Reduced lipogenesis in rats fed a high-protein carbohydrate-free diet

Rates of fatty acid synthesis were assessed in carcass, liver, and adipose tissue from rats fed for 30 to 40 days a balanced diet (66% wt/wt carbohydrate, 17% casein, 8% fat) or a high-protein carbohydrate-free diet (70% casein, 8% fat). Despite similar body weight increases, carcass fatty acid content of rats on the high-protein (HP) diet was 13% less, and the weight of their epididymal fat pads was reduced by 29% in relation to the controls. In vivo incorporation of 3H2O into carcass fatty acids (FA) and into liver triacylglycerol (TAG) was significantly reduced in HP-fed rats. FA synthesis from 14C-acetate, glucose, or leucine and from 3H2O was also markedly decreased in liver slices from HP rats. The amount of 3H-TAG that accumulated in plasma of rats injected with triton WR 1339 to block peripheral utilization of lipoprotein corresponded in HP and control rats to only 4.1% and 5.0%, respectively, of 3H-FA recovered in carcasses from animals not treated with triton, indicating that almost all of the carcass 3H-TAG was synthesized in situ. However, on a long term basis, the reduced hepatic lipogenesis and the resulting decreased transport of TAG might affect lipid accumulation in HP rats. In vivo lipogenesis from 3H2O and in vitro FA synthesis from 3H2O and from 14C-precursors did not differ significantly in retroperitoneal and epididymal adipose tissue from HP and control rats. In both groups of animals, in vivo rates of lipogenesis were higher in retroperitoneal than in epididymal adipose tissue but still did not account for rates of FA synthesis by carcasses, suggesting the existence of other sites with higher lipogenic activity.     

Dietary protein, fat, and minerals in nephrocalcinosis in female rats.

Young female rats fed semipurified diets containing casein or a soy protein isolate had extensive nephrocalcinosis at the junction between the outer and inner stripe of the outer medullary zone after 5 wk on the diets, whereas rats fed a diet containing a lactalbumin concentrate did not. Although the percentages of actual protein and of total ash were similar in all three diets, the concentrations of individual minerals were not, owing to methods used in isolating the proteins. Comparison of the individual mineral contents of these diets with those in other laboratories as compiled from the literature suggested that factors other than minerals, including protein, are also implicated. Dietary fat appeared to be another such factor in a series of experiments in which saturated medium-chain triglycerides and corn oil were included in diets containing soy protein isolate. Although these diets had identical mineral compositions, the rats fed medium-chain triglycerides had less severe lesions.     

Oxacillin hepatitis: Two patients with liver biopsy,and review of the literature

Hepatotoxicity associated with intravenous sodium oxacillin therapy is reported in two drug abusers cured of staphylococcal endocarditis. Coincident with the administration of oxacillin, marked increases in hepatic transaminase were observed and liver biopsy showed nonspecific hepatitis. Upon cessation of oxacillin therapy, liver enzyme values returned to(ward) normal.Reports of oxacillin-associated changes in hepatic enzyme levels are reviewed; further observation of oxacillin-associated hepatotoxicity is warranted.     

Glyceroneogenesis in rat and guinea pig adipose tissue during the fed and fasted states

While both pyruvate and lactate are good substrates for glyceride-glycerol synthesis in isolated adipocytes from fed rats and guinea pigs, neither alanine nor serine appear to support glyceroneogenesis. Fasting increases the proportion of radioactive pyruvate or lactate incorporated into glyceride-glycerol and reciprocally decreases the proportion incorporated into fatty acids. However, the total incorporation of radioactivity into triacylglycerol is considerably lower in isolated adipocytes from fasted than from fed animals. Addition of glucose to the incubation medium promotes the incorporation of radioactive lactate into both fatty acids and glyceride-glycerol by adipocytes from fasted as well as fed animals. The concentration of α-glycerolphosphate is considerably higher in adipose tissue of fed than fasted animals. In general, these results support the presence of a glyceroneogenic pathway in rat and guinea pig adipose tissue. However, it would appear that the physiologic significance of this pathway is less important in the fasted than the fed state, where it may play some role in the esterification of intracellular fatty acids.     

