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Biomedical subjects

J F Williams

Publications and source records attributed to J F Williams.

At least 127 records · Page 7Linked to original sources
PubMed1989

Comparison of glycolysis and glutaminolysis in Onchocerca volvulus and Brugia pahangi by 13C nuclear magnetic resonance spectroscopy.

Comparison of glycolysis in Brugia pahangi and Onchocerca volvulus by 13C nuclear magnetic resonance (NMR) spectroscopy showed that the former organism is predominantly a lactate fermenter and the latter resembles more closely the metabolism of a mixed acid fermenter producing lactate, succinate, acetate, ethanol, formate and carbon dioxide. Both organisms synthesize glycogen as a storage carbohydrate. Glutaminolysis in both organisms proceeds by the delta-amino-butyrate shunt to produce succinate which is then further metabolized to acetate and carbon dioxide as end-products.

Animals↗
PubMed1989

Onchodermatitis--correlation between skin disease and parasitic load in an endemic focus in Ecuador.

Onchocerciasis is a chronic parasitic infection in which infiltration of the skin by microfilariae has been associated with a number of different pathological changes. This survey compared the prevalence of different forms of skin disease in two villages, one of which was located within the endemic zone for onchocerciasis (Zapallo Grande), in a lowland rain forest area of western Ecuador. The commonest skin diseases in both villages were scabies, pyoderma and pityriasis versicolor. In addition changes closely correlated with the presence of microfilariae in skin snips were found in Zapallo Grande--such as atrophic gluteal changes, and acute and chronic papular dermatitis. The only other skin disease associated with onchocerciasis was widespread tinea corporis due to T. rubrum. The Amerindians in the endemic onchocerciasis area were more likely than Negroes to have generalized atrophic changes of the skin, whereas in the latter group significant numbers of individuals had no obvious skin lesions but large numbers of microfilariae were detected in skin snips. Acute papular dermatitis was common in both groups and in biopsied lesions microfilariae could usually be identified within the epidermis or close to the dermo-epidermal junction. One patient had developed severe reactive onchodermatitis (Sowda). Swabs taken from onchocercal skin lesions showed no evidence of skin surface carriage of Staphylococcus aureus. Changes classically associated with onchocerciasis such as pretibial hypopigmentation (leopard skin) and hanging groin were notably absent in this population.

Adolescent↗
PubMed1989

Pyruvate metabolism by lymphocytes: evidence for an additional ketogenic tissue.

The rate of utilization of pyruvate (at various concentrations) was measured in lymphocytes prepared from rat mesenteric lymph nodes. The quantitative contribution of pyruvate to CO2, lactate, aspartate, alanine, citrate, acetate, acetyl-CoA and ketone bodies accounted for the pyruvate metabolized. Pyruvate utilization was depressed by increasing concentrations of pyruvate. The maximum catalytic activities and selected intracellular distributions of the following enzymes of pyruvate, citrate and acetyl-CoA metabolism were measured: citrate synthase, ATP-citrate lyase, lactate dehydrogenase, acetyl-CoA hydrolase, acetylcarnitine transferase, NAD+- and NADP+- isocitrate dehydrogenases, HMG-CoA lyase, HMG-CoA synthase, Pyruvate dehydrogenase, acetoacetyl-CoA thiolase, 3-oxoacid-CoA transferase, 3-hydroxybutyrate dehydrogenase and pyruvate carboxylase. Acetyl-CoA formed from pyruvate did not contribute to the respiratory energy metabolism of resting lymphocytes. Instead acetyl-CoA was converted to acetoacetate by reactions which may favour the pathway catalyzed by acetoacetyl-CoA thiolase and 3-oxoacid-CoA transferase. Acetate, acetyl- and palmitoyl-carnitine inhibited the decarboxylation of [1-14C] pyruvate. These observations may be connected with the suppression of pyruvate utilization by increased pyruvate substrate concentration. Only very small amounts of either pyruvate or acetate were incorporated into lipids in resting lymphocytes. The amounts incorporated were partitioned in approximately the same pattern into FFA, T.G., cholesterol and cholesterol esters. Taken together the data show that pyruvate metabolism is directed inter alia at the formation of acetoacetate which may serve as a lipid synthesis precursor. When pyruvate utilization and metabolism was enhanced by concanavalin A, then acetoacetate formation was not favoured and from this it is proposed that the acetyl units may then be directed into lipid synthesis and may also make a contribution to the energy metabolism of the activated lymphocyte.

