Search PubMed⌕ Search

Biomedical subjects

T H Williams

Publications and source records attributed to T H Williams.

At least 73 records · Page 4Linked to original sources
PubMed1981

Biological effects of modified colchicines. Improved preparation of 2-demethylcolchicine, 3-demethylcolchicine, and (+)-colchicine and reassignment of the position of the double bond in dehydro-7-deacetamidocolchicines.

A variety of colchicine, demecolcine, and isocolchicine derivatives were examined for their potency in the lymphocytic leukemia P388 screen in mice, for their toxicity in mice, and for their binding to microtubule protein. A qualitatively direct correlation was found between in vivo potency and toxicity; potency appeared to be less well correlated with tubulin binding. The most potent compounds were N-acylated analogues of colchicine and demecolcine. Among the monophenols, only 3-demethylcolchicine showed an appreciable effect in vitro and in vivo and was less toxic than colchicine. Improved methods were found for the preparation of 3- and 2-demethylcolchicine, which involved the use of 85% phosphoric acid and concentrated sulfuric acid, respectively. Decoupling experiments with 1H NMR proved that the double bond of dehydro-7-deacetamidocolchiceine and its derived tropolonic methyl ethers 24 and 25 was in the 5,6 position, rather than the 6,7 position formerly tentatively assigned.

Animals↗
PubMed1981

Glucocorticoids increase tyrosine hydroxylase activity in cultured murine neuroblastoma.

Cyclic AMP and glucocorticoids appear to have a role in regulating the activity of tyrosine hydroxylase (TH), as well as the expression of "morphological differentiation" in murine neuroblastoma. Monolayer cultures of C-1300 murine neuroblastoma (clone NBP2) were treated with the following compounds in ethanol: dexamethasone, triamcinolone acetonide, hydrocortisone, cortexolone, androstenedione, testosterone, estradiol-17 beta; or with the phosphodiesterase inhibitor Ro20-1724 [4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone]. Treatment with either 200 micrograms/ml Ro20-1724 or 50 micrograms/ml dexamethasone produced significant increases in TH activity compared to alcohol controls (1.44 vs. 0.82 nmol 14CO2/mg protein/hr compared to 0.095). Triamcinolone acetonide or hydrocortisone also produced smaller, but significant, increases in TH activity compared to dexamethasone. When steroid activities were compared at 25 microM concentration and after 60 min of incubation (to maximize TH activity), triamcinolone acetonide was not as effective (62%) as dexamethasone. The relatively inactive glucocorticoid cortexolone produced a slight but significant increase, while the androgens androstenedione and testosterone and the estrogen estradiol-17 beta were without effect.

4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone↗
PubMed1981

Biotransformation of [14C]midazolam in the rat in vitro and in vivo.

1. Aerobic incubation of the maleate salt of midazolam, 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine, with rat liver 9000 g supernatant fluid fortified with an NADPH-generating system yielded three metabolites. These were identified with an 1-hydroxymethyl derivative formed by oxidation of the methyl substituent on the imidazo moiety, the derivative hydroxylated at C-4 of the diazepine ring, and the corresponding dihydroxy derivative. 2. Pretreatment of rats with phenobarbital stimulated the oxidative metabolism in vitro of midazolam by 9000 g liver supernatant. 3. Rats given 2.5 mg/kg of [14C]midazolam maleate i.v. excreted 81% of the administered radioactivity in the faeces and 10% in the urine in 24 h. The highest levels of 14C were in the liver and the lowest in the brain during the first day. 4. Four phenolic derivatives of midazolam were identified in rat bile. These were the 4'-hydroxy and the 4'-hydroxy-1-hydroxymethyl derivatives of midazolam and two benzophenones. Evidence that the benzophenones were artifacts derived from the 4-hydroxy derivatives of the two biliary benzodiazepine metabolites is presented. These biliary metabolites were excreted as glucuronide and/or sulphate conjugates. 5. The Propensity of the rat to excrete phenolic metabolites of midazolam in bile is in agreement with the metabolism of several other benzodiazepines in this species.

Animals↗
PubMed1981

Microbial production of vitamin B12 antimetabolites. IV. Isolation and identification of 4-keto-5-amino-6-hydroxyhexanoic acid.

4-Keto-5-amino-6-hydroxyhexanoic acid was isolated from Bacillus cereus 102804 fermentations and found to inhibit the growth of Gram-positive and Gram-negative bacteria, when grown in a chemically defined medium. The mechanism appeared to be the inhibition of delta-aminolevulinic acid dehydratase. The Ki value of 4-keto-5-amino-6-hydroxyhexanoic acid in an enzyme preparation of Propionibacterium shermanii was 0.72 microM. Similar test conditions with 4-keto-5-aminohexanoic acid resulted in Ki of 12.1 microM. In both cases competitive inhibition was found. The structure of 4-keto-5-amino-6-hydroxyhexanoic acid was determined.

