Alterations in human serum alkaline phosphatase and its isoenzymes by hypolipidemic agents: colestipol and clofibrate

Total serum alkaline phosphatase (TSAP) determinations were done as part of the biochemical screening in comparative studies of lipid lowering agents in type lla hyperlipoproteinemic patients. TSAP determinations were made by using a modification of the Bessey-Lowry method and the Statland method. Increases in TSAP following colestipol treatment of 20% (P less than 0.05) and 32% (P less than 0.005) were seen by using the respective methods. Isoenzymatic determinations were done by employing the Statland method and all fractions were increased from baseline levels during colestipol therapy. Clofibrate was associated with 34% (P less than 0.005) and 28% (P less than 0.005) reductions in TSAP activity by using the respective methods; significant reductions in both "bone" and "other" isoenzymatic components occurred. Gamma-glutamyltransferase (gamma GT) results did not consistently reflect TSAP or "liver" isoenzyme results.     

Intestinal biosynthesis of apolipoproteins in the rat: apoE and apoA-I mRNA translation and regulation

Rat intestinal poly(A) RNA was translated in wheat germ and reticulocyte lysate systems in vitro. ApoA-I and apoE were demonstrated to be specific products by immunoprecipitation and fractionation on sodium dodecyl sulfate acrylamide gels. They were identical in size to the respective products from rat liver. In pulse-labeling studies, apoE was shown to be synthesized by slices of rat intestine in situ. Furthermore, a high cholesterol diet stimulated the synthesis of apoE and apoA-I at the pretranslational level.     

The effect of nifedipine on serum digoxin concentrations in patients

Drug interactions with digoxin are being increasingly recognized. Some calcium antagonists have been shown to alter digoxin kinetics and changes in digoxin dosage have been recommended. To determine whether nifedipine affects serum digoxin concentrations in patients during combined drug administration, serum digoxin concentrations were determined before and during concomitant drug administration in 14 cardiac patients. The mean (+/- SD) digoxin concentration was 0.92 +/- 0.5 ng/ml before and 0.96 +/- 0.5 ng/ml after 4 days of nifedipine therapy in eight inpatients. For the group of 14 patients, the mean level was 0.78 +/- 0.4 ng/ml before nifedipine and 0.8 +/- 0.4 ng/ml after 1 week of combined drug administration, and 0.84 +/- 0.5 ng/ml after 2 weeks of combined drug administration. These data suggest that nifedipine does not significantly alter serum digoxin concentrations in cardiac patients receiving combined digoxin and nifedipine in the clinical setting.     

Telemetry of electrophysiologic variables from conscious dogs: system design, validation, and serial studies

Pulmonary congestion is usually absent in cardiac tamponade. To examine the effects of experimental pericardial tamponade on pulmonary fluid volumes, we studied 14 anesthetized dogs with indicator-dilution techniques to measure extravascular (EVLW) and intravascular (PBV) pulmonary fluid volumes. Seven dogs were studied at two levels of tamponade and seven were studied during two levels of left atrial (LA) hypertension produced with an LA balloon. EVLW and PBV were measured in both groups at control state and then at two levels of elevated LA pressure (P). When LAP was raised by the balloon, PBV rose with the increase in LAP (4.9 +/- 2 cc/kg control at LAP 1.2 +/- 1.0 mm Hg versus 6.8 +/- 2.1 cc/kg at LAP 8.4 +/- 1.4 mm Hg and 6.8 +/- 2.1 cc/kg at LAP 14.7 +/- 2.0 mm Hg; both intervention PBV values p less than 0.01 vs control). During tamponade, PBV did not change (4.1 +/- 1.1 cc/kg at LAP 1.3 +/- 2.2 mm Hg control versus 4.4 +/- 1.0 cc/kg at LAP 7.4 +/- 1.4 mm Hg and 4.8 +/- 1.3 cc/kg at LAP 12.7 +/- 2.8 mm Hg). EVLW changes were similar during elevation of LAP in both groups (tamponade dogs 7.1 +/- 2.6 cc/kg, 7.1 +/- 1.6 cc/kg and 8.9 +/- 2.1 cc/kg, respectively; and LA hypertension dogs 6.9 +/- 2.5 cc/kg, 7.3 +/- 2.0 cc/kg, and 8.0 +/- 2.0 cc/kg, respectively. We conclude that during cardiac tamponade there is little change in PBV in response to rises in LAP. This is significantly different from the changes seen when increasing LAP by inflating an LA balloon, where fluid is shifted from the peripheral to the central circulation. EVLW changes were similar for the two methods during elevation of LAP.     

