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D Bell

Publications and source records attributed to D Bell.

At least 55 records · Page 3Linked to original sources
PubMed1998

D-myo inositol 1,2,6, triphosphate (alpha-trinositol, pp56): selective antagonist at neuropeptide Y (NPY) Y-receptors or selective inhibitor of phosphatidylinositol cell signaling?

1. D-myo inositol 1,2,6 trisphosphate (alpha-trinositol, pp56), an isomer of the second messenger substance, D-myo inositol 1,4,5 trisphosphate, has an interesting pharmacological profile that includes anti-inflammatory and analgesic effects and antagonism of neuropeptide Y (NPY)-mediated cellular responses. 2. However, not all responses elicited by this neuropeptide are sensitive to antagonism by pp56. Evidence is emerging, at least in certain tissues, that other receptor populations, in addition to those for NPY, are also sensitive to inhibition by pp56. 3. A direct or allosteric interaction of pp56 at receptors for NPY is now considered unlikely and it is more probable that pp56 might interfere at some point in the phosphatidylinositol signaling pathway, possibly at the level of the plasmalemmal inositol 1,3,4,5, tetrakisphosphate receptor. 4. Full realization of the therapeutic potential of this novel compound, however, must await a thorough characterization of the cellular mechanism(s) associated with the various pharmacological effects of pp56.

Animals↗
PubMed1998

A phase II study of gemcitabine in platinum pre-treated patients with advanced epithelial ovarian cancer.

BACKGROUND: Most patients with advanced ovarian cancer will relapse following platinum-based combination chemotherapy and be considered for second-line treatment. Gemcitabine, a nucleoside analogue, is active against a range of solid tumors. This phase II study investigated the activity of single-agent gemcitabine in patients with recurrent ovarian cancer. PATIENTS AND METHODS: Thirty-eight patients with FIGO stage III (34%) or IV (64%) ovarian cancer who were previously treated with platinum-containing regimens were enrolled. Patients received 1200 mg/m2 gemcitabine on days 1, 8 and 15 of a 28-day cycle. RESULTS: Patients completed an average of 3.6 cycles. Two complete and three partial responses were seen in 36 evaluable patients, for an overall response rate of 13.9% (95% CI: 4.7%-29.5%). The median survival time was 6.7 months. Toxicities were generally mild. The most common were grade 3-4 neutropenia and grade 3 leukopenia reported in 23.7% and 10.5% of patients, respectively. One patient had grade 4 pulmonary toxicity. CONCLUSION: Single-agent gemcitabine is active and well tolerated in patients with recurrent ovarian cancer.

Adult↗
PubMed1998

Rates of and risk factors for trichomoniasis among pregnant inmates in New York City.

BACKGROUND: Trichomonas vaginalis is a common pathogen that is associated with adverse pregnancy outcomes and may serve as a cofactor in human immunodeficiency virus (HIV) transmission. GOAL: To define the epidemiology of trichomoniasis in a population of newly incarcerated pregnant women in New York City. STUDY DESIGN: Prospective study of 213 pregnant prisoners attending prenatal clinic. Patients participated in an interview regarding sexual and drug-related behaviors, and underwent direct culture for T. vaginalis in addition to routine testing for syphilis, gonorrhea, and chlamydia. RESULTS: The prevalence of trichomoniasis was 46.9%. On univariate analysis, there was a significant association between trichomoniasis and older age, crack use, prostitution, known HIV infection, and positive serological test for syphilis. Multivariate analysis showed a significant association of trichomoniasis with crack use and positive serological test for syphilis. CONCLUSION: Trichomoniasis is highly prevalent in pregnant prisoners in New York City. The extent of disease observed may justify a formal program of testing and treatment and emphasizes the urgent need for harm reduction education and expanded HIV counseling and testing services in this high-risk population.

Adolescent↗
PubMed1998

Type 2 diabetes mellitus and Aboriginal Australians. Options for oral therapy in the control of glyceamia.

BACKGROUND: Type 2 diabetes mellitus is a major and increasing cause of morbidity and early mortality among the Aboriginal population of northern Australia. Due to differing social, dietary and probably metabolic factors, management needs differ from the mainstream Australian diabetic population. OBJECTIVE: This paper concentrates on the options for oral therapy in the control of glycaemia, taking into account various current guidelines and recent trials of oral antihyperglycaemic therapy, and the specific metabolic and clinical associations with type 2 diabetes mellitus in this population. DISCUSSION: In the abscence of specific contraindications, and in variance with some present guidelines, the evidence suggests that initial therapy with metformin rather than the sulphonylureas is likely to provide greater clinical benefit, and have a greater margin of safety.

Administration, Oral↗
PubMed1997

Evidence for Y1 and Y2 subtypes of neuropeptide Y receptors linked to opposing postjunctional effects observed in rat cardiac myocytes.