Aminocaproates↗
PubMed1980

Medical audit in neonatal care.

A system of medical audit on a neonatal unit based on the primary reason for admission may be used alongside the more conventional type of audit of mortality and morbidity by birthweight and gestation using a diagnostic classification of disease. The method provides a more accurate description of all babies admitted to a neonatal unit and thus a more comprehensive measure of work undertaken.

Congenital Abnormalities↗
PubMed1980

Total occlusion of the left main coronary artery: clinical and catheterization findings.

In this report clinical and angiographic data on three patients with total occlusion of the left main coronary artery is presented. Two of our cases demonstrated rich collateralization with good preservation of left ventricular (LV) function. The third case, with initial subtotal occlusion and no collaterals, sustained a severe anterolateral myocardial infarction (MI) responding to the use of the intra-aortic balloon pump (IABP). This report is consistent with the findings of others who suggest the possible beneficial effect of collaterals in preserving myocardial contractility in this unusual situation. We suggest that the IABP may be of benefit in patients with total occlusion of the left main coronary artery and sparse collaterals who remain unstable and cannot be operated on immediately.

Adult↗
PubMed1980

Metabolism of carprofen, a nonsteroid anti-inflammatory agent, in rats, dogs, and humans.

The metabolic disposition of 14C-labeled carprofen [(+/-)-6-chloro-alpha-methylcarbazole-2-acetic acid] was investigated in rats, dogs, and humans. Carprofen is eliminated predominantly by biotransformation in these three species. In dogs and rats, the direct conjugation of carprofen to form an ester glucuronide and oxidation to the C-7 and the C-8 phenols followed by their conjugation represent the major metabolic pathways. Small amounts of the alpha-hydroxy derivative also are formed by these species and are excreted free in the urine. In dogs, biliary secretion predominates, and 70% of an intravenous dose of carprofen is excreted in the feces while 8--15% of the dose is excreted in the urine. In rats, fecal excretion due to biliary secretion varies from 60 to 75%, and urinary excretion accounts for 20--30% of an intravenous dose. In humans direct conjugation of carprofen represents the only significant pathway of metabolism. Between 65 and 70% of the orally administered carprofen was found to be excreted as the ester glucuronide in the urine, and most of the remaining dose was estimated to be secreted as this metabolite in the bile. Due to enterohepatic circulation, only a fraction of the biliary metabolite was recovered in the feces in humans. Less than 5% of the dose was excreted in human urine as free, intact carprofen. In dogs and humans, plasma levels of carprofen and of total radioactivity exhibit a multiphasic decline. In the three human subjects studied, the terminal component declined with a 13--26 hr half-life; the terminal half-life was approximately 40 hr in dogs.

Adult↗
PubMed1980

Ultrastructural investigation of ACTH immunoreactivity in arcuate and supraoptic nuclei of the rat.

Fine structural localization of an ACTH-like substance was obtained in neurons of the rat arcuate nucleus using immuno-electron microscopy, whereas it could not be confirmed that ACTH-containing cell bodies are present in the supraoptic nucleus. The immunoreactive cells of the arcuate nucleus appeared to be more numerous than the unreactive neurons. Immunostaining was carried out before embedding in resin. Empty vesicles of irregular shape were found in dendrites of immunoreactive arcuate neurons, but their significance and nature remain enigmatic. The reaction product was distributed uniformly throughout the cytoplasm of the ACTH-positive cells, except that the mitochondria, rough endoplasmic reticulum and Golgi vesicles and cisternae were devoid of PAP molecules. This distribution differed from the localization reported in ACTH-secreting cells of the rat anterior pituitary, where the reaction product was found in the rough endoplasmic reticulum and Golgi complex as well as in secretory granules.

Adrenocorticotropic Hormone↗
PubMed1980

Changes induced by 6-hydroxydopamine in the paraventricular nucleus. A correlated fluorescence microscopic/electron microscopic evaluation.

Remodelling of catecholaminergic (CA) fibers after cerebral intraventricular 6-hydroxydopamine (6-OH-DA) administration was evaluated quantitatively in the paraventricular nucleus ( PAR) of young adult rats, using fluorescence microscopy (FM) and electron microscopy (EM). Fluorescent CA varicosities and CA boutons (marked with 5-OH-DA) were counted after survival periods of 4, 21, 56 or 180 days. Four days after 6-OH-DA treatment, the number of fluorescent varicosities dropped to 45% of control numbers but was restored to 79% of control values by 180 days. In the EM study, marked boutons had dropped more dramatically: to 12% of control numbers, after 4 days and 54% by 180 days post-neurotoxin. These data provide strong evidence that substantial but incomplete restoration of CA terminals occurred in PAR. It is of interest that, in all survival intervals, percentage reductions in numbers of CA terminals were more extreme when EM was used for quantification. Nevertheless, the trends indicating partial restoration of terminal numbers with time were parallel in the FM and EM studies. Structures identified as CA growth cones in PAR contained a feltwork of fine filaments together with mitochondria, granular vesicles (often with electron-dense cores marked by the 5-OH-DA label), vacuoles and smooth-surfaced reticulum. The presence of growth cones, some of which persisted 11 months after neurotoxin administration, further supports the inference that a regenerative response of CA elements was evoked in PAR by the 6-OH-DA treatment.