Animals↗
PubMed1989

Anti-filarial effects of nine quinoline-containing drugs on adult filariae in vitro.

The potencies and efficacies of 9 quinoline-containing anti-malarials including chloroquine, (bis)desethylchloroquine, SN6911, SN12108, amodiaquine, CN-2999-2K, primaquine, quinacrine, and quinine were examined in vitro against adult female Brugia pahangi. Parasite motility and lactate excretion were measured as indicators of drug effects. All of the agents tested showed time-dependent increases in potency over a 24-72-hr incubation period. SN12108 was the most potent at 72 hr, reducing motility by greater than or equal to 50% (IC50) at 1.0 x 10(-7) M. Chloroquine (IC50 2.3 x 10(-6) M), desethylchloroquine (IC50 7.0 x 10(-6) M), quinacrine (IC50 1.9 x 10(-6) M), and quinine (IC50 1.5 x 10(-5) M) were the least potent. All of the drugs caused time-dependent decreases in lactate excretion, except quinine; decreases were found to be dose dependent. A high correlation (r greater than 0.85) was seen between time-dependent effects on motility and lactate excretion. The effects of chloroquine (10 microM) on motility were also examined in female Acanthocheilonema viteae, Dirofilaria immitis, Onchocerca volvulus, and male Onchocerca gutturosa. Dirofilaria immitis was less sensitive to chloroquine than B. pahangi; A. viteae was equally sensitive. Species of Onchocerca were the most sensitive parasites studied. Adult O. gutturosa and O. volvulus were affected by 10 microM chloroquine within 4-6 hr; motility was reduced by 80% within 24 hr. Although the mechanism of anti-filarial activity of the quinoline-containing drugs is not known, their in vitro activity against a variety of adult filariae at clinically relevant concentrations, as well as differential sensitivity seen between the different filariae examined, warrants further study of these compounds.

Animals↗
PubMed1989

Sensitivity of the recently infarcted heart to cardioplegic arrest. Beneficial effect of pretreatment with orotic acid.

The mortality and morbidity of cardiac operations are increased in the presence of an established, recent myocardial infarct. To help understand the mechanisms for this and to develop a therapeutic strategy, we studied the response of the recently infarcted canine heart to hypothermic cardioplegia and the effect of pretreatment with orotic acid. Orotic acid is a precursor of nucleic acids with the ability to enhance protein synthesis. In 21 greyhound dogs, a myocardial infarct was produced by ligation of the left anterior descending coronary artery. Ten of these then received oral orotic acid (100 mg/kg/day) for 4 days and 11 were untreated. A sham group of eight dogs had a thoracotomy only and therefore had normal hearts (normal group). Four days later, all dogs underwent 60 minutes of cardioplegic arrest at 28 degrees C. Before arrest, stroke work index was lower and myocardial oxygen consumption at comparable work levels was higher in both the orotic acid and untreated infarct groups than in the normal group. After arrest and reperfusion, there was a severe depression of ventricular function in the untreated infarct group, with only 18% recovery of prearrest stroke work. In the orotic acid infarct group, recovery of prearrest function (43%) was similar to that in the normal group (56%) and significantly greater than in the untreated infarct group (p less than 0.01). After reperfusion, the untreated infarct group had a lower oxygen consumption, lower myocardial levels of adenosine triphosphate and glycogen, and higher lactate and water contents than before arrest (all p less than 0.05). In the orotic acid and normal groups, these variables returned to prearrest levels. We conclude that an established, recent myocardial infarct places the noninfarcted myocardium under stress and increases its sensitivity to hypothermic cardioplegia. This sensitivity is markedly reduced by treatment with orotic acid.

Animals↗
PubMed1988

Host range mutants of adenovirus type 12 E1 defective for lytic infection, transformation, and oncogenicity.

