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C Bryant

Publications and source records attributed to C Bryant.

At least 37 records · Page 2Linked to original sources
PubMed1998

Case-control, haplotype relative risk and transmission disequilibrium analysis of a dopamine D2 receptor functional promoter polymorphism in schizophrenia.

The dopamine system has long been suspected of aetiological involvement in schizophrenia because of a number of lines of evidence pointing to excess dopaminergic activity in the illness. Recently, negative allelic association was reported between a single base deletion in the promoter region of the DRD2 gene, -141 delta C, and schizophrenia, with an odds ratio of 0.60. This was of particular interest since the deletion, which occurs in about 22% of the Japanese population, is functional in that it results in reduced (20-40% of wild-type) basal levels of receptor expression. We have examined this polymorphism in 229 family trios from SW China, consisting of both parents and a single offspring affected by schizophrenia, and 151 Caucasian cases with schizophrenia and 145 Caucasian normal controls from the UK. Using the haplotype-based haplotype relative risk method (HHRR), the frequency of the -141 delta C allele was 6.9% in the affected Chinese subjects compared to an estimated frequency of 9.0% in this population (chi 2 = 1.21, 1 df, ns), with an odds ratio of 0.76 (95% CI 0.46-1.25). Using the transmission disequilibrium test, we likewise found no evidence for linkage or linkage disequilibrium with this polymorphism (chi 2 = 0.94, 1 df, ns). In the Caucasian cases, the frequency of the -141 delta C was 13% compared to 10% in controls (chi 2 = 1.57, p = 0.21) with an odds ratio of 1.39 (95% CI 0.81-2.40). We thus conclude that the DRD2 -141 delta C polymorphism is less frequent in Chinese and Caucasian populations (9%) than in Japan (22%) and is not a significant risk factor for schizophrenia in our populations. The -141 delta C allele remains a strong candidate for a variety of other traits and diseases, including reward-related behaviours such as drug abuse, which have been associated with the dopamine system.

Adolescent↗
PubMed1998

Advances in trematode biology.

edited by Bernard Fried and Thaddeus K. Graczyk, CRC Press, 1997. pound88.50 (466 pages) ISBN 0 8493 2645 1.

Journal Article↗
PubMed1998

Increasing consumer satisfaction. One social service and public health initiative shows how social marketing can increase consumer satisfaction.

The key to a successful social marketing approach to health care is continually listening to consumers' feedback and being willing to change the health product or service according to their needs and preferences. This approach can increase the likelihood of consumers being satisfied with, and continuing to utilize or provide the particular health service.

Consumer Behavior↗
PubMed1997

Orally active trifluoromethyl ketone inhibitors of human leukocyte elastase.

This paper describes the development a series of peptidyl trifluoromethyl ketone inhibitors of human leukocyte elastase which are found to have excellent pharmacological profiles. Methods have been developed that allow for the synthesis of these inhibitors in stereochemically pure form. Two of these compounds, 1k and 1l, have high levels of oral bioavailability in several species. Compound 1l has entered development as ZD8321 and is presently undergoing clinical evaluation. These compounds demonstrate that peptidyl trifluoromethyl ketone inhibitors can achieve high levels of oral activity and bioavailability, and therefore they may prove useful as therapeutic agents in the treatment of diseases in which elastase is implicated.

Administration, Oral↗
PubMed1997

Dissociation of lipopolysaccharide-mediated induction of nitric oxide synthase and inhibition of DNA synthesis in RAW 264.7 macrophages and rat aortic smooth muscle cells.

1. The active component of endotoxin, lipopolysaccharide (LPS), inhibited basal DNA synthesis in both RAW 264.7 macrophages (IC50 0.05 +/- 0.03 microgram ml-1) and rat aortic smooth muscle cells (RASMC) (IC50 9.7 +/- 0.4 micrograms ml-1). 2. In both cell types, serum differentially affected LPS-stimulated inhibition of DNA synthesis. In RAW 264.7 macrophages the presence of serum reduced the IC50 for LPS-stimulated inhibition of DNA synthesis (1.4 +/- 0.85 ng ml-1). However, in RASMC serum stimulated DNA synthesis and further increased the IC50 value for LPS-stimulated inhibition of thymidine incorporation (57.3 +/- 7.8 micrograms ml-1). 3. LPS also stimulated the induction of nitric oxide synthase (NOS) in RAW 264.7 macrophages with maximal expression at concentrations of 1-3 micrograms ml-1. This was wholly dependent upon the presence of serum. In RASMC LPS alone, up to concentrations of 100 micrograms ml-1, did not induce nitric oxide synthase and required co-incubation with the direct activator of adenylyl cyclase, forskolin. Under these conditions stimulated expression of NOS was inhibited by the presence of serum. 4. Incubation with the nitric oxide synthase inhibitors N omega-nitro-L-arginine methyl ester (L-NAME) and L-canavanine did not reverse the inhibition of [3H]-thymidine incorporation in response to LPS but prevented the formation of nitrite in both cell types. 5. These results indicate that the effects of LPS upon cell growth are independent of the induction of the 130 kDa isoform of nitric oxide synthase and nitric oxide formation in both RAW 264.7 macrophages and RASMC.

