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Biomedical subjects

A Bryant

Publications and source records attributed to A Bryant.

At least 19 recordsLinked to original sources
PubMed2001

Transformation of cells overexpressing a tyrosine kinase by phospholipase D1 and D2.

Phospholipase D (PLD) activity is elevated in response to most mitogenic signals. Two mammalian PLD genes (PLD1 and PLD2) have been cloned and their gene products have been characterized. PLD1 is a downstream target of the Ras/RalA GTPase cascade implicated in mitogenic and oncogenic signaling. Consistent with a role in mitogenic signaling, elevated expression of PLD1 transforms cells overexpressing the epidermal growth factor (EGF) receptor (EGFR). However, PLD2 colocalizes with the EGFR in caveolin-enriched light membrane microdomains. We therefore investigated whether PLD2 could also contribute to the transformation of cells overexpressing a tyrosine kinase. We report here that elevated expression of PLD2 transforms rat fibroblasts overexpressing either the EGFR or c-Src. Since overexpression of a tyrosine kinase is a common genetic alteration in several human cancers, these data suggest that elevation of either PLD1 or PLD2 may contribute to the progression to a malignant phenotype in cells with elevated tyrosine kinase activity.

Animals↗
PubMed2001

Paying for the pill.

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Contraceptives, Oral↗
PubMed2001

Nicotine yield from machine-smoked cigarettes and nicotine intakes in smokers: evidence from a representative population survey.

BACKGROUND: The relevance of nicotine yields from machine-smoked cigarettes for quantifying smokers' nicotine intakes and exposure to cigarette toxins has been called into question. However, most studies of the relationship between nicotine yield and nicotine intake have been on relatively small and unrepresentative samples and have included few smokers of "ultra-low" brands (i.e., those yielding around 1 mg of tar and 0.1 mg of nicotine). METHODS: We examined the relationship between salivary cotinine (a major metabolite of nicotine) concentrations and nicotine yields of machine-smoked cigarettes in a nationally representative sample of 2031 adult smokers of manufactured cigarettes surveyed in the 1998 Health Survey for England. We used standard linear regression techniques to examine associations and two-sided tests of statistical significance. RESULTS: Cotinine concentrations varied widely between smokers at any level of nominal brand nicotine yield. On average, cotinine levels were slightly lower in smokers of lower nicotine-yielding brands, but these smokers differed in terms of sex, socioeconomic profile, and cigarette consumption. After we controlled for potential confounders, nicotine yield from the brand smoked accounted for only 0.79% of the variation in saliva cotinine concentrations. Nicotine intake per cigarette smoked, as estimated from salivary cotinine level, did not correspond with machine-smoked yields at any level of nicotine yield. Nicotine intake per cigarette was about eight times greater than machine-smoked yields at the lowest deliveries (1.17 mg estimated nicotine intake per cigarette from brands averaging 0.14-mg delivery from machine smoking) and 1.4 times greater for the highest yield cigarettes (1.31-mg estimated nicotine intake per cigarette from brands averaging 0.91 mg from machine smoking). CONCLUSIONS: Smokers' tendency to regulate nicotine intake vitiates potential health gains from lower tar and nicotine cigarettes. Current approaches to characterizing tar and nicotine yields of cigarettes provide a simplistic guide to smokers' exposure that is misleading to consumers and regulators alike and should be abandoned.

Adolescent↗
PubMed2001

Effects of dexmedetomidine on adrenocortical function, and the cardiovascular, endocrine and inflammatory responses in post-operative patients needing sedation in the intensive care unit.

We have compared the effects of dexmedetomidine and propofol on endocrine, metabolic, inflammatory and cardiovascular responses in patients in the intensive care unit (ICU) after major surgery. Twenty patients who were expected to require 8 h of post-operative sedation and ventilation were allocated randomly to receive either an infusion of dexmedetomidine 0.2-2.5 microg kg(-1) h(-1) or propofol 1-3 mg kg(-1) h(-1). Arterial pressure, heart rate and sequential concentrations of circulating cortisol, adrenocorticotrophic hormone (ACTH), growth hormone, prolactin, insulin, glucose and interleukin 6 were measured. An ACTH stimulation test was performed in all patients who received dexmedetomidine. Heart rate was significantly lower in the dexmedetomidine patients. There were no differences in arterial pressure, cortisol, ACTH, prolactin and glucose concentrations between the two groups. A positive response to the ACTH stimulation test varied depending on the diagnostic criteria used. The insulin concentration was significantly lower in the dexmedetomidine group at 2 h (P=0.021), although this did not affect blood glucose concentrations. Growth hormone concentrations were significantly higher in dexmedetomidine-treated patients overall (P=0.036), but circulating concentrations remained in the physiological range. Interleukin 6 decreased in the dexmedetomidine group. We conclude that dexmedetomidine infusion does not inhibit adrenal steroidogenesis when used for short-term sedation after surgery.