Alteration by fasting of the effects of methylprednisolone on carbohydrate metabolism in the normal dog

Replacement regimen of cortisol was found to increase hepatic glucose release and overall glucose uptake by tissues (glucose turnover) in the postabsorptive adrenalectomized or hypophysectomized dog, but had no effect in the normal dog. A more potent glucocorticoid, methylprednisolone, has been reported to increase glucose turnover in the normal dog. In the present study, measurements of glucose turnover are correlated with measurements of liver glycogen and of plasma glucose, lactate and insulin. The studies were done in normal postabsorptive and starved dogs, in the control state and during a methylprednisolone regimen. Glucose turnover was measured in unanesthetized, trained dogs, using glucose -6-¹⁴C, which was administered in tracer amounts as a priming injection following immediately by a constant infusion. Methylprednisolone (2–2.5 mg/kg/day for 3–4 days) increased glucose turnover in the postabsorptive state. Plasma glucose concentration was unchanged, but lactate and insulin levels were elevated and liver glycogen was markedly increased. Fasting for 5 days decreased glucose turnover as well as liver glycogen and plasma insulin, with little change in plasma levels of glucose and lactate. Administration of methylprednisolone for 3–4 days with continuation of the fast did not alter significantly the plasma levels of glucose and lactate, but insulin levels increased to values seen in the postabsorptive state. The most striking effect was the increase in liver glycogen from the low values of the long-fasted state to values exceeding those in the postabsorptive state. Despite the elevated glycogen content hepatic glucose release (and turnover) was not increased above the depressed values of the long-fasted state. It was established that these glycogen stores could be mobilized by glucagon infusion.     

Effects of streptozotocin on glucose metabolism, insulin response, and adiposity in ob/ob mice.

To determine whether hyperglycemia in the obese hyperglycemic (ob/ob) mouse is related to enhanced activity of the pancreatic beta cell, streptozotocin (175 mg/kg) was injected into lean and ob/ob mice at 8 wk of age. The influence of this injection upon glucose metabolism, adipose cellularity, pancreatic morphology and immunoreactive insulin (IRI) release from isolated pancreatic islets was measured. The plasma glucose levels before and after an oral glucose load were elevated in lean and decreased in ob/ob mice 2 wk after treatment with streptozotocin. By 5 wk after this treatment, a reduced pancreatic islet size, beta cell number and a decreased pancreatic islet IRI release were present in both lean and ob/ob mice. At this time, plasma glucose was still elevated in lean, but depressed in ob/ob mice and the insulin responsiveness in muscle and adipocytes was unchanged. Hyperglycemia abates in the ob/ob mouse as hypersecretion of insulin is diminished, but these observations may not be directly related, since streptozotocin affects key metabolic activities of the livers as well as the pancreatic beta cell. The progression of obesity and status of adipose cellularity are not directly related to hyper-insulinemia, since they are not altered following streptozotocin treatment.     

Incorporation of orally administered glucose-U-14C and fructose-U-14C into the triglyceride of liver, plasma, and adipose tissue of rats

Male rats, fasted for 5–6 hr, were given glucose-U-¹⁴C or fructose-U-¹⁴C, with their respective carrier, by intragastric instillation. Sequential radioactivity in plasma carbohydrates and in the triglyceride of the liver, plasma, and adipose tissue and plasma immunoreactive insulin and free fatty acids were measured. The validity of taking the triglyceride labeling rate as the triglyceride synthesis rate was tested by measuring the metabolic activity of endogenous glucose. Two or three times greater radioactivity was found in the liver and plasma triglycerides after fructose than after glucose while the reverse was true for adipose tissue. The greater radioactivity in triglyceride of the liver and plasma after fructose was mainly due to triglyceride-glycerol radioactivity. The greater radioactivity in adipose tissue triglyceride was due to the radioactivity of both triglyceride-fatty acids and triglyceride-glycerol. Three hours after glucose, 92% of the total radioactivity in triglyceride was in adipose tissue and 8% was in the liver. However, 3 hr after fructose, 57% of the radioactivity was in adipose tissue and 42% was in the liver. Daily repetition of such a pattern of fructose handling may lead to abnormal metabolism of endogenous triglyceride.     