The aim of this study was to confirm the existence of and identify the receptor subtypes for neuropeptide Y that are present post-junctionally in myocardium. The effects of the selective agonists, [Leu31, Pro34] neuropeptide Y (neuropeptide Y Y1 receptors), neuropeptide Y-(13-36) and peptide YY-(3-36) (neuropeptide Y Y2 receptors), and neuropeptide Y and the related peptide YY, which have differential action at neuropeptide Y Y3 receptors, on amplitudes of contraction of adult rat ventricular cardiomyocytes were studied. Also, the effect of the neuropeptide Y Y1-selective antagonist, bis(31/31')[[Cys31, Trp32, Nva34] neuropeptide Y-(31-36)] on neuropeptide Y-mediated changes in myocyte contraction was investigated. Neuropeptide Y, peptide YY, neuropeptide Y-(13-36) and peptide YY-(3-36) attenuated the isoprenaline (10(-7) M)-stimulated contractile response, and the EC50 values were 9.0 x 10(-9), 4.3 x 10(-10), 3.1 x 10(-11) and 8.5 x 10(-11) M, respectively. [Leu31, Pro34] neuropeptide Y increased the contractile response of cardiomyocytes, and the EC50 values were 8.1 x 10(-9) and 1.5 x 10(-9) M, in the absence and presence of isoprenaline, respectively. Since [Leu31, Pro34] neuropeptide Y caused a positive effect on ventricular myocyte contraction and neuropeptide Y-(13-36) and peptide YY (3-36) produced the most potent negative effects, it is proposed that both neuropeptide Y Y1 and neuropeptide Y Y2 receptors, linked respectively to the positive and negative responses, are expressed in cardiomyocytes. The finding of receptors with neuropeptide Y Y2 characteristics on cardiomyocytes represents a further example of a postjunctional location for this subtype. As there was no significant discrepancy between the potencies of peptide YY and neuropeptide Y to attenuate the contractile response, it appears that neuropeptide Y Y3-like receptors are not linked principally to contractile function in rat cardiomyocytes. Bis(31/31')[[Cys31, Trp32, Nva34] neuropeptide Y-(31-36)] antagonised the neuropeptide Y-mediated stimulation of contractile activity through neuropeptide Y Y1 receptors, but the compound also inhibited the attenuation of isoprenaline-stimulated contraction, apparently by acting as a partial agonist at the neuropeptide Y Y2 receptors.

Animals↗
PubMed1997

Calcitonin gene-related peptide (CGRP) increases cell surface area and induces expression of skeletal alpha-actin ANP mRNA in hypertrophying neonatal cardiomyocytes.

We have reported previously that calcitonin gene-related peptide (CGRP) exerts hypertrophic effects, defined in the broadest sense as increased mass of protein per cell, in adult rat ventricular in vitro. The aim of the present investigation was to determine whether the peptide also increases the cell surface area of, and induces expression of ANP and skeletal alpha-actin mRNA in hypertrophying neonatal rat ventricular cardiomyocytes. Cells cultured in the presence of CGRP were invisibly hypertrophied after 48 h compared to cells cultured in serum-free MEM for the same period. CGRP, 100 pM and 1 nM, increased cell surface area significantly and to values 1.82- and 2.15-fold greater, respectively, than in the absence of peptide (659.64 +/-23.48 microns 2, n = 10). The selective antagonist at CGRP1, receptors, CGRP8-37(200nM), significantly attenuated the effects of CGRP (100 pM and 1 nM). CGRP caused a marked up-regulation of the expression of mRNA encoding skeletal alpha-actin and ANP, respectively, maximally after 12 h and at a concentration of 100 pM, to values approximately 3.6- and 2.5-fold greater than in the absence of peptide. These effects of the peptide were completely abolished in the presence of CGRP8-37(100 nM). In conclusion, CGRP increases cell surface area and induces expression of ANP and skeletal alpha-actin mRNA in hypertrophying cardiomyocytes via the CGRP1, receptor subtype.

Actins↗
PubMed1997

Transcriptional induction of cholesterol 7alpha-hydroxylase by dexamethasone in L35 hepatoma cells requires sulfhydryl reducing agents.

