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Biomedical subjects

D Bell

Publications and source records attributed to D Bell.

At least 73 records · Page 4Linked to original sources
PubMed1997

Inhibition of metallo-beta-lactamases by a series of mercaptoacetic acid thiol ester derivatives.

A series of mercaptoacetic acid thiol esters have been identified as metallo-beta-lactamase inhibitors. Electrospray mass spectrometry (ESMS) has shown that irreversible inhibition of the Bacillus cereus II metallo-beta-lactamase by SB214751, SB214752, and SB213079 was concomitant with a 90-Da increase in mass of the enzyme. Tryptic digestion of the B. cereus II inhibited with SB214751 illustrated that the peptide fragment, containing the only cysteine of the enzyme, had undergone a mass increment of 90 Da. It was further demonstrated that B. cereus II hydrolyzed this type of compound across the thiol ester bond to yield mercaptoacetic acid. Mercaptoacetic acid is the only molecular fragment common to SB214751, SB214752, and SB213079, and free mercaptoacetic acid does not bind covalently to B. cereus II. Therefore, it is concluded that these compounds inhibit B. cereus II by the mechanism-based delivery of mercaptoacetic acid, forming a disulfide linkage with the active sites cysteine (predicted mass shift = +90 Da) under the aerobic conditions of the assay. The different thiol esters examined had a broad range of potencies against the metallo-beta-lactamases tested. For example SB214751, SB214752, and SB213079 all had 50% inhibitory concentrations of < 10 and > 1,000 microM for the Stenotrophomonas maltophilia L-1 and Bacteroides fragilis CfiA enzymes, respectively. SB216968 was particularly active against the Aeromonas hydrophila CphA metallo-beta-lactamase and was found to be an uncompetitive inhibitor of this enzyme (Ki = 3.9 microM), whereas it exhibited irreversible inhibition of the L-1 enzyme. These observations with this series of compounds have revealed subtle differences between the active sites of different metallo-beta-lactamases. Finally, a novel application for isothermal titration calorimetry for assessing the zinc chelating activity of candidate inhibitors is also presented.

Aeromonas hydrophila↗
PubMed1997

Presence of UDP-N-acetylmuramyl-hexapeptides and -heptapeptides in enterococci and staphylococci after treatment with ramoplanin, tunicamycin, or vancomycin.

Analyses of the peptidoglycan nucleotide precursor contents of enterococci and staphylococci treated with ramoplanin, tunicamycin, or vancomycin were carried out by high-pressure liquid chromatography coupled with mass spectrometry (MS). In all cases, a sharp increase in the UDP-N-actetylmuramoyl-pentapeptide or -pentadepsipeptide pool was observed. Concomitantly, new peptidoglycan nucleotide peptides of higher molecular masses with hexa- or heptapeptide moieties were identified: UDP-MurNAc-pentapeptide-Asp or pentadepsipeptide-Asp in enterococci and UDP-MurNAc-pentapeptide-Gly or -Ala and UDP-MurNAc-pentapeptide-Gly-Gly or -Ala-Gly in staphylococci. These new compounds are derivatives of normal UDP-MurNAc-pentapeptide or -pentadepsipeptide precursors with the extra amino acid(s) linked to the lysine epsilon-amino group as established by various analytical procedures (MS, MS-MS fragmentation, chemical analysis, and digestion with R39 D,D carboxypeptidase). Except for tunicamycin-treated cells, it was not possible to ascertain whether these unusual nucleotides were formed by direct addition of the amino acids to UDP-MurNAc-pentapeptide (or -pentadepsipeptide) or whether they arose by reverse reactions from lipid I intermediates to which the amino acids had been added.

Anti-Bacterial Agents↗
PubMed1997

Campylobacteriosis in New Zealand: results of a case-control study.