Lipolysis and the antilipolytic effect of insulin in adipocytes from rats adapted to a high-protein diet

Free fatty acid (FFA) mobilization during fasting was investigated in rats fed a high-protein, carbohydrate-free (HP) diet (70% casein, 8% fat, wt/wt) or a balanced diet (66% carbohydrate, 17% casein, 8% fat) for 30 to 40 days. In vivo, rats on the HP diet showed reduced rates of plasma FFA increase during fasting. Their blood sugar remained unchanged and was higher than that of control rats 24 hours after removal of food. In the fed state, serum insulin levels were smaller in HP-fed rats but did not differ significantly in the two experimental groups during fasting. In vitro, the rates of glycerol and FFA release by epididymal fat pads obtained from fasted rats were similar in rats consuming the HP diet. Fat cells isolated from rats on the HP diet also had reduced rates of basal lipolysis. Furthermore, they showed a significant increase in responsiveness to the lipolytic action of noradrenaline and an increase in both sensitivity and responsiveness to the inhibitory effect of insulin on noradrenaline-stimulated lipolysis. Adipocytes from HP-fed and control rats had mean diameters of 51 and 60 mu, respectively, and estimated average volumes of 90 and 142 pL. On the basis of existing data on the correlation between size and lipolytic activity of fat cells, the smaller size of the adipocytes from HP-fed rats might account for the lower rate of basal lipolysis but not for the increased response to the hormones. The increased sensitivity of fat cells to the antilipolytic action of insulin may have been an important factor in the reduced lipomobilization during fasting in rats under the high-protein regimen.     

Renin and aldosterone and the pathogenesis of hypertensive vascular damage

Arterial hypertension often leads to vascular injury that clinically may be expressed as malignant hypertension, heart attack, stroke, or nephrosclerosis. Many different mechanisms have been suggested to operate in the various types of hypertensive disease that cause vascular lesions. Most of these incriminate either blood pressure elevations per se as a mechanical stress upon the arterial wall or the direct vasculotoxic action of an overactive renin-angiotensin system affecting the structure and the permeability of the small vessels, or a combination of these two factors. These theories are supported by the finding of more frequent cardiovascular complications in the high-renin hypertensive patients, while low-renin patients appear relatively protected. However, both experimentally and clinically similar types of vascular lesions may be encountered in conditions characterized by the absence of abnormally increased renin-angiotensin or even in the absence of blood pressure elevation. For the most part, however, vascular damage that is produced without the participation of the renin-angiotensin component can be directly related to salt excess induced by mineralocorticoid excess and amplified by attendant renal damage.This review analyzes the evidence accumulated from studying the sequence of events leading to vascular damage in experimental models that express pathogenetically different types of hypertension, i.e., vasoconstrictor hypertension due mainly to arteriolar constriction induced by clamping of a renal artery with angiotensinemia (renindependent) and volume hypertension due mainly to arterial overfilling, induced by administration of salt with a mineralocorticoid (salt-dependent). It is noteworthy that in both models, the onset of malignant vascular changes is marked by the sudden occurrence of profuse diuresis accompanied by loss of sodium, decrease in body weight, and evidence of hemoconcentration.On the basis of these observations, a unifying theory is presented to explain the occurrence of similar lesions as they develop in these two different types of hypertension. Both forms induce arteriolar narrowing, impaired arteriolar wall and tissue perfusion, transudation, plasmatic vasculosis, pressure natriuresis, hemoconcentration, fibrin deposition, and, finally, fibrinoid necrosis. In the case of salt hypertension, vasoconstriction may not be present, but it is replaced by edema of the arteriolar wall. With this hypothesis, all vascular changes in chronic hypertension can be explained in terms of an inappropriate interaction between a vasoconstrictor component (largely angiotensin) and a volume factor (determined by renal excretory capacity modulated by aldosterone).     

Methyldopa hepatitis: A report of six cases and review of the literature

Six cases of methyldopa hepatitis, including two in which the patients died are reported; and 77 cases from the literature are reviewed. Patients in whom severe hepatotoxic reactions to methyldopa develop usually complain of prodromal symptoms typical of hepatitis, often with fever, one to four weeks after therapy is initiated. Jaundice, when it occurs, is usually manifest within three months.

Asymptomatic, transient elevations of serum transaminase levels may occur in patients receiving methyldopa. However, since the clinical and histologic features of hepatic injury from methyldopa are indistinguishable from viral hepatitis, it is suggested that the incidence of this iatrogenic disease is higher than generally appreciated.

