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Biomedical subjects

G C Williams

Publications and source records attributed to G C Williams.

At least 55 records · Page 3Linked to original sources
PubMed1979

The question of adaptive sex ratio in outcrossed vertebrates.

Of various published theories of adaptive control of progeny sex ratio only two are plausible, a physiological theory by Trivers & Willard, and a demographic theory by Verner. The first applies to species in which sons and daughters impose different costs on parents, and in which only one or very few young are produced at once. They ought to show positive correlations in the sex of successive offspring and high sex-ratio variance among progenies. Verner's theory postulates a minimization of competition for mates in neighbourhoods subject to random fluctuation in sex ratio. Optimal progenies would exactly match the population's evolutionary equilibrium sex ratio. There would be little variance among progenies. Evidence from vertebrates is unfavourable to either theory and supports, instead, a non-adaptive model, the purely random (Mendelian) determination of sex. The apparent absence of parental control of progeny sex ratio is a serious theoretical difficulty.

Adaptation, Biological↗
PubMed1979

Formation of cholic acid via 3 alpha, 7 alpha,12 alpha-trihydroxy-5 beta-cholestan-26-oic acid in the dog.

The proposed cholic precursor, 3 alpha, 7 alpha, 12 alpha-trihydroxy-5 beta-[3H]cholestan-26-oic acid, and [14C]cholesterol were infused intravenously at a constant rate into two dogs for 25 days. If the specific activities of trihydroxy[3H]cholestanoic acid and [3H]cholic acid will be equal after an isotopic steady-state is achieved. The specific activities of [14C]deoxycholic acid (formed from [14C]cholic acid) isolated in the stool of these two dogs were equal the last four days of the infusion indicating that labeled deoxycholic acid (and presumably labeled cholic acid) was in an isotopic steady-state. However, the specific activities of trihydroxy[3H]cholestanoic acid were 3.3 and 5.7 times greater than the specific activities of [3H]cholic acid, respectively. These data suggest that either an alternate route of cholic acid synthesis exists exclusive of trihydroxycholestanoic acid or that an isotopic steady state of trihydroxycholestanoic acid cannot be reached during an infusion of labeled trihydroxycholestanoic acid.

Animals↗
PubMed1979

Defects of bile acid synthesis in Zellweger's syndrome.

Abnormal mitochondrial structure and function have been documented in patients with Zellweger's syndrome (cerebrohepatorenal syndrome). In vitro studies have suggested that the formation of C24 bile acids (chenodeoxycholic acid and cholic acid) from C27 cholesterol requires mitochondrial oxidative clevage of the terminal three carbons of the side chain. Therefore, three patients with Zellweger's syndrome were examined for the presence of mitochondrial defects in bile acid synthesis. All three excreted excessive amounts of 3 alpha, 7 alpha-dihydroxy-5 beta-cholestan-26-oicacid, 3 alpha, 7 alpha, 12 alpha-trihydroxy-5 beta-cholestan-26-oic acid, and 3 alpha, 7 alpha, 12 alpha, 24 xi-tetrahydroxy-5 beta-cholestan-26-oic acid (varanic acid), precursors of chenodeoxycholic acid and cholic acid that have undergone only partial side chain oxidation. These findings give added support to the role of mitochondrial oxidative side chain cleavage in the overall scheme of bile acid synthesis.

Bile Acids and Salts↗
PubMed1979

Hepatic extraction of bile salts in conscious dogs.

The enterohepatic circulation of cholic acid conjugates (CAC) was studied in three conscious dogs by comparing the relationship of the concentration of CAC in portal, hepatic, and peripheral venous plasma samples collected simultaneously. The pool of CAC in each dog was labeled with 14C. Catheters were surgically placed in the jugular, left hepatic, and portal veins. Each dog was studied on 2 consecutive days, and each study consisted of a series of samples withdrawn from each catheter at 15-min intervals before and after gallbladder contraction with cholecystokinin. The concentration of CAC in the portal vein ranged from 3 micron (fasting) to 235 micron (after gallbladder contraction). In individual studies, the concentration of CAC increased four to sixfold. A linear relationship exists between the concentration of CAC in the portal vein to that in the hepatic and jugular veins. Thus, the fractional hepatic extraction of CAC is constant over the physiological range of the concentration of CAC in portal venous plasma. Mean extraction varied among the six studies from 0.618 +/- 0.072 (+/- 1 SD) to 0.983 +/- 0.010.