The human adenovirus type 12 (H12) E1A region encodes two early proteins of 266 amino acid residues (266R) and 235R whilst the H12 E1B promoter directs the synthesis of two major proteins of 163R and 482R. To determine the functions of E1A and E1B in lytic infection and oncogenic transformation we have isolated and characterized a series of H12 E1 mutants. Mutant H12 hr 700 contains a point mutation in exon 1 that alters a single amino acid common to both the 266 and 235R proteins. This mutant synthesized reduced levels of E1 and structural proteins at delayed times in HEK cells, transformed BRK cells, and induced tumors in newborn rats at reduced efficiency compared to wild-type virus. The mutation in H12 in 600 truncates the 266R protein in its unique sequences but this mutant synthesized the 235R, E1B, and structural proteins at delayed times in HEK cells. H12 in 600 was nontransforming but induced rare tumors in newborn rats. A third E1A mutant H12 in 601 synthesized no E1A proteins, reduced levels of E1B and structural proteins at delayed times in lytic infections, and was not a transforming or oncogenic virus. Three E1B mutants were studied in detail. Both H12 hr 703 and H12 in 602 encode N-terminal truncated 482R proteins whereas H12 del 620 encodes an in-frame internally deleted 482R protein. All three synthesized reduced amounts of E1A proteins and the E1B 163R protein, identifying a regulatory function for the 482R protein. None of the E1B mutants could transform and only H12 del 620 could induce rare tumors in newborn rats. These results show that H12 oncogenesis requires the coordinated expression of the E1 proteins.

Adenovirus Early Proteins↗
PubMed1988

Pharmacology of ivermectin.

Ivermectin is a semi-synthetic macrocyclic lactone (Fig. I) active in single low doses against many parasites - particularly nematodes and arthropods. It has been registered for animal health use since early 1985, and was earlier this year approved for human use by the French Directorate o f Pharmacy and Drugs. Of particular interest is ivermectin's potential as a micro filaricide for treatment o f onchocerciasis. Clinical trials leave little doubt about the potential o f ivermectin as a therapeutic tool for symptomatic relief from the effects o f infection with Onchocerca volvulus, and the drug is also recognized to have potential in reducing transmission o f the parasite. The manufacturers (Merck, Sharp and Dohme) recently arranged to provide the drug free o f charge to the WHO for mass trials against onchocerciasis in 12 African and Central American countries. In this article we focus on the pharmacological properties o f ivermectin, with a brief consideration of its absorption, fate, excretion and side-effects, and a discussion o f its micro filaricidal action.

Journal Article↗
PubMed1988

Carbon tetrachloride hepatotoxicity in endotoxin tolerant and polymyxin B-treated rats.

Gut-derived endotoxin has been implicated in the hepatotoxic effects of CCl4. The present study has investigated whether two procedures known to block LPS effects would alter the action of CCl4 to decrease hepatic cytochrome P-450 and microsomal drug-metabolizing activity. Administration of polymyxin B or induction of LPS tolerance were shown to attenuate the effect of CCl4 administration to increase SGOT and SGPT levels, signs of hepatic damage. Polymyxin B administration but not LPS tolerance caused a slight decrease in cytochrome P-450. In pretreated animals given CCl4, only those which had received polymyxin B showed a reduced effect of CCl4 to alter cytochrome P-450 level and activity. However, the apparent protective effect was of the same magnitude as the loss of cytochrome P-450 caused by polymyxin B itself. These results suggest that the ability of polymyxin B to ablate the CCl4 loss of P-450 might be due to a reduced metabolic activation of CCl4 by P-450 and not due to any anti-LPS activity. The results suggest that gut-derived LPS does not participate in the effect of CCl4 decreasing cytochrome P-450-mediated reactions. However, participation of LPS in other hepatotoxic effects of CCl4 is not excluded.

Alanine Transaminase↗
PubMed1988

Rapid methods for the high yield synthesis of carbon-13 enriched intermediates of the pentose-phosphate pathway.