It is known that hepatic levels of reduced glutathione correlate with the activity of the liver-specific enzyme cholesterol-7alpha-hydroxylase. We examined the possibility that sulfhydryl reducing agents activate transcription of cholesterol 7alpha-hydroxylase. Adding dithiothreitol (DTT, 1 mM) and dexamethasone to L35 hepatoma cells increased the content of 7alpha-hydroxylase mRNA 3-fold above the levels observed with dexamethasone alone. Without dexamethasone, DTT had no affect. The addition of reduced glutathione to L35 cells demonstrated a similar potentiation of expression dependent on dexamethasone. Nuclear run-on assays showed that in the presence of both dexamethasone and DTT, the transcription of the 7alpha-hydroxylase gene was clearly increased. In contrast, by itself, dexamethasone did not cause a detectable increase in the transcription of the 7alpha-hydroxylase gene. Dexamethasone and DTT did not affect the transcription of beta-actin, suggesting a selective induction of the 7alpha-hydroxylase gene. DTT reversed repression of 7alpha-hydroxylase expression by insulin but not the repression by phorbol ester. Our data show for the first time that the sulfhydryl redox potential of the hepatocyte (i.e. level of reduced glutathione) has a marked influence on the transcription and expression of the liver-specific gene 7alpha-hydroxylase.

Animals↗
PubMed1997

Use of D-myo inositol 1,2,6 trisphosphate to inhibit contractile activity in rat ventricular cardiomyocytes induced by neuropeptide Y and other cardioactive peptides through phospholipase C.

1. D-Myo inositol 1,2,6 trisphosphate (alpha-trinositol, pp56), an isomer of the second messenger substance, inositol 1,4,5 trisphosphate, has an interesting pharmacological profile that includes antagonism of a number of neuropeptide Y (NPY)-mediated cellular processes. The ability of pp56 to inhibit selectively the myocardial contraction mediated by NPY in relation to the responses to other cardioactive peptides, including endothelin-1, calcitonin gene-related peptide (CGRP), secretin and vasoactive intestinal peptide (VIP), was assessed. In order to investigate the possible interaction of pp56 with mechanisms of inositol phosphate signalling generated in heart muscle cells by activation of the beta-isoenzyme of phospholipase C (PLC beta), noradrenaline was used as a positive control, and isoprenaline and forskolin were included as negative controls. 2. Ventricular cardiomyocytes, isolated from the hearts of adult rats, were stimulated to contract at 0.5 Hz in the presence of calcium ion (2 mM). The concentrations of agonists used were in the region of their maximally effective concentrations for myocyte contraction and the concentration of pp56 was in the range of 1-100 microM. Contractile activity was monitored by video microscopy and maximum shortening determined by image analysis. 3. In the absence of agonist, contractile amplitudes following 20 min preincubation with pp56 were not different from that observed in the absence of pp56. Pp56 (1-100 microM) inhibited significantly the positive contractile response to noradrenaline (5 microM) in the presence of propranolol (500 nM), such that the response was almost completely attenuated at the highest concentration of the inhibitor. Pp56 did not inhibit the positive contractile responses to forskolin (40 microM) or isoprenaline (100 nM). 4. NPY alone does not influence the basal level of contraction of cardiomyocytes, but can attenuate isoprenaline-stimulated contraction and can increase contractile amplitude from basal when the transient outward current is blocked with 4-aminopyridine. In the presence of isoprenaline (100 nM), the negative response to NPY (100 nM) was attenuated significantly by pp56 (1-100 microM). With 4-aminopyridine, the positive contractile response to NPY (200 nM) was decreased by pp56, although this was not statistically significant. 5. Pp56 inhibited the positive contractile responses to CGRP (1 nM) and endothelin-1 (20 nM) completely, but did not affect the responses to secretin (20 nM) or VIP (20 nM). 6. In conclusion, these data challenge the previously obtained selectivity of pp56 as an antagonist of NPY-mediated cellular processes, since responses to CGRP and endothelin-1 were at least equally sensitive. Furthermore, as pp56 discriminated clearly in its inhibition of responses to alpha-adrenoceptor by comparison with beta-adrenoceptor/adenylate cyclase stimulation, it appears that pp56 may be a useful pharmacological agent with which to distinguish between PLC beta-dependent and PLC beta-independent coupling mechanisms. On this basis, further evidence has been obtained that, in rat cardiomyocytes, the contractile responses to NPY, CGRP and endothelin-1 are attributable to the activation of PLC beta-dependent pathways, whereas the responses to secretin and VIP are mediated by PLC beta-independent pathways.

Animals↗
PubMed1997

Aromatic DNA adducts in foundry workers in relation to exposure, life style and CYP1A1 and glutathione transferase M1 genotype.

Levels of aromatic DNA adducts in foundry workers and controls were followed at four annual samplings. During this time exposure to polycyclic aromatic hydrocarbons (PAH) decreased and the level of DNA adducts decreased accordingly. In the total group exposure was related to the level of adducts. Adduct levels correlated with urinary 1-hydroxypyrene (LOGU1OH), air benzo[a]pyrene, weekly working hours and daily cigarette consumption. In a multivariate model 1-hydroxypyrene had a consistent effect. Neither glutathione transferase M1 (GSTM1) nor cytochrome P450 1A1 (CYP1A1) genotypes had clear effects. Yet the individuals lacking GSTM1 had a stronger effect of LOGU1OH and some effect by other sources of PAH, such as charcoal broiled food, although all these variables were not significant in the multivariate model. The rare individuals with a CYP1A1 polymorphism MspI containing an amino acid change at isoleucine had an increased level of adducts. The results showed that the postlabelling method used was able to detect an increase in aromatic DNA adducts in leukocytes when exposure to benzo[a]pyrene in air was approximately 5 ng/m3. At such low levels smoking and charcoal broiled food may be important contributors to adducts.