Animals↗
PubMed1996

Four cases of polymorphous low-grade adenocarcinoma.

Since its histologic recognition by the World Health Organization in 1990, polymorphous low-grade adenocarcinoma (PLGA) is now regarded as the second most common salivary gland tumour after mucoepidermoid carcinoma. Distinguishing it from high-grade tumours such as adenoid cystic carcinoma or carcinoma arising within a pre-existing pleomorphic adenoma is important, as PLGA may usually be treated by local excision alone. Any evidence of incomplete marginal clearance, perineural and perivascular spread, and lymph-node involvement is treated with a course of radiotherapy. Follow-up should be for life, and as reported in this series, long-term survival rates are very good, one of our patients surviving for 11 years. The importance of reporting these cases is emphasized.

Adenocarcinoma↗
PubMed1996

Adenomatoid hyperplasia of palatal minor salivary glands.

Adenomatoid hyperplasia of palatal minor mucous glands is rare but significant because the clinical appearance mimics malignant disease. The typical history of a painless, indolent palatal swelling, together with the histological picture of benign glandular hyperplasia and hypertrophy, are illustrated in this report.

Humans↗
PubMed1995

Non-peptidic inhibitors of human leukocyte elastase. 4. Design, synthesis, and in vitro and in vivo activity of a series of beta-carbolinone-containing trifluoromethyl ketones.

A novel series of human leukocyte elastase (HLE) inhibitors containing the beta-carbolinone ring system are reported. The design of these trifluoromethyl ketone-based inhibitors used a combination of structural information obtained from X-ray crystallography and molecular modeling investigations. The beta-carbolinone ring in these compounds serves as a highly efficient peptidiomimetic for the P2-P3 region of peptidyl trifluoromethyl ketone inhibitors of HLE. Several of the beta-carbolinones exhibit significant in vitro potency, with Ki values in the nanomolar range. Using aqueous molecular dynamics simulations, realistic models for the molecular recognition of these inhibitors by HLE have been obtained and are discussed. This series of compounds are found to have excellent selectivity for HLE over a number of other proteolytic enzymes, including closely related enzymes such as porcine pancreatic elastase.

Amino Acid Sequence↗
PubMed1995

Nonpeptidic inhibitors of human leukocyte elastase. 5. Design, synthesis, and X-ray crystallography of a series of orally active 5-aminopyrimidin-6-one-containing trifluoromethyl ketones.

The effects of changes in substitution in a series of 5-amino-2-pyrimidin-6-ones on both in vitro activity and oral activity in an acute hemorrhagic assay have been explored. These compounds contained either a trifluoromethyl ketone or a boronic acid moiety to bind covalently to the Ser-195 hydroxyl of human leukocyte elastase (HLE). Boronic acid-containing inhibitors were found to be more potent than the corresponding trifluoromethyl ketones in vitro but were less active upon oral administration. Compound 13b was found to offer the best combination of oral potency, duration of action, and enzyme selectivity and, as such, was selected for further biological testing. X-ray crystallography of a cocrystallized complex of compound 19m and porcine pancreatic elastase demonstrated that the inhibitor is bound to the enzyme in a manner similar to that found previously for a closely related series of pyridone-containing inhibitors of HLE.

Administration, Oral↗
PubMed1995

Cyclical etidronate plus ergocalciferol prevents glucocorticoid-induced bone loss in postmenopausal women.