Isolated stenosis of left anterior descending or right coronary artery: Relation between site of stenosis and ventricular dysfunction and therapeutic implications

Indications for coronary arterial bypass surgery in single vessel coronary artery disease are unresolved. To determine the extent of myocardium at risk with stenosis (70 percent or more) of a single coronary artery, left ventricular angiograms of 200 patients with stenosis confined to either the left anterior descending or right coronary artery and of 15 normal control subjects were assessed. Among patients without myocardial infarction, ejection fraction was unchanged (p > 0.05 versus normal values) in (1) those with stenosis of the proximal (above first septal branch, n = 19), mid (between septal and first diagonal branches, n = 14) and distal (within 2 cm distal to diagonal branch, n = 15) left anterior descending coronary artery, and (2) those with stenosis of the proximal (above acute marginal branch, n = 16) and distal (between acute marginal and posterior descending branches, n = 16) right coronary artery. In contrast, ejection fraction was depressed (p < 0.001 versus normal values) In left anterior descending arterial stenosis with anterior myocardial Infarction: proximal (38 ± 10 percent, n = 33), mid (46 ± 12 percent, n = 24; p < 0.01 versus proximal), and distal (56 ± 9 percent, n = 15; p < 0.01 versus mid). Ejection fraction was similar with proximal and distal stenosis of the right coronary artery and inferior Infarction: 54 ± 11 percent versus 55 ± 9 percent, p > 0.05; both p < 0.05 versus normal value. Shortening velocity was assessed in three anterior (I to III, base to apex) and three inferior (IV to VI, apex to base) equidistant hemichords perpendicular to the long axis, 30 ° right anterior oblique view. With anterior Infarction and left anterior descending stenosis, shortening of hemichords I to V, I to IV and II to III with proximal, mid and distal stenosis, respectively, was depressed (p < 0.05 versus normal value). Septal excursion and thickening on M mode echocardiography with proximal left anterior descending stenosis and infarction were depressed (p < 0.05 versus mid and distal stenosis with infarcts). Hemichordal shortening with Inferior infarction was similarly depressed (p > 0.05) with proximal and distal stenoses.In conclusion, stenosis of the left anterior descending coronary artery is a heterogenous disease, the extent of jeopardized myocardium is highly dependent on the site of stenosis, and the criteria for surgery cannot be applied uniformly. When the surgical goal is myocardial preservation, these data provide an objective rationale for bypass of stenosis of the proximal left anterior descending coronary artery. In stenosis confined to the right coronary artery, left ventricular preservation alone should not be considered an indication for coronary bypass grafting.     

Prostacyclin in experimental myocardial ischemia: Effects on hemodynamics,regional myocardial blood flow,infarct size and mortality