Animals↗
PubMed1979

Metabolism of 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha, 26-tetrol and 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha, 25-tetrol into cholic acid in normal human subjects.

Side chain oxidation and cleavage of precursors in cholic acid synthesis is thought to involve initial hydroxylation at either position 25 or 26 of the side chain. Therefore, the conversion of 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha, 26-tetrol and 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha, 25-tetrol into cholic acid was studied in normal subjects after single intravenous injections of these labeled alcohols. Eighty-six percent and 82% of 5 beta-cholestane, 3 alpha, 7 alpha, 12 alpha, 26-tetrol was converted into cholic acid in two subjects, respectively. However, only 14 and 16% of the injected 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha, 25-tetrol was converted into cholic acid in two subjects, respectively. Thus, this study indicates that 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha, 25-tetrol is an inefficient substrate for cholic acid biosynthesis in man and that the major route of cholic acid synthesis probably involves the 26-hydroxylated intermediate.

Carbon Radioisotopes↗
PubMed1979

Micellar properties of 3 alpha, 7 alpha, 12 alpha-trihydroxy-5 beta-cholestan-26-oyl taurine and relationship to in vitro red cell disruption.

Patients with a metabolic block in the conversion of THCA to cholic acid develop cirrhosis and hemolysis. Tauro-THCA has been shown to distort hepatic architecture and cause hemolysis in bile-fistula rats. In this study, the critical micellular concentration of tauro-THCA was found to be one fourth of that measured for the primary human bile salt, taurocholate. In short-term incubations with intact red cells, tauro-THCA was more effective than taurocholate in removing red cell membrane lipid, inducing morphological red cell sphering, and decreasing functional cellular membrane surface area. These detergent biological membrane effects were most apparent at a concentration above the critical micellar concentration, with the membrane toxicity of the two bile salts roughly paralleling their differences in critical micellar concentration. The lower critical micellar concentration, greater hydrophobicity, and enhanced surface-active properties of tauro-THCA are speculated on as possible factors contributing to the bile salt's toxicity in vivo.

Animals↗
PubMed1978

Effect of taurocholate on the conversion of 3alpha, 7alpha, 12alpha-trihydroxy-5beta-cholestan-26-oic acid into cholic acid.

To determine if the conversion of the intermediate, 3alpha, 7alpha, 12alpha-trihydroxy-5beta-cholestan-26-oic acid (THCA), into cholic acid is influenced by taurocholate, two rats were infused intravenously with [3H] THCA until they reached a steady state. Taurocholate was then added and infused at a rate of 1 mumole/min/rat for 48 hours. The percentage of [3H] THCA recovered in the bile did not increase indicating that taurocholate does not suppress the conversion of THCA into cholic acid.

Animals↗
PubMed1977

The synthesis of D-ribofuranosyl derivatives of methyl propiolate and a study of the activating influence of the ester group in cycloaddition reactions.

2,3,5-Tri-O-benzyl-D-ribofuranosyl bromide (17) has been converted into methyl 3-(2,3,5-tri-O-benzyl-beta-D-ribofuranosyl) propiolate (8) and its alpha anomer 10 in 21 and 42% yields, respectively, by reaction with the silver salt of methyl propiolate. Attempts to prepare 8 from (beta-D-ribofuranosyl)ethyne (1) by standard methods were unsuccessful. The reactions of the esters 8 and 10 and the ethyne 1 with several 1,3-dipoles have been examined. With diazomethane, 8 and 10 gave the pyrazole esters 20 and 28, respectively, whereast the ethyne 1 reacted more slowly to give a mixture of 23 (37%) and 26 (31%). The ester 10 was converted into the triazoles 32 (51%) and 36 (34%) by reaction with benzyl azide. Treatment of the ester 10 with phenylhydrazine gave the pyrazolone 38 in 71% yield. A number of the products of dipolar addition have been converted into new D-ribofuranosyl-pyrazoles and -triazoles by hydrogenolysis.