Methods for the synthesis of carbon-13 enriched substrates, intermediates and products of the pentose-phosphate pathway, viz. ribose, arabinose, xylulose and ribulose 5-phosphates, sedoheptulose mono- and bisphosphates, octulose (both the ido- and altro-epimers) mono- and bisphosphates, are described. The procedure of the classical Kiliani synthesis was adopted for the preparation of the two starting compounds, [1-13C]ribose and [1-13C]arabinose 5-phosphates. Using these initial reactants and enzymic methods involving the group-transferring enzymes, transketolase, aldolase and transaldolase, a variety of specifically 13C-labelled five-, six-, seven- and eight-carbon sugar phosphates were synthesized in high yield and purity. The isolation and authenticity of each of the 13C-labelled sugars were established by column, paper and thin layer chromatographic methods and specific enzymic assays. The purity and positional isotopic analysis of these sugar-P's were confirmed by 13C-NMR spectroscopy. These specifically 13C-enriched compounds are required for enzymatic, mechanistic and quantitative investigations of pentose-pathway reactions in animal, plant and tumour tissues in vitro and in vivo.

Carbon Isotopes↗
PubMed1988

In vitro motility of isolated adults and segments of Onchocerca volvulus, Brugia pahangi and Acanthocheilonema viteae.

Observations were made on the spontaneous motility in vitro of entire adult worms and segments of Onchocerca volvulus, Brugia pahangi and Acanthocheilonema viteae. Segment motility was recorded in a mechano-transducer apparatus and responses of worm tissues to anthelmintics and other pharmacological agents were compared. Entire adult female O. volvulus showed varied patterns of motor activity, ranging from continuous low level whole body motion to periodic spasmodic contractions interspersed between intervals of quiescence lasting from a few to 30 seconds. The same range characterized movements of 1.5-4 cm segments cut from worms liberated from collagenase digested nodules. However, fresh segments dissected directly from surgical specimens were completely inactive due to the paralyzing effect of xylocaine, used as local anesthetic. This effect wore off in 2-5 hours in vitro, and recovered segments behaved in the same way as those from enzymatically liberated worms. Segments of B. pahangi and A. viteae also showed motor activity patterns which reflected those of whole adults. Segments of O. volvulus behaved reproducibly, whether examined in the field in endemic areas, or after transport of nodules or freed worms to Michigan from Guatemala or Sudan. Segments of all worms were unresponsive to most anthelmintics, but O. volvulus was susceptible to paralysis by CGP 6140, levamisole, pyrantel and carbachol at concentrations of ten to a thousand times lower than those required to produce any influence on B. pahangi. Segments of A. viteae more closely resembled O. volvulus in their dose responses to these drugs, although CGP 6140 was without effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Chronic alcoholic cardiomyopathy. Protection of the isolated ischaemic working heart by ribose.

The effects of ribose on the pre- and post-ischaemic functional performance of the isolated working heart from 24 month old chronically alcoholic animals was investigated. The improved perfusion model permitted the isolated heart to perform work analogous to that of the normal physiological load, in a system where systemic pressure and atrial pressure could be altered over a wide range and oxygen loss from the perfusion fluid was a minimum. There was a remarkable improvement in the performance of isolated hearts taken from alcoholic animals that were perfused with 1.7 mM ribose both before and after a 25.0 min period of global myocardial ischaemia (at 25 degrees C), however ribose treatment did not greatly affect the performance of hearts of isocaloric control aged rats. Chronic alcohol consumption significantly affected heart performance, causing a marked reduction in both cardiac and work output. After ischaemia the work of all hearts was notably decreased; there was no work output in untreated hearts of alcoholic animals, whereas in hearts of alcoholic animals treated with ribose work output was only decreased by 35%. The acute response to ribose by hearts of aged chronically alcoholic animals suggests a role for this compound as a positive inotropic agent and clearly indicates the beneficial potential of ribose for inclusion in cardioplegic solutions or for infusion in alcoholic subjects showing signs of heart failure or chronic heart disease.

Animals↗
PubMed1988

Vascular perfusion of Onchocerca volvulus nodules.

Perfusion of the vascular bed was achieved in 24 freshly excised nodules of Onchocerca volvulus varying from 0.5 to 2 cm in diameter. India Ink, Microfil polymer, or acrylate perfusates were passed through the vascular supply via cannulation of superficial capsular vessels. After clearing in glycerol or methyl salicylate, or KOH corrosion in the case of the acrylate, nodules were examined microscopically. Small nodules had an extensive blood supply, diffusely distributed throughout the nodule matrix, and in close association with the coils of the worms. In bigger nodules the central area appeared more dense, and intense vascularization appeared to be more peripheral; in the largest nodules the central core was not well vascularized, but a band of heavy vascularization was seen at the margin of the core, fed by superficial vessels and in close contact with worm coils. Very fine branches of the vascular tree were perfused by all three contrast media, but histologically there was evidence of incomplete filling of the smallest vessels. However, there was no extravasation of per-fusates around parasites, even where the approximation between between vessels and parasite surfaces was close. The possibility is considered that O. volvulus may control blood vessel proliferation by release of angiogenesis factors, analogous to rapidly growing solid tumors.