STUDY OBJECTIVE: To identify and assess the contributions of major risk factors for campylobacteriosis in New Zealand. DESIGN: Case-control study. Home interviews were conducted over nine months using a standardised questionnaire to assess recent food consumption and other exposures. SETTING: Four centres in New Zealand with high notification rates of campylobacter infections--Auckland, Hamilton, Wellington, and Christchurch. PARTICIPANTS: Case patients were 621 people notified between 1 June 1994 and 28 February 1995 as having campylobacter infection. Control subjects were selected randomly from telephone directories, and were matched 1:1 with case patients in relation to sex, age group, and home telephone prefix. RESULTS: Risk of campylobacteriosis was strongly associated with recent consumption of raw or undercooked chicken (matched odds ratio 4.52, 95% confidence interval 2.88, 7.10). There was also an increased risk with chicken eaten in restaurants (matched odds ratio 3.85; 2.52, 5.88). Recent consumption of baked or roasted chicken seemed to be protective. Campylobacteriosis was also associated with recent overseas travel, rainwater as a source of water at home, consumption of raw dairy products, and contact with puppies and cattle, particularly calves. CONCLUSIONS: Improperly cooked chicken seems to be associated with a large proportion of campylobacteriosis in New Zealand. Thorough cooking of chicken in homes and restaurants could reduce considerably the incidence of this disease.

Campylobacter Infections↗
PubMed1997

Calcitonin gene-related peptide (CGRP) and hypertrophy of cardiomyocytes.

We studied whether calcitonin gene-related peptide (CGRP), a neuropeptide secreted from the sensory nervous supply to the myocardium, induces hypertrophy of cardiomyocytes in culture. CGRP increased the cell surface area of neonatal rat cardiomyocytes; the surface area of the cells was almost doubled by treatment with CGRP for 48 h. Furthermore, CGRP up-regulated mRNA expression for skeletal alpha-actin and atrial natriuretic peptides, which are genetic markers for cardiac hypertrophy. These results indicate that CGRP is a potent hypertrophic factor for cardiomyocytes.

Animals↗
PubMed1997

Malaria in Honiara, Solomon Islands: reasons for presentation and human and environmental factors influencing prevalence.

During February and March 1995, out-patients attending health clinics and the Central Hospital in East Honiara, Guadalcanal, Solomon Islands, were surveyed with the aim of determining factors influencing the differing rates of malaria, the proportion of transmission occurring within the town, and the reasons for presentation. Three hundred and nine adult patients, who were sick and had blood smears taken, were asked about their general knowledge of malaria transmission. Of those interviewed, 120 were visited at their home in East Honiara, to determine variables. EpiInfo 5.1 was used in analysis. A history of fever alone was not a good indicator of parasitemia. Most precautions, including bed nets, window screens and personal precautions were of little benefit. Significant protection was afforded individuals and families with indoor kitchens. Patients not completing their antimalarial treatment fared worse in terms of parasitemia and malaria history. Most malaria/parasitemia was indigenous to Honiara. Many patients had a good knowledge of malaria transmission and mosquitos, but this did not translate into a lower rate of parasitemia or malaria.

Adolescent↗
PubMed1996

Peptidoglycan structure of Enterococcus faecium expressing vancomycin resistance of the VanB type.

Resistance to glycopeptide antibiotics in enterococci is due to the synthesis of UDP-MurNAc-tetrapeptide-D-lactate (where Mur is muramic acid) replacing the normal UDP-MurNAc-pentapeptide precursor. The peptidoglycan structures of an inducible VanB-type glycopeptide-resistant Enterococcus faecium, D366, and its constitutively resistant derivative, MT9, were determined. Using HPLC, 17 muropeptides were identified and were present regardless of whether resistance was expressed or not. The structures of 15 muropeptides were determined using MS and amino acid analysis. The cross-bridge between D-alanine and L-lysine consisted of one asparagine. No monomer pentapeptide or tetrapeptide-D-lactate could be identified. These results obtained with D366 (non-induced) and MT9 indicate that, in the absence of vancomycin, the cell wall synthetic machinery of E. faecium can process the lactate-containing precursor as efficiently as the normal pentapeptide. In contrast, the presence of subinhibitory inducing concentrations of vancomycin interfered with the synthesis of oligomers.