To determine the actions of prostacyclin in acute myocardial ischemia, the left anterior descending coronary artery was ligated in 26 anesthetized dogs. At 15 and 45 minutes after coronary ligation, regional myocardial blood flow (ml/min per 100 g) and cardiac output (ml/min) were measured by the radiolabeled microsphere technique (strontium-85 or cerium-141 18 to 10μ]). The dogs were randomly allocated 17 minutes after coronary ligation to a control group (n = 17) or to treatment with prostacyclin infusion at 0.32 μg/kg per min for 6 hours (n = 9). Heart rate and cardiac output were unchanged (p > 0.05) by prostacyclin; mean systemic arterial pressure decreased from 121 ± 8 to 90 ± 3 mm Hg (mean ± standard error of the mean) (p < 0.01) and systemic vascular resistance from 2,690 ± 339 to 2,372 ± 398 dynes · s · cm^?5 (p < 0.05). Prostacyclin reduced blood flow in nonischemic myocardium from 116 ± 12 to 80 ± 3 ml/min (p < 0.01); flow in the ischemic zone was unchanged (p > 0.05) from 22 ± 5 to 20 ± 4 ml/min. Thus, the ratio of ischemic to nonischemic flow was increased by prostacyclin from 0.20 ± 0.03 to 0.25 ± 0.05 (p < 0.05); neither the ischemic nor the nonischemic endocardial/epicardial flow ratio was altered (p > 0.05). In the control dogs, all variables remained constant (p > 0.05) from 15 to 45 minutes. Mortality to 6 hours after coronary ligation was 0 of 9 in prostacyclin-treated versus 6 of 17 (35 percent) in control dogs (p < 0.06). Surviving dogs were killed 24 hours after ligation and infarct size, determined by planimetry and weight techniques, was 18 ± 2 percent of left ventricle in prostacyclin-treated dogs versus 22 ± 2 percent in control dogs (p > 0.05). Thus, prostacyclin in acute myocardial ischemia decreases myocardial oxygen demands, maintains ischemic myocardial blood flow while decreasing nonischemic flow, and greatly reduces early mortality.     

Oviduct progesterone receptor: Physical and chemical studies

Chicken oviduct progesterone receptor has been purified to homogeneity. The protein consists of two dissimilar hormone-binding subunits, A and B, present in equal amounts in the complex. They have molecular weights of 79,000 and 108,000, respectively, as shown by both SDS-gel electrophoresis of the purified proteins and photoaffinity labeling of both with a labeled synthetic progestin. The two subunits show considerable homology (or identity) of structure at the hormone-binding domain, located at the N-terminus of the proteins. Considerable divergence of sequence must exist elsewhere in A and B, as shown by tryptic peptide mapping and by the fact that subunit A has a strong DNA-binding site lacking in B. Both are phosphorylated in vitro by cAMP-dependent protein kinase; this phosphorylation appears to be responsible for creation of a second, weaker progesterone-binding site on each subunit.     

Impact of hemodialysis on the abnormal glucose and alanine kinetics of chronic azotemia.

Rates of alanine and glucose turnover and precursor-product interrelationships were determined in patients on chronic hemodialysis and in matched controls using simultaneous primed injection-continuous infusions of [U-14C] alanine and [2-3h] glucose. In eight chronically dialyzed patients studied before their first dialysis of the week, glucose turnover was 866 +/- 120 micromole/min (mean +/- SE); after their last dialysis of the week, glucose turnover was 880 +/- 63 micromole/min. These rates were 35% (p less than 0.05) and 37% (p less than 0.01) greater than rates observed in ten normal volunteers (642 +/- 28.3 micromole/min). Fasting glucose and insulin levels in dialyzing patients were unchanged from normal. Alanine turnover was increased predialysis (318 +/- 55.2 micromoles/min; p less than 0.01) and postdialysis (248 +/- 32.4 micromole/min; p less than 0.01) as compared to normal (168 +/- 14.3 micromole/min). In patients pre- and postdialysis, gluconeogenesis from alanine was increased to 34.6 +/- 10.9 micromole/min (p less than 0.05) and 39.0 +/- 6.33 micromole/min (p less than 0.05) compared to 20.9 +/- 1.63 micromole/min in normal subjects. We conclude that neither acute nor chronic hemodialysis corrects the increased glucose and alanine production and utilization and gluconeogenesis observed in chronic renal failure.     