OBJECTIVE: To assess the benefit of cyclical etidronate plus ergocalciferol for the prevention of glucocorticoid-induced bone loss in a 2-year, prospective, open study based in an osteoporosis clinic. PATIENTS AND METHODS: Group 1 consisted of 15 postmenopausal women (mean age 62.6 +/- 3.3 years) who commenced glucocorticoid therapy and were treated with cyclical etidronate (400 mg/d for the first month; thereafter, 400 mg/d for 2 weeks of every 3-month period), elemental calcium (1 g/d), and ergocalciferol (0.5 mg/wk). Group 2 consisted of 11 postmenopausal women (mean age 60.2 +/- 4.7 years) with glucocorticoid-induced osteoporosis, who were attending the clinic at the same time and were treated with calcium supplements only (1 g/d). MEASUREMENTS: Lumbar spine and femoral neck bone mineral densities (BMD) were measured at baseline and after 12 and 24 months of glucocorticoid therapy using a dual energy x-ray absorptiometer. RESULTS: The two groups did not differ with respect to age, years since the menopause, mean daily glucocorticoid dose, and baseline BMD values. During the first year of therapy, mean lumbar spine BMD increased from an initial value of 0.88 g/cm2 to 0.94 g/cm2, an increase of 7% per year (95% confidence interval [CI] 3.7% to 10.2%; P < 0.001 compared with controls). Significant increases in BMD of 2.5% per year were also observed in the femoral neck (95% CI -1% to 6%; P < 0.01 compared with controls). After the second year of cyclical etidronate therapy, femoral neck BMD continued to increase (P < 0.05 compared with value at 12 months), while lumbar spine BMD remained stable. CONCLUSION: Chronic glucocorticoid therapy may result in bone loss at most skeletal sites. Therapy with cyclical etidronate plus ergocalciferol not only prevented glucocorticoid-induced bone loss, but even increased lumbar spine and femoral neck BMD in postmenopausal women commencing glucocorticoid therapy.

Absorptiometry, Photon↗
PubMed1994

Ancient biochemistries and the evolution of parasites.

The characteristic respiratory metabolism of parasites consists of fermentation to carbon-rich, highly reduced volatile fatty acids which are excreted, and electron transport systems emphasising fumarate reductase and b-type cytochromes. The taxonomic groups that contribute major parasites (the heterogeneous protozoa and the helminths) have their evolutionary origins in environments from which oxygen was absent or present in very low concentrations. The Ediacarian period, about 700 million years ago, contains fossils of the appropriate grade of organisation to be contemporaneous with the ancestors of platyhelminths, nematodes and acanthocephalans. With the oxygen transition, carbon flow in the biosphere resulted in conservative, anoxic environments together with oxygen rich ones. The organisms of the former retained their emphasis on anaerobic energy generation, while cytochrome systems were as much concerned with oxygen detoxification as energy generation. Metabolic pathways in the modern parasitic groups are echoes of such ancient biochemistries.

Anaerobiosis↗
PubMed1993

Acid stabilization of insulin.

The effect of pH on the conformational stability of insulin was studied. Surprisingly, the Gibbs free energy of unfolding increased approximately 30% by acidification. pH titration of insulin's conformational stability is described by a transition involving a single proton with an apparent pK(a) of 7.0. The acid stabilization of insulin's conformation was attributed to the protonation of histidine at position 5 on the B-chain (HB5) as determined by 1H-NMR of the histidines, selective amino acid alteration, and enthalpies of ionization. Further acidification (at least to pH 2) does not decrease the free energy of unfolding. A conformational change in the tertiary structure, as indicated by the near-UV circular dichroism spectrum, accompanies this change in stability. We propose that this acid stabilization of insulin is physiologically important in maintaining insulin stability in the acid environment of the secretory/storage granules of the beta-cell of the pancreatic islets of Langerhans.

Chemical Phenomena↗
PubMed1993

Molecular variation in Trichinella.

The taxonomic status of variants within the genus Trichinella is problematical. Some authors recognise no fewer than four species (Trichinella spiralis, T. pseudospiralis, T. nativa and T. nelsoni), others regard T. nativa and T. nelsoni as strains of T. spiralis (T. spiralis var nativa or sylvatica), while others consider the genus to be monospecific, with a variety of more or less well defined isolates. Much of the current evidence adduced to support these various positions is similar to that used pre-1983. It derives from studies of the incidence of Trichinella infections in wild and in domestic animals, comparisons of infectivity of different isolates in laboratory animals and studies of immunity. However, it has become clear that infectivity and epidemiological studies are unreliable tools for discriminating between isolates of Trichinella and it has been shown that differences in the elicitation of immune responses are as much a function of the host as of the parasite. The introduction of monoclonal antibody technology has, however, permitted the identification of specific antigens in different isolates. The information is as yet scant, and one antigen does not a species make. Isozyme analysis provides some support for separating the various isolates of Trichinella into distinct groups, but cannot of itself shed light on the species problem until certain conditions are met. These conditions are difficult to achieve even in organisms abundantly available and without the baggage of the parasitic habit. Isozyme analysis is probably best used to support the newer studies of genomic DNA. Recent analyses of DNA by restriction endonucleases and dot-blot hybridisation techniques show ample promise of insights into speciation, and a new technique for amplifying the DNA from a single larva by the polymerase chain reaction offers exciting prospects. However, the position yet remains as stated in the first section of this abstract.