Animals↗
PubMed1988

Comparative effects of anthelmintics on motility in vitro of Onchocerca gutturosa, Brugia pahangi and Acanthocheilonema viteae.

The effects of standard anthelmintics on the motor activity in vitro of adult Onchocerca gutturosa, Brugia pahangi and Acanthocheilonema viteae were determined using a micromotility meter. Fresh adult males dissected from bovine tissues were the best source for observations on O. gutturosa. Parasites liber-ated by collagenase digestion showed poor viability and motility. Only segments of O. gutturosa females were obtainable by dissection and these were not able to sustain motility in vitro. Adult males and females of O. volvulus were active after collagenase digestion of human nodular tissue, but behaved so irregularly that satisfactory monitoring of their movements with the meter was not possible on a regular enough basis to permit quantitation of drug-induced changes. Inhibitory effects on motility of O. gutturosa, B. pahangi and A. viteae were produced by anthelmintics which showed macrofilaricidal effects in vivo in a laboratory rodent model, with the exception of the benzimidazoles. O. gutturosa was, however, much more sensitive than B. pahangi or A. viteae to the temporary paralyzing effects of levamisole and pyrantel. The utility of in vitro screening against O. gutturosa and B. pahangi was evaluated by determining the discriminatory capacity of the tests in detecting novel compounds with reproducible in vivo activity in the jird-B. pahangi/A. viteae model. The results suggested that this would be a valuable selective screening procedure. Although false positives were detected at the rate of 15-17% of the novel anthelmintic chemical series tested, no false negatives were allowed through the screen provided both O. gutturosa and B. pahangi were included.2=

Animals↗
PubMed1987

Cell adherence to microfilariae of Onchocerca volvulus: a comparative study.

The conditions were examined for in vitro antibody-mediated adherence of granulocytes to microfilariae of Onchocera volvulus and Dirofilaria immitis. Reactivity in human sera from patients in endemic foci in Sudan was specific for O. volvulus and no reactions were observed with heterologous Onchocerca species or with Mansonella perstans. Microfilariae from skin, nodules or adult female worms were satisfactory targets for cell adherence, and the cells involved were almost exclusively eosinophils. The reaction was inhibited by indomethacin but not by nordihydroguaiaretic acid, an inhibitor of leukotriene production. Agents that slowed or stopped microfilarial motility (e.g. nifedipine, lidocaine, chloroquine) inhibited the reaction, probably by reducing target/cell contact. Ivermectin did not enhance the reaction, and in the absence of cells exerted only slight effects on the movement of microfilariae at higher concentrations (greater than 10 micrograms/ml). Antibody activity was labile, and did not persist well through freeze-thaw cycles. Some differences between homologous and heterologous mixtures (microfilariae/cells/serum) were seen but they could not be resolved satisfactorily. There were no apparent geographical differences between microfilariae from different foci in Sudan. In the D. immitis system neutrophils were the dominant cell type adhering to microfilariae, and the activity was stable to storage and freeze-thaw. No enhancement was detectable with diethylcarbamazine. Antibody activity was absorbable with microfilarial antigens and was reduced by agents that inhibited microfilarial motility. In dogs, adherence-mediating antibody was seen only in amicrofilaraemic animals with occult infection, and in only a minority of these sera. In humans the relationship to clinical findings was less clear, but patients with punctate keratitis were the most likely to have positive serum and were the most reactive in the assay. This system may therefore offer some insights into disease mechanisms in vivo, and its molecular mechanisms deserve further characterization.

Animals↗
PubMed1987

Clinical responses in human onchocerciasis: parasitological and immunological implications.