Adrenergic Fibers↗
PubMed1980

Immuno-electron microscopic identification of somatostatin in cells and axons of sympathetic ganglia in the guinea pig.

The superior cervical ganglia (SCG), celiac superior mesenteric ganglia (CMG), and splanchnic nerve of unoperated guinea pigs, as well as both proximal and distal stumps of a previously transected branch of the postganglionic plexus of the CMG, were immunostained for somatostatin (SS). In addition, the PAP technique was adapted for fine-structural visualization of SS. A greater proportion of cells were labeled for SS in the CMG than in the SCG. PAP molecules were present in one type of intraganglionic axons. Only two labeled axons were found in the splanchnic nerve. Neither proximal nor the distal stump of the transected CMG postganglionic nerve contained labeled axons. The present results support the hypothesis that the intraganglionic axons labeled for SS arise from SS-containing intraganglionic neurons.

Animals↗
PubMed1980

Growth cones in differentiated neuroblastoma: a time-lapse cinematographic and electron microscopic study.

Growth cones of 'differentiating' neuroblastoma cells in monolayer culture were studied by time-lapse cinematography and electron microscopy. Morphological differentiation, and thus growth cone formation, was induced by the glucocorticoid dexamethasone. Growth cones lengthened gradually at an average rate of 30 microns/h, advancing in stages that involved alternating extensions and retractions of the filopodia and lamellar sheets. During neurite growth the cell body usually remained stationary. The ultrastructure of growth cones was typified by several filopodia, each containing a bundle of microfilaments, agranular endoplasmic reticulum, aggregates of large agranular vesicles lying adjacent to filopodia (previously termed vesicle-filled mounds), many dense-cored vesicles, 100-140 nm in diameter, microtubules, bizarre and distorted mitochondria, and scattered from ribosomes. Comparing the findings with previous ultrastructural accounts of growth cones of cultured ganglion cells, similarities outnumbered differences. The organization of the microfilament bundles and the abundance of free ribosomes were remarkable in the neuroblastoma cell as was the profusion of dense-cored vesicles which were most numerous in the proximal portion of the growth cone.

Animals↗
PubMed1980

Chronic intravascular hemolysis after aortic valve replacement with Ionescu-Shiley xenograft: comparative study with Bjork-Shiley prosthesis.

Twenty patients with a prosthetic valve (Ionescu-Shiley or Bjork-Shiley) in the aortic position were studied for evidence of intravascular hemolysis. Serum lactic dehydrogenase and serum haptoglobin levels were used as the most sensitive indicators of hemolysis. Elevated concentrations of lactic dehydrogenase were found in all 10 patients with an Ionescu-Shiley prosthesis (mean 402 IU/liter) and in 7 of 10 patients with a Bjork-Shiley prosthesis (mean 234 IU/liter). The mean serum haptoglobin was 15 mg/dl (range 10 to 28) in patients with the Ionescu-Shiley valve and 96 mg/dl (15 to 284) for those with the Bjork-Shiley valve. This study indicates the presence of chronic intravascular hemolysis in patients with the Ionescu-Shiley aortic valve. The increase in lactic dehydrogenase was significantly greater in patients with the Ionescu-Shiley prosthesis than in those with the Bjork-Shiley prosthesis, indicating a slightly shorter red cell life span in the former group.

Adult↗
PubMed1980

Differentiation between the 25R- and 25S-isomers of 5 beta-cholestane-3 alpha, 7 alpha, 26-triol by 13C NMR spectroscopy.

This study was designed to examine whether 13C nuclear magnetic resonance (NMR) spectroscopy can be used to differentiate between the 25R and 25S diastereoisomers of 5 beta-cholestane-3 alpha, 7 alpha, 26-triol, a key intermiediate in the biosynthetic pathway of chenodeoxycholic acid. Chemical shift values were assigned to the individual carbon atoms with the help of model compounds and multiplicity in the single-frequency off-resonance decoupled spectra. It was found that the corresponding carbons 1-20 afforded identical chemical shifts for both compounds, whereas five of the remaining side-chain carbons gave observed shift differences of 0.05-0.20 ppm. Thus 13C NMR can be used as an additional tool to distinguish between the two 5 beta-cholestanetriols isomeric at C-25.

Chemical Phenomena↗