Animals↗
PubMed1993

The effects of changes in the definitive host environment on the metabolism of Hymenolepis diminuta during growth and maturation.

Flexibility in the metabolism of Hymenolepis diminuta is associated with changing intrinsic requirements during maturation but is also influenced by extrinsic factors, that is, by the nature of the host environment. End-products of carbohydrate metabolism and enzyme activities in worm extracts were used as indicators of metabolic regulation in H. diminuta recovered at various times postinfection. The predominant end-product from 6-day-old worms is lactate, generated by cytosolic glycolysis. As the cestode matures in the host, lactate production by the whole worm decreases and greater amounts of the mitochondrial end-products, succinate and acetate, are detected. A stable, dichotomous carbon flow to lactate, succinate and acetate is observed from 12 days post-infection. A metabolic gradient along the length of individual strobila is also evident. It extends from glycolysis, in the anterior region, to mitochondrial dismutation in the posterior region. The transition from cytosolic to mitochondrial pathways during maturation and along the strobilus is delayed or suppressed in worms recovered from immunosensitized hosts. Four host environments were compared: unsensitized rats, rats immunosensitized with a primary infection of H. diminuta, rats immunosensitized with a primary infection of Nippostrongylus brasiliensis and mice concurrently infected with Heligmosomoides polygyrus. The specific activities of PK and PEPCK in whole worm extracts were similar in 10-, 21- and 35-day-old worms and did not differ in worms isolated from different host environments. However, the PEPCK/PK ratio is high in worms that utilize mitochondrial pathways and low in worms that produce predominantly lactate. LDH activity is high in lactate producers. It is concluded that the pattern of metabolism in H. diminuta is influenced by many effectors in the host environment.

Acetates↗
PubMed1992

Detection of an equilibrium intermediate in the folding of a monomeric insulin analog.

To determine the conformational properties of the C-terminal region of the insulin B-chain relative to the helical core of the molecule, we have investigated the fluorescence properties of an insulin analog in which amino acids B28 and B29 have been substituted with a tryptophan and proline residue respectively, ([WB28,PB29]insulin). The biological properties and far-UV circular dichroism (CD) spectrum of the molecule indicate that the conformation is similar to that of native human insulin. Guanidine hydrochloride (GdnHCl)-induced equilibrium denaturation of the analog as monitored by CD intensity at 224 nm indicates a single cooperative transition with a midpoint of 4.9 M GdnHCl. In contrast, when the equilibrium denaturation is observed by steady-state fluorescence emission intensity at 350 nm, two distinct transitions are observed. The first transition accounts for 60% of the observed signal and has a midpoint of 1.5 M GdnHCl. The second transition roughly parallels that observed by CD measurements with an approximate midpoint of 4.5 M GdnHCl. The near-UV CD spectrum, size-exclusion, and ultracentrifugation properties of [WB28,PB29]insulin indicate that this analog does not self-associate in a concentration-dependent manner as does human insulin. Thus, the observed fluorescence changes must be due to specific conformational transitions which occur upon unfolding of the insulin monomer with the product of the first transition representing a stable folding intermediate of this molecule.

Amino Acid Sequence↗
PubMed1992

Improved insulin stability through amino acid substitution.

Insulin analogs designed to decrease self-association and increase absorption rates from subcutaneous tissue were found to have altered stability. Replacement of HB10 with aspartic acid increased stability while substitutions at B28 and/or B29 were either comparable to insulin or had decreased stability. The principal chemical degradation product of accelerated storage conditions was a disulfide-linked multimer that was formed through a disulfide interchange reaction which resulted from beta-elimination of the disulfides. The maintenance of the native state of insulin was shown to be important in protecting the disulfides from reduction by dithiothreitol and implicitly from the disulfide interchange reaction that occurs during storage. To understand how these amino acid changes alter chemical stability, the intramolecular conformational equilibria of each analog was assessed by equilibrium denaturation. The Gibbs free energy of unfolding was compared with the chemical stability during storage for over 20 analogs. A significant positive correlation (R2 = 0.8 and P less than 0.0005) exists between the conformational stability and chemical stability of these analogs, indicating that the chemical stability of insulin's disulfides is under the thermodynamic control of the conformational equilibria.

Amino Acid Sequence↗