Chemical Phenomena↗
PubMed1977

Hepatic lesions and hemolysis following administration of 3alpha, 7alpha, 12alpha-trihydroxy-5beta-cholestan-26-oyl taurine to rats.

Patients with a metabolic block in the conversion of THCA into cholic acid develop cirrhosis and hemolysis, and die of hepatic failure. In these patients, THCA is largely conjugated to taurine (tauro-THCA) and excreted instead of being converted into cholic acid. In the present study, the effects of tauro-THCA on hemolysis, bile flow, and hepatic morphology were evaluated in bile fistula rats. All rats infused with tauro-THCA at rates of 0.25, 0.50 or 0.75 micronmol/min developed hemolysis with hemoglobinuria. A direct toxic effect of tauro-THCA on washed human red blood cell membranes was demonstrated at a concentration of 8 X 10(-4) M. Liver biopsy sections from rats infused for a 2 hr period with tauro-THCA were examined by electron microscopy and showed dilation of the rough endoplasmic reticulum and distortion of mitochondrial membranes. Cholestasis was not induced, since tauro-THCA actually caused a greater choleretic response for a given rate of bile salt excretion than did taurocholate. This study raises the possibility that the clinical liver disease seen in patients with a metabolic block in the conversion of THCA into cholic acid may be caused by tauro-THCA.

Anemia, Hemolytic↗
PubMed1977

Metabolism of 3alpha, 7alpha, 12alpha-trihydroxy-5beta-cholestan-26-oic acid in normal subjects with an intact enterohepatic circulation.

The formation of cholic acid from 3alpha, 7alpha, 12alpha-trihydroxy-5beta-cholestan-26-oic acid (THCA) was studied in two normal subjects. [3H]THCA and [14C]cholic acid were administered intravenously by simultaneous injection and the specific activities (percent injected amount/mumol) of [3H]- and [14C]cholic acid were measured in bile samples collected over a 5-day period. If the administered [3H]-THCA is rapidly and completely metabolized into cholic acid, the areas under the specific activity curves of [3H]- and [14C]cholic acid should be identical. In these two subjects, the area under the [3H]cholic acid specific activity decay curves was only 18.4% and 9.0% less than the area under the [14C]cholic acid specific activity decay curves. Thus, there is rapid and nearly complete metabolism of intravenously administered [3H]THCA into cholic acid.

Adult↗
PubMed1976

Evidence for carrier proteins in bile acid synthesis. The effect of squalene and sterol carrier protein and albumin on the activity of 12alpha-hydroxylase.

The possibility that carrier proteins are involved in bile acid synthesis was investigated using rat liver homogenates. The 105 000 X g supernatant fraction was found to contain heat stable proteins that bound the bile acid precursor, 7alpha-hydroxy-4-cholesten-3-one, and increased the amount of 7alpha, 12alpha-dihydroxy-4-cholesten-3-one formed by the microsomal enzyme, 12alpha-hydroxylase. Subsequent studies were carried out to determine if squalene and sterol carrier protein or albumin, two lipid binding proteins present in the 105 00 X g supernatant fraction of rat liver homogenates, may be responsible for the effects seen with this fraction. Squalene and sterol carrier protein bound several water insoluble bile acid precursors, including 7alpha-hydroxy-4-cholesten-3-one, and increased the apparent activity of 12alpha-hydroxylase. Squalene and sterol carrier protein, however, did not bind either cholic acid or chenodeoxycholic acid. Rat serum albumin also bound 7alpha-hydroxy-4-cholesten-3-one and increased the apparent activity of 12alpha-hydroxylase. Kinetic analysis indicated that the apparent stimulation of 12alpha-hydroxylase by squalene and sterol carrier protein and albumin was due to increased solubilization of the substrate, 7alpha-hydroxy-4-cholesten-3-one. Thus, these studies indicate that bile acid precursor carrier proteins are present in the 105 000 Xg supernatant fraction of rat liver homogenates and suggest that squalene and sterol carrier protein or albumin may participate as carrier proteins in bile acid synthesis.