Onchocerciasis can cause severe dermal and ocular disease due, it is thought, to the events surrounding the destruction of the microfilarial stage. The evolution of papular pruritic dermatitis and punctate keratitis is clearly related to the killing of microfilariae. Other more chronic changes such as dermal and epidermal atrophy are probably due to repeated episodes of microfilarial killing. It is common to find that not all patients are, at any one time, mounting clinically obvious destructive host responses against the microfilariae, and such individuals can carry very high loads of parasites without any apparent adverse effects. The immunological basis of the differences between these types of patients forms one of the most important questions in the pathogenesis of onchocerciasis today. Various explanations are now emerging. These include immunosuppressive factors and variation in the form of Onchocerca volvulus antigens presented to the host. Clinical presentations of this disease appear to reflect variations in host responses and can be used to provide information concerning the protective immune responses an individual can mount against this parasite.

Animals↗
PubMed1987

Introduction and metabolism of pentose and hexose phosphates in permeabilized Morris hepatoma 5123TC cells.

Metabolism of arabinose 5-P, ribose 5-P and glucose 6-P in permeabilized and resealed Morris hepatoma 5123TC cells was investigated by measuring the contribution of these compounds to nucleic acid biosynthesis. The level of [14C]-arabinose (non-phosphorylated) incorporation into nucleic acids was slight, presumably due to the low activity of the transport system or the absence or low activity of a specific 'kinase' enzyme. The permeabilizing procedure involved the brief treatment of Morris hepatoma 5123TC cells with lysolecithin and resulted in a cell population which was permeable to charged compounds i.e. sugar phosphates and nucleotides, that otherwise could not cross the plasma membrane. The permeabilized (and resealed cells) retained normal cellular morphology and intactness of specific organelles as judged by the maintenance of functional properties. Following permeabilization, these cells resealed when transferred back to normal growth medium, and continued to divide and increase at the same rates as control non-permeabilized cell cultures. The permeabilized cells incorporated deoxyribonucleotides ([methyl -3H]-TTP) into DNA at a linear rate of 0.047 nmol per 10(7) cells min-1, representing 90-100 per cent of the DNA synthesis rate in vivo. The permeabilization technique, when coupled with procedures to establish cell synchrony, permitted the comparative estimate of the contributions of [14C]-labelled arabinose 5-P, ribose 5-P and glucose 6-P to RNA, DNA, amino acids, CO2, lactate and sugar mono- and bisphosphates. The percentage of [14C]-isotope incorporated into total nucleic acids by these three labelled sugar phosphates were 2.3, 4.9 and 6.3 respectively. Possible reasons for the lower incorporation of 14C from arabinose 5-P are given. The results are consistent with the proposal that arabinose 5-P, an intermediate of the L-type pentose pathway activity of 5123TC cells, was incorporated into nucleic acids by its interconversion with ribulose 5-P and ribose 5-P and thus into PRPP. This study represents the first report of sugar phosphate as opposed to free sugar metabolism by tumour cells in culture.

Animals↗
PubMed1987

A histocytochemical study of the macrophages present in tissue responses to adult Onchocerca volvulus.

Immunocytochemical and histochemical properties of macrophages present in the subcutaneous chronic inflammatory responses surrounding adult Onchocerca volvulus (nodules) in human tissues were examined. Macrophages with strong non-specific esterase (NSE) and acid phosphatase (AcPase) activities but weak adenosine triphosphatase (ATPase) activity and HLA-DR expression (NSE+++, AcPase+++, ATPase-/+, HLA-DR-/+) were present in the centre of nodules. Many of the cells adhering to the surface of worms were NSE+++, AcPase+++, ATPase-, HLA-DR+++. The inner zone of the fibrous capsule of nodules contained macrophages with the profile NSE+++, AcPase-, ATPase-/+, HLA-DR-/+. A fourth type, NSE+++, AcPase-/+, ATPase-/+, HLA-DR+++, was located in the outer zone of the capsule, frequently within perivascular accumulations of macrophages, lymphocytes and plasma cells. Active fibroblasts were identified at the inner edge of the fibrous capsule by alkaline phosphatase staining. A feature of all nodules examined was the presence of lipid-filled macrophages, demonstrated by Oil Red O stain; these cells were usually situated in zones adjacent to the centre of nodules, and were of the NSE++, AcPase++, ATPase-/+, HLA-DR-/+ type. Lipid accumulation was not found to be related to the clinical status of the patients studied. The origin and functional significance of this lipid is unknown.

HLA-DR Antigens↗