The effect of diet upon carbohydrate metabolism, insulin resistance, and blood pressure in congenital total lipoatrophic diabetes

An 11-yr-old female with congenital total lipodystrophy had nonketotic hyperglycemia with resistance to both endogenous and exogenous insulin and systemic hypertension. Twenty-four hour patterns of secretion and mean concentrations of growth hormone, cortisol, Luteinizing Hormone (LH), and Follicle-Stimulating Hormone (FSH) were normal. Plasma glucagon was elevated during periods of hyperglycemia, but was normal during normoglycemia, even though insulin resistance was still evident. Insulin receptor density and affinity for insulin as determined in monocytes and erythrocytes were normal during hyperglycemia. Therapy with insulin and pimozide were not effective in controlling hyperglycemia. However, a diet restricted to 1800–2000 cal per day of average sodium content resulted in euglycemia and normal blood pressure without insulin therapy. Fasting serum glucose decreased from 393 to 65 mg/dl. In addition, triglycerides decreased from 304 to 115 mg/dl, glucagon from 421 to 126 pg/ml, and liver size returned to normal. There was a correlation between blood pressure and fasting glucose: systolic, r = 0.725, n = 54, p < 0.001; diastolic, r = 0.424, n = 54, p < 0.001. Plasma renin activity (PRA) and plasma aldosterone (PA) levels were mildly elevated in both the hypertensive and normotensive states. Plasma renin activity was 2.15 ± 0.73, (SD) ng/ml/hr supine and 5.32 ± 1.81 upright over an 11-day period when urinary sodium excretion was 96.0 ± 25.5 meq/day. When fasting glucose levels were 332–393 mg/dl, glucose turnover was 1967 μmole/min (normal, 696 ± 120, SD), net glucose decay during i.v. glucose tolerance (IVGTT) 15.6 g/50 min/1.73m² (normal, 16.7 ± 3.7), and Kg was 0.52%/min (normal, 1.86 ± 0.51, SD). After intensive diet therapy, fasting glucose was 97 and glucose turnover was 810 μmole/min, net glucose decay was 15.18 and Kg was 0.92. When the subject was hyperglycemic, plasma alanine concentration was normal, as was alanine conversion to glucose. Basal unbound insulin levels were elevated during hyperglycemia and normal during euglycemia. Insulin release, which was negligible during the first IVGTT, had a more normal pattern during the second test. In this patient with lipoatrophy, insulin resistance did not appear to derive from known insulin antagonists. The data suggested that insulin resistance may derive from a reversible loss of coupling of a normal insulin receptor to metabolic pathways. This loss may be tissue specific, involving adipose tissue and liver but not muscle, and appears to occur at insulin levels that are increased but lower than would otherwise cause a loss of hormone responsiveness in normal and obese individuals. An unknown antagonist, if present, must be diet-dependent.     

The evolution of a complex eucaryotic gene

Two thirds of the natural chicken ovomucoid gene has been sequenced, including all exons and the intron sequences surrounding all fourteen intron/exon junctions. The junction sequences surrounding four of the introns are redundant; however, the sequences surrounding the other three introns contain no redundancies and thus the splicing sites at either end of these three introns are unambiguous. The splicing in all cases conforms to the GT-AG rule. We compare the structural organization of the ovomucoid gene with the ovomucoid protein sequence to examine theories of the evolution of ovomucoids as well as the origin of intervening sequences. This analysis suggests that the present ovomucoid gene evolved from a primordial ovomucoid gene by two separate intragenic duplications. Furthermore, sequence analyses suggest that introns were present in the primordial ovomucoid gene before birds and mammals diverged, about 300 million years ago. Finally, the positions of the introns within the ovomucoid gene support the theory that introns separate gene segments that code for functional domains of proteins and provide insight on the manner by which eucaryotic genes were constructed during the process of evolution.