Animals↗
PubMed1976

Formation of bile acids in man. Metabolism of 7alpha-hydroxy-4-cholesten-3-one in normal subjects with an intact enterohepatic circulation.

The formation of bile acids in man is thought to involve a series of reactions in which the initial steps are the same for both cholic acid and chenodeoxycholic acid. The point of bifurcation of the pathway is postulated to occur after the formation of 7alpha-hydroxy-4-cholesten-3-one. To test the hypothesis that the entire synthesis of both bile acids proceeds through this intermediate we studied the metabolism of labeled 7alpha-hydroxy-4-cholesten-3-one in eight normal subjects with an intact enterohepatic circulation. If all the production of cholic acid and chenodeoxycholic acid takes place via 7alpha-hydroxy-4-cholesten-3-one, the areas under the specific decay curves of cholic acid and chenodeoxycholic acid should be identical following a single injection of this labeled intermediate. However, in 6 of the 8 subjects studied the area under the cholic acid specific activity decay curve was significantly less than the area under the chenodeoxycholic acid specific activity decay curve. These results that the production of cholic acid in man may not always involve the intermediate 7alpha-hydroxy-4-cholesten-3-one.

Adult↗
PubMed1976

Immunodeficiency, xanthomas and obstructive liver disease.

Chronic obstructive liver disease and secondary hyperlipidemia developed in an immunodeficient boy. Sequential addition of cholestyramine and phenobarbital to his medical regimen, following an initial response to bile drainage, resulted in the disappearance of xanthomas and pruritus, and the restoration of normal serum concentrations of lipids and bile acids. This improvement may result from shifting the bile acid pool from the peripheral blood compartment to the enterohepatic circulation.

Bile Acids and Salts↗
PubMed1976

The metabolism of 3alpha, 7alpha, 12alpha-trihydroxy-5beta-cholestan-26-oic acid into cholic: an enzyme assay using homogenates of human liver.

An enzyme assay was developed to measure the conversion of the bile acid precursor, 3alpha, 7alpha, 12alpha-trihydroxy-5beta-cholestan-26-oic acid (THCA), into cholic acid using homogenates of human liver biopsies. The average rate of metabolism of THCA into cholic acid was found to be 3.9 +/- 0.5 (+/- 1 SD) pmoles of cholic acid formed/mg liver/minute in twelve normal liver biopsies. This assay system can be used to determine if the syndrome of neonatal cholestasis associated with a metabolic block in the conversion of THCA into cholic acid is transmitted as a genetic trait.

Adolescent↗
PubMed1975

Articulatory-defective children's discrimination of their production errors.

Discrimination and production performance of seven severely misarticulating children was analyzed in terms of errors in distinctive features and phonemes. Their performance on the McDonald Deep Test of Articulation and a minimal pairs discrimination test was also compared to the performance of children without articulation errors on the same measures. The normal children performed equally well in production and discrimination. However, the articulatory-error children performed poorly on the production test but performed almost as well as the normal children on the discrimination test. A discrepancy in articulatory-error children's production and discrimination of their error phonemes was obtained. They discriminated features and phonemes they did not produce. Clinical relevance of these findings are discussed.

Auditory Perception↗
PubMed1975

The relationship between discrimination and articulation training in children with misarticulations.

In the context of a training study, the functional relationship between discrimination and production was investigated. Four subjects were selected for study. For two subjects, Condition I consisted of production training followed by a discrimination probe and Condition II consisted of discrimination training followed by a production probe. For the other two subjects, the conditions were reversed. In production training, the subjects were trained to correctly articulate three consonant-vowel (CV) syllables in response to nonsense pictures. In discrimination training the subjects were trained to find nonsense pictures in response to three CV syllables. Probe measures were administered to determine if changes occurred in one modality after training the other modality. Results indicated that production training was effective in changing both articulation and discrimination; however, discrimination training was effective in changing only discrimination.

Auditory Perception↗