Amino Acid Sequence↗
PubMed1996

Increased oxidative DNA damage in livers of 2,3,7,8-tetrachlorodibenzo-p-dioxin treated intact but not ovariectomized rats.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a more potent hepatocarcinogen in female than in male or ovariectomized rats. A possible mechanism for this increased sensitivity is through enhanced metabolic activation of estrogens by TCDD-induced enzymes leading to oxidative damage in the cell. As a marker for oxidative DNA damage, 8-oxo-deoxyguanosine (8-oxo-dG) was quantitated in livers of intact and ovariectomized Sprague-Dawley rats chronically treated with TCDD (125 ng/kg per day) with and without diethylnitrosamine as initiator. Elevated levels of 8-oxo-dG were detected in a significantly greater number of the intact compared to ovariectomized TCDD-treated rats. Expression of CYP1B1 mRNA, a newly identified cytochrome P450 with proposed estrogen hydroxylase activity, was highly induced by TCDD. The results are consistent with the hypothesis that increased metabolism of endogenous estrogens to catechols by TCDD-induced enzymes may lead to increased oxidative DNA damage and hence contribute to TCDD-mediated hepatocarcinogenicity in female rats.

Animals↗
PubMed1996

Peptidoglycan synthesis and structure in Staphylococcus haemolyticus expressing increasing levels of resistance to glycopeptide antibiotics.

The structures of cytoplasmic peptidoglycan precursor and mature peptidoglycan of an isogenic series of Staphylococcus haemolyticus strains expressing increasing levels of resistance to the glycopeptide antibiotics teicoplanin and vancomycin (MICs, 8 to 32 and 4 to 16 microg/ml, respectively) were determined. High-performance liquid chromatography, mass spectrometry, amino acid analysis, digestion by R39 D,D-carboxypeptidase, and N-terminal amino acid sequencing were utilized. UDP-muramyl-tetrapeptide-D-lactate constituted 1.7% of total cytoplasmic peptidoglycan precursors in the most resistant strain. It is not clear if this amount of depsipeptide precursor can account for the levels of resistance achieved by this strain. Detailed structural analysis of mature peptidoglycan, examined for the first time for this species, revealed that the peptidoglycan of these strains, like that of other staphylococci, is highly cross-linked and is composed of a lysine muropeptide acceptor containing a substitution at its epsilon-amino position of a glycine-containing cross bridge to the D-Ala 4 of the donor, with disaccharide-pentapeptide frequently serving as an acceptor for transpeptidation. The predominant cross bridges were found to be COOH-Gly-Gly-Ser-Gly-Gly-NH2 and COOH-Ala-Gly-Ser-Gly-Gly-NH2. Liquid chromatography-mass spectrometry analysis of the peptidoglycan of resistant strains revealed polymeric muropeptides bearing cross bridges containing an additional serine in place of glycine (probable structures, COOH-Gly-Ser-Ser-Gly-Gly-NH2 and COOH-Ala-Gly-Ser-Ser-Gly-NH2). Muropeptides bearing an additional serine in their cross bridges are estimated to account for 13.6% of peptidoglycan analyzed from resistant strains of S. haemolyticus. A soluble glycopeptide target (L-Ala-gamma-D-iso-glutamyl-L-Lys-D-Ala-D-Ala) was able to more effectively compete for vancomycin when assayed in the presence of resistant cells than when assayed in the presence of susceptible cells, suggesting that some of the resistance was directed towards the cooperativity of glycopeptide binding to its target. These results are consistent with a hypothesis that alterations at the level of the cross bridge might interfere with the binding of glycopeptide dimers and therefore with the cooperative binding of the antibiotic to its target in situ. Glycopeptide resistance in S. haemolyticus may be multifactorial.

Amino Acid Sequence↗
PubMed1996

Molecular epidemiology in environmental carcinogenesis.