Adult↗
PubMed1997

Involvement of endothelin (ET)A and ETB receptors in the hypertrophic effects of ET-1 in rabbit ventricular cardiomyocytes.

The question was addressed whether endothelin-1 (ET-1) exerts hypertrophic effects in cardiomyocytes isolated from ventricles of adult rabbits and maintained in short-term (24 h) serum-free primary culture providing mechanical quiescence. ET-1 (> or =100 pM) increased significantly total mass of cellular protein and incorporation of L-U-[(14)C]phenylalanine and 2-[(14)C]uridine into cellular protein and RNA, respectively. Cycloheximide (35 microM), an inhibitor of protein synthesis, significantly reduced the incorporation of L-U-[(14)C]phenylalanine and 2-[(14)C]uridine into cellular protein and RNA, respectively, under control conditions and in response to ET-1. Actinomycin D (5 microM), a selective inhibitor of transcription, abolished the incorporation of 2-[(14)C]uridine into cellular RNA and significantly reduced the incorporation of L-U-[(14)C]phenylalanine into cellular protein under control conditions and in response to ET-1. The selective antagonists at the ET(A) receptor [BQ123 (100 nM) and PD155080 (100 nM)] and the selective antagonist at the ET(B) receptor [BQ788 (100 nM)] significantly reduced the incorporation of L-U-[(14)C]phenylalanine into cellular protein in response to ET-1 (10 nM). The selective inhibitor of protein kinase C (PKC), bisindolylmaleimide (BIM) (5 microM), reduced markedly the incorporation of 2-[(14)C]uridine into cellular RNA and, to a lesser degree, the incorporation of L-U-[(14)C]phenylalanine into cellular protein in response to ET-1 (100 pM to 10 nM). ET-1 exerts hypertrophic effects directly in vitro in ventricular cardiomyocytes isolated from the hearts of adult rabbits. These effects are (a) due to de novo synthesis since total mass of cellular protein and incorporation of L-U-[(14)C]phenylalanine and 2-[(14)C]uridine into cellular protein and RNA, respectively, were increased; (b) mediated by both the ET(A) and ET(B) receptor subtypes; and (c) may be associated, at least partly, with the activation of PKC.

Animals↗
PubMed1997

Frequencies of the defective CYP2C19 alleles responsible for the mephenytoin poor metabolizer phenotype in various Oriental, Caucasian, Saudi Arabian and American black populations.

The 4'-hydroxylation of S-mephenytoin is polymorphic in man. The poor metabolizer (PM) phenotype exhibits a lower frequency in Caucasians (2-5%) compared to Oriental populations (13-23%). Previous studies from our laboratory have described two mutations (CYP2C19m1 and CYP2C19m2) which account for approximately 100% of Oriental and approximately 85% of Caucasian PM alleles. The present study examined whether the genotype predicted the phenotype in Japanese, Filipino and Saudi Arabian populations, and compared the frequencies of the defective CYP2C19 alleles in these populations with those found in European-Americans, Chinese-Taiwanese, and African-Americans from North Carolina. Among 53 Japanese, 15% were PMs and among 52 Filipinos 23% were PMs. Among 97 Saudi Arabians, only two were PMs. There was a complete concordance between genotype and phenotype in all three populations. The incidence of CYP2C19m1 was 0.23 (95% confidence limits 0.15-0.31) in Japanese, 0.39 (95% confidence limits 0.29-0.48) in Filipinos, 0.32 (95% confidence limits 0.26-0.38) in Chinese-Taiwanese, 0.15 (95% confidence limits 0.10-0.20) in Saudi Arabians, 0.13 (95% confidence limits 0.08-0.17) in European-Americans, and 0.25 in African-Americans from North Carolina (95% confidence limits (0.14-0.31). The incidence of CYP2C19m1 in Saudi Arabians was similar to that found in European-Americans, and significantly lower than that found in Oriental populations or African-Americans (p < 0.05). CYP2C19m2 was not found in European-Americans, Saudi Arabians or African-Americans (95% confidence limits 0-0.014). The incidence of CYP2C19m2 in the three Oriental populations ranged from 0.10 (95% confidence limits 0.05-0.17) in Japanese and 0.08 (95% confidence limits 0.03-0.13) in Filipinos to 0.06 (95% confidence limits 0.03-0.08) in Chinese-Taiwanese.

Alleles↗
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↗