this abnormality bearing a close relationship to the reduction in expiratory reserve volume, a finding predictable from recently published data on normal nonobese subjects (1). The abnormalities of ventilation/perfusion relationships that were demonstrated in four of the eight obese subjects could cause a reduction in arterial oxygen tension during resting tidal ventilation.

Plasma Volume in Cirrhosis of the Liver: Its Relation of Portal Hypertension, Ascites, and Renal Failure

Abstract: Plasma volume was measured by using albumin-(131)I- and (51)Cr-labeled erythrocytes in 24 control subjects, 140 patients with hepatic cirrhosis, and 10 patients with various portal-systemic shunts for the relief of noncirrhotic portal hypertension. The cirrhotic patients included subgroups with ascites, functional renal failure, and portacaval anastomoses. Elevated values for plasma volume, by both methods, were found in each group of patients.The lymph space drained by the thoracic duct was measured by a radioisotopic technique in six patients with cirrhosis and ascites. The amount of radioactivity in this space was found to be negligible in accounting for the elevated plasma volume. Similar results were obtained when the degree of leakage of albumin-(131)I into the ascites was determined in 10 patients with cirrhosis.The plasma volume was unusually elevated in patients who had bled from esophageal varices, and paired comparisons before and after portacaval shunt normal values. There was a statistically significant correlation between normal values. There was a statistically significant correlation between plasma volume and wedged hepatic venous pressure measured in 36 patients.We concluded that the elevated values for plasma volume in cirrhosis are valid and are not artifacts due to leakage of albumin-(131)I from the circulation during mixing. We also concluded that portal hypertension is responsible for the plasma volume expansion; however, we were unable on this basis to explain the failure of portacaval shunting to return the plasma volume to normal, unless the shunt or some other factor keeps the plasma volume elevated.

The State of Copper in Human Serum: Evidence for an Amino Acid-bound Fraction

Abstract: In addition to copper bound to ceruloplasmin and to albumin, there is a third small fraction of copper in human serum that is bound to amino acids. The amino acid-bound fraction of copper is in equilibrium with albumin-bound copper, and both fractions are probably in equilibrium with ionic copper. Of the 23 amino acids that are known to be in human serum, a substantial number were shown (in physiological concentrations) to compete effectively with albumin for the binding of copper. In this respect, histidine had the most marked effect followed by glutamine, threonine, cystine, and others. The effect of the combined presence of 23 amino acids on the state of copper in human serum could not be explained on the basis of their individual abilities to compete with albumin for the binding of copper. It is suggested that copper may also be present in serum in the form of mixed amino acid-copper complexes consisting of one atom of copper and two different amino acids. Under normal conditions, histidine is the amino acid primarily involved in the formation of mixed amino acid-copper complexes in serum. In combination with histidine and copper, threonine, glutamine, and asparagine are the other amino acids that are most likely to be the third members of these mixed complexes. The first binding site for copper on human albumin is different from subsequent ones in that its binding affinity to copper is much higher. We propose that the amino acid-bound fraction of copper in serum may have a physiological role in the biological transport of copper.

Immunopathologic studies of systemic lupus erythematosus. II. Antinuclear reaction of gamma-globulin eluted from homogenates and isolated glomeruli of kidneys from patients with lupus nephritis.

Abstract: The gammaG-globulin eluted at acid pH from kidney cortex homogenates and isolated glomeruli of five of six patients with lupus nephritis was found to exhibit antinuclear activity, which was not dependent on presence of fresh human serum. Specificity, as demonstrated by absorption of antinuclear activity, was related to nucleoprotein in three glomerular acid eluates and to DNA in two acid eluates as well as in a deoxyribonuclease digest of disrupted glomeruli in one patient. Antinuclear activity was not found in acid eluates of kidneys from two patients with chronic liver disease and chronic discoid lupus, respectively, and one with lupus nephritis. These patients had a low titer of serum antinuclear factor and lesser amounts of kidney bound immunoglobulins. The presence of antinuclear activity in eluates of kidneys appeared to correlate with the amount of glomerular bound immunoglobulin and the level of antinuclear antibodies in serum. These findings suggest that in lupus nephritis, part of the glomerular bound immunoglobulin is derived from serum antinuclear factors possibly deposited as immune complexes.