Serum transaminase levels should be determined at the initiation of therapy with methyldopa and four weeks later. Moreover, any patient who has unexplained fever or the prodromal symptoms of hepatitis should undergo liver chemistry studies immediately.     

Alkaline ribonuclease inhibitor in human thyroid.

Thyroids of goitrogen-treated rats contain increased amounts of a protein inhibitor of ribonuclease activity at pH greater than 7 (alkaline ribonuclease inhibitor, ARI). We report here that thyroids from hyperthyroid patients contain more ARI than normal human thyroids. This increase parallels RNA concentration. The inhibitor is heat labile, inactivated by sulfhydryl blocking agents, and has a molecular weight near 50, 000 daltons. ARI is quantitated by its activity against bovine pancreatic RNase, but it also inhibits human thyroid RNase. Analyses of a solitary toxic nodule and its surrounding suppressed tissue confirm in tissues from a single patient our results in tissue from numbers of thyrotoxic and euthyroid individuals and decrease the likelihood that changes are induced by antithyroid medication. A possible regulatory role for ARI is suggested.     

Metabolic, endocrine, and drug-induced interference with pituitary function tests: a review.

Data are summarized concerning some common disease-induced and drug-induced alterations of pituitary function tests. These factors must be kept in mind in order to avoid errors in the diagnosis and treatment of pituitary disease.     

Effect of a high carbohydrate diet on apoprotein-B catabolism in man

We have previously demonstrated that while VLDL-TG production increased in subjects fed high CHO diets, VLDL apo-B production did not change. To further define the effects of high CHO diets on apo-B metabolism in man, we studied the catabolism of this apoprotein in VLDL, IDL, and LDL in three hypertriglyceridemic subjects during control and high CHO diets. ¹²⁵I-VLDL was injected intravenously into subjects and 18 blood samples obtained over the following 48-hr period. VLDL, IDL, and LDL were isolated by sequential ultracentrifugation at each time point and the specific radioactivity of apo-B in each lipoprotein class was determined. A multicompartmental analysis was utilized to analyze the three radioactivity curves obtained in each study. The major change in apo-B catabolism during the high CHO diet involved the conversion of VLDL apo-B to LDL apo-B. During the control diet, 40%–62% of VLDL apo-B was converted to LDL apo-B while during the high CHO period, only 16%–42% of VLDL apo-B was converted to LDL. The reduction in conversion resulted from two separate processes. First, direct catabolism of VLDL apo-B without conversion to higher density lipoprotein classes increased during the high CHO diet. Second, although during the control period approximately 25% of VLDL apo-B was converted directly to LDL apo-B (without passing through the IDL density range), essentially no VLDL apo-B degradation occurred via this route during the high CHO period. Thus, although the rate of VLDL apo-B secretion into plasma was the same during both diet periods, significant alterations in the routes of catabolism of apo-B occurred on the high CHO diet.     

Dynamic intercoronary collateral flow in a patient with variant angina and coronary artery spasm

Intermittent intercoronary collateral flow was observed in a patient with coronary vasospasm associated with variant angina. Collateral flow began almost immediately after total occlusion of the right coronary artery, but did not prevent pain or S-T segment elevation. Some collateral vessels may pre-exist ischemic conditions and flow across these channels may be immediately dependent on the pressure gradient across them.     

Mezlocillin in the therapy of serious infections

Mezlocillin, a new semisynthetic penicillin chemically related to ampicillin which is more active than carbenicillin against Ps. aeruginosa, B. fragilis and Strep. faecalis and which inhibits many Klebsiella, was evaluated in the therapy of 34 episodes of infection in 26 patients. Infection sites included pulmonary, urinary tract and tissue infections, including peritonitis. Seven patients had bacteremia. Clinical cures were achieved in 83 per cent and bacteria cures in 76 per cent of infections. Cure was achieved with mezlocillin in patients with infections caused by carbenicillin-resistant species. Adverse effects of therapy were minimal, one rash and one episode of reversible neutropenia. Serum and body fluid levels were easily maintained above the inhibitory levels of susceptible organisms. Mezlocillin was a safe, well tolerated and effective antibiotic in the treatment of infections due to susceptible organisms.