Molecular epidemiology has significant potential in preventing cancer and other diseases caused by environmental exposures (related to lifestyle, occupation, or ambient pollution). This approach attempts to prevent cancer by incorporating laboratory methods to document the molecular dose and preclinical effects of carcinogens, as well as factors that increases individual susceptibility to carcinogens. Recently we have carried out validation studies of biologic markers such as carcinogen--DNA and carcinogen--protein adducts, gene and chromosomal mutations, alterations in target oncogenes or tumor suppressor genes, polymorphisms in putative susceptibility genes (individual P450s, glutathione transferase M1), and serum levels of micronutrients. This research involves adults, infants, and children exposed to varying levels of carcinogens, as well as cancer cases and controls. On a group level, dose-response relationships have frequently been seen between various biomarkers and environmental exposures such as polycyclic aromatic hydrocarbons, cigarette smoke (active and passive), and ambient indoor and workplace air pollution. However, there is significant interindividual variation in biomarkers that appears to reflect a modulating effect on biomarkers (hence potential risk) by genetic and acquired susceptibility factors. Ongoing retrospective and nested case-control studies of lung and breast cancer are examining the association between biomarkers and cancer risk. Results of these studies are encouraging; they suggest that biomarkers, once validated, can be useful in identifying populations and individuals at risk in time to intervene effectively.

Biomarkers, Tumor↗
PubMed1996

Malaria in Honiara, Solomon Islands: vector studies.

Adult and larval specimens of anopheline mosquitos were collected throughout eastern Honiara during a study into risk factors for malaria illness in adults. Species identification was by morphology, DNA probes and by PCR. Only Anopheles farauti s.s. were identified from part-night landing catches carried out from 1900 to 2200 hours. Most mosquitos attracted to humans were culicines. The majority of anophelines (85%) were captured between 1900 and 2000 hours. An. farauti s.s. larvae were most common but one An. farauti No. 7, and ten An. punctulatus larvae were also collected.

Adult↗
PubMed1995

Activity of amylin at CGRP1-preferring receptors coupled to positive contractile response in rat ventricular cardiomyocytes.

Calcitonin gene-related peptide (CGRP) exerts a positive contractile response directly in rat ventricular cardiomyocytes. This response is mediated by receptors of the CGRP1-subtype. Amylin is 46% homologous with CGRP and binds to receptors selective for CGRP in a range of tissues. The ability of amylin to influence ventricular contractility has been assessed using cardiomyocytes isolated from the ventricles of adult rats. Cardiomyocytes were subjected to biphasic electrical stimulation at 0.5 Hz. CGRP produced a concentration-dependent positive contractile response which became maximal 4 min after initial stimulation. CGRP increased the contractile amplitude maximally at 1 nM and to a value which was 23.3% greater than in the absence of peptide (EC50 value = 21 pM). Amylin increased the contractile amplitude maximally at 20 nM and to a value which was 17.3% greater than in the absence of peptide (EC50 value = 216 pM). In the presence of amylin (20 nM), the concentration-dependence of the contractile response to CGRP was shifted to the left, so that the response became maximal when CGRP was present at 50 pM. In the presence of CGRP8-37 (100 nM), a selective antagonist at CGRP1-preferring receptors, the concentration-dependence of the contractile response to CGRP was shifted to the right (dose ratio = 54). Similarly, in the presence of CGRP8-37 (100 nM), the contractile response to amylin was inhibited significantly (P < or = 0.01). Amylin8-37 (100 nM) did not inhibit the concentration-dependence of the contractile responses to CGRP and amylin significantly (dose ratios = 4.2 and 2.4, respectively). In conclusion, these data indicate that amylin exerts a contractile response directly in rat ventricular cardiomyocytes via CGRP1-preferring receptors. This effect could assume greater significance in non-insulin-dependent diabetes mellitus and in hypertensive states, in which the concentration of amylin is elevated in plasma.

Amyloid↗