Studies of the In Vivo Behavior of Human C′3 in Normal Subjects and Patients*

Abstract: The metabolic behavior of C′3 labeled with radioactive iodine was investigated in 10 normal subjects and in 20 patients with diseases in which complement is thought to play a pathophysiological role. The mean fractional catabolic rate of C′3 in normal subjects was 2.3 ± 1.0% of the plasma pool per hr, whereas the fractional catabolic rate of C′3i, the inactive conversion product of C′3 produced by complement activation, was at least five times as great. Increased catabolic rates were found in some patients with acute glomerulonephritis, systemic lupus erythematosus, idiopathic nephrotic syndrome of childhood, and progressive glomerulonephritis. Depressed synthesis was found in each of four studies of patients with progressive glomerulonephritis and seemed to be the major factor in the lowering of plasma C′3 concentrations regularly observed in patients with this disease. Of three patients with acute glomerulonephritis, synthesis rates of C′3 were markedly depressed in one subject, at the lower limit of normal in another, and entirely normal in the third. Increased extravascular: plasma pool ratios were observed in the studies of C′3i metabolism in a normal subject, and of C′3 metabolism in two of three patients with acute glomerulonephritis, in one of four patients with systemic lupus erythematosus, and in one patient with idiopathic nephrotic syndrome. The increased pool ratios are possibly compatible with tissue attachment of part of the injected C′3 or its conversion products. No important abnormalities of metabolism were found in patients with acquired hemolytic anemia, paroxysmal nocturnal hemoglobinuria, hereditary angioneurotic edema, or rheumatoid arthritis. By means of antigen-antibody crossed electrophoresis, C′3i could be demonstrated in the fresh plasma of three of eight patients who had acute glomerulonephritis. This finding was used as evidence for in vivo complement activation in this disease. Since C′3i was demonstrated only in plasma from patients with very low plasma concentrations whose onset of symptoms was very recent, there may be two phases in the metabolism of C′3: early complement activation with resultant increased catabolism and later depressed synthesis, both of which lead to lowered serum concentrations.

Effect of Diet upon Intestinal Disaccharidases and Disaccharide Absorption

Abstract: The administration of a carbohydrate-containing diet for 24 hours to rats previously fasted for 3 days led to a twofold increase in total intestinal sucrase and sucrase specific activity The specific activity of maltase was similarly increased, but lactase activity was unaffected The sucrose-containing diet led to a greater increase in sucrase than maltase activity, whereas the converse was true of the maltose-containing diet A carbohydrate-free isocaloric diet led to a slight increase in the total intestinal sucrase, but sucrase specific activity was unchanged Assay of sucrase activity of mixed homogenates from casein-fed and sucrose-fed rats or fasted and sucrose-fed animals yielded activities that were additive The Michaelis constant (Km) of the enzyme hydrolyzing sucrose was similar in the fasted, casein-fed, and sucrose-fed rats The maximal velocity (Vmax) was twice greater in sucrose-fed as compared to casein-fed or fasted rats, suggesting an increased quantity of enzyme subsequent to sucrose feeding Adrenalectomized rats maintained on 10% salt intake had sucrase and maltase levels comparable to those of controls Steroid administration did not significantly increase their activities The response to sucrose feeding was similar in both control and adrenalectomized rats, indicative of the absence of steroidal control on sucrase and maltase activity in the adult animal Studies using intestinal ring preparations indicated that sucrose hydrolysis by the intact cells proceeded more rapidly when animals were fed sucrose Additional corroboration of the physiologic significance of the increased enzyme levels in homogenates was afforded by intestinal perfusion studies Sucrose hydrolysis increased twofold and fructose absorption fourfold in animals fed sucrose when compared to either fasted or casein-fed rats

Studies on the intracerebral toxicity of ammonia.

Abstract: Interference with cerebral energy metabolism due to excess ammonia has been postulated as a cause of hepatic encephalopathy. Furthermore, consideration of the neurologic basis of such features of hepatic encephalopathy as asterixis, decerebrate rigidity, hyperpnea, and coma suggests a malfunction of structures in the base of the brain and their cortical connections. The three major sources of intracerebral energy, adenosine triphosphate (ATP), phosphocreatine, and glucose, as well as glycogen, were assayed in brain cortex and base of rats given ammonium acetate with resultant drowsiness at 5 minutes and subsequent coma lasting at least 30 minutes. Cortical ATP and phosphocreatine remained unaltered during induction of coma. By contrast, basilar ATP, initially 1.28 ± 0.15 μmoles per g, was unchanged at 2.5 minutes but fell by 28.1, 27.3, and 26.6% (p < 0.001) at 5, 15, and 30 minutes after NH4Ac. At comparable times, basilar phosphocreatine fell more strikingly by 62.2, 96, 77.1, and 71.6% (p < 0.001) from a control level of 1.02 ± 0.38 μmoles per g. These basilar changes could not be induced by anesthesia, psychomotor stimulation, or moderate hypoxia and were not due to increased accumulation of ammonia in the base. Glucose and glycogen concentrations in both cortex and base fell significantly but comparably during development of stupor, and prevention of the cerebral glucose decline by pretreatment with glucose did not obviate ammonia-induced coma or the basilar ATP fall. These findings represent the first direct evidence that toxic doses of ammonia in vivo acutely affect cerebral energy metabolism and that this effect is preferentially localized to the base of the brain.

Intestinal Lymphangiectasia: a Protein-Losing Enteropathy with Hypogammaglobulinemia, Lymphocytopenia and Impaired Homograft Rejection

Abstract: Intestinal lymphangiectasia is a disease characterized by dilated intestinal lymphatics, protein-losing enteropathy, hypoalbuminemia, and edema. The immunologic status of 18 patients with intestinal lymphangiectasia was studied. Concentrations of IgG, IgA, and IgM were measured by immune precipitation and metabolism of these three immunoglobulins was studied using purified radioiodinated proteins. The serum concentration and total body pool of each immunoglobin were greatly reduced. The fraction of the intravascular protein pool catabolized per day was increased to 34% for IgG, 59% for IgA, and 66% for IgM; these are in contrast with control values of 7%, 28%, and 17%, respectively. Synthetic rates of the immunoglobulins were normal or slightly increased. Primary circulating antibody response was tested in five patients with Vi and tularemia antigens. Titers elicited in patients with the Vi antigen were significantly lower than those seen in a control group, whereas no difference was seen between patient and control responses to the tularemia antigen. Lymphocytopenia was noted in patients with intestinal lymphangiectasia. The mean circulating lymphocyte count was 710 +/- 340/mm(3) in contrast to 2500 +/- 600/mm(3) in controls. Cellular hypersensitivity was studied with skin tests and skin grafts. 91% of normal individuals reacted to at least one of the four skin test antigens: purified protein derivative, mumps, Trichophyton, and Candida albicans; in contrast, only 17% of patients with intestinal lymphangiectasia had a positive reaction. Each of three patients tested with dinitrochlorobenzene had a negative reaction. Finally, all four patients who received skin homografts have retained these grafts for at least 12 months. The immunological disorders in patients with intestinal lymphangiectasia appear to result from loss of immunoglobulins and lymphocytes into the gastrointestinal tract secondary to disorders of lymphatic channels. Lymphocyte depletion then leads to skin anergy and impaired homograft rejection.

The Concentration Dependence of Active Potassium Transport in the Human Red Blood Cell

Abstract: The relation between the active potassium influx in the human red blood cell and the extracellular potassium concentration does not appear to be consistent with the Michaelis-Menten model, but is adequately described by a model in which two potassium ions are required simultaneously at some site or sites in the transport mechanism before transport occurs. The same type of relation appears to exist between that portion of the sodium outflux that requires the presence of extracellular potassium and the extracellular potassium concentration. Rubidium, cesium, and lithium, which are apparently transported by the same system that transports potassium, stimulate the potassium influx when both potassium and the second ion are present at low concentrations, as is predicted by the two-site model.

Renal bicarbonate reabsorption and hydrogen ion excretion in normal infants.

Abstract: After acute administration of ammonium chloride, infants 1 to 16 months of age were similar to older children in their capacity to acidify their urine. The infants had a higher rate of excretion of titratable acid and a lower rate of excretion of ammonium but were similar in their rate of excretion of total hydrogen ion.Bicarbonate titrations performed in infants during the first year of life demonstrated a threshold ranging from 21.5 to 22.5 mmoles per L, maximal rate of reabsorption from 2.6 to 2.9 mmoles per 100 ml glomerular filtrate, and marked titration splay. A nephronic frequency distribution curve of the ratio of glomerular filtration rate to tubular reabsorptive capacity demonstrated both heterogeneity and skewing to the right, suggesting the presence of significant numbers of nephrons with low tubular transport capacity relative to filtration rate.It is suggested that the "physiologic acidosis" of the infant is due neither to a limited renal capacity to excrete hydrogen ion nor to a reduced capacity for reabsorption of bicarbonate, but rather to a low renal plasma bicarbonate threshold. Although the level of the threshold may relate to the kinetics of bicarbonate reabsorption during this period, it appears to be due at least in part to functional and morphologic heterogeneity of nephrons.

Human Placental Lactogen: Studies of Its Acute Metabolic Effects and Disposition in Normal Man

Abstract: Summary. The acute metabolic effects and disposition of human placental lactogen (HPL) have been studied in 15 men and 8 women during continuous intravenous infusions. The mean plasma half-life, metabolic pool size, and turnover rate of HPL are comparable to the values previously reported for human growth hormone (HGH). From the data presented, we calculate that the placenta secretes approximately 290 mg HPL daily at term. After 12-hour infusions of HPL in physiologic amounts, impairment of glucose tolerance despite increased plasma insulin responses to glucose was observed in 7 of 8 subjects tested. However, HPL, unlike HGH, did not produce significant changes in blood glucose, plasma insulin, or plasma free fatty acid concentrations in fasting subjects before glucose administration or in carbohydrate tolerance or plasma insulin responses to glucose during 5-hour infusions. These findings are compatible with the thesis that HPL is a physiologic antagonist to insulin during pregnancy.