Adrenal Cortex↗
PubMed2001

Passive smoking in the home: plasma cotinine concentrations in non-smokers with smoking partners.

BACKGROUND: Risks of lung cancer and of heart disease attributable to passive smoking have been evaluated mainly in non-smokers married to smokers, but there has been little quantitative assessment of the extent of exposure in marriage partners as indicated by markers of inhaled smoke dose. OBJECTIVE: To relate plasma cotinine concentrations in non-smoking English adults to the smoking behaviour of their partners and to demographic and other factors. DATA: Population survey. Data from two years (1994 and 1996) of the Health Survey for England. MAIN OUTCOME MEASURES: Plasma cotinine concentrations in non-smoking adults married to or cohabiting with a partner. RESULTS: There was a strong dose-response relation between cotinine concentrations in non-smoking adults and the smoking behaviour of their partners, rising from a geometric mean of 0.31 ng/ml in those with non-smoking partners to 1.99 ng/ml in those whose partners smoked 30 or more cigarettes per day. In addition, exposure was greater in men, in the autumn and winter, and in those living in more disadvantaged circumstances, and there was an increasing gradient of exposure from the south to the north of the country. On average, cotinine concentrations in non-smokers with a smoking partner were 0.6-0.7% of those in cigarette smokers. CONCLUSIONS: If cotinine is taken as a measure of risk relevant dose, the implied increase in risk of lung cancer in non-smokers with smoking partners is consistent with the risk observed in epidemiological studies. Smoking by partners in the home is a major source of non-smoking adults' exposure to passive smoking.

Adult↗
PubMed2001

Lateral intermetatarsal angle: a useful measurement of metatarsus primus elevatus?

The lateral intermetatarsal angle, a measurement of the sagittal plane angular divergence between the dorsal cortices of the first and second metatarsals of lateral weightbearing foot radiographs, was compared in 30 normal and 30 hallux limitus feet. The results suggest that the angle may be measured reliably and that although the measured angles are relatively small, a significant difference exists between the normal and hallux limitus subjects studied. Accordingly, the lateral intermetatarsal angle may prove to be a useful radiographic measurement to assist the podiatric physician in the clinical assessment of hallux limitus.

Adult↗
PubMed2001

Hampshire depression project: changes in the process of care and cost consequences.

Records of patients included in a trial of educating practice teams about the management of depression were examined to determine changes in the process of care. There were no significant differences in the proportions recognised or treated for depression. Only 15% of those with possible, and 26% of those with probable, major depressive disorder were prescribed recommended doses and duration of antidepressants. The education apparently delayed a switch away from tricyclics while achieving a similar outcome. However health service costs were mainly non-psychiatric, and there were no significant savings as a result.

Antidepressive Agents↗
PubMed2000

Children's exposure to passive smoking in England since the 1980s: cotinine evidence from population surveys.

OBJECTIVE: To determine whether children's exposure to passive smoking has changed since the late 1980s. DESIGN: Cross sectional surveys of nationally representative samples of secondary school children carried out between 1988 and 1998 by Office for National Statistics. SETTING: England. SUBJECTS: Secondary school children aged 11-15. MAIN OUTCOME MEASURES: Salivary cotinine concentrations in non-smoking children. RESULTS: Cotinine concentrations in all non-smoking children almost halved between 1988 and 1998, from a geometric mean of 0.96 (95% confidence interval 0.83 to 1.11) ng/ml in 1988 to 0.52 (0.43 to 0.62) ng/ml in 1998. This reduction was largely due to reductions in exposure in children from non-smoking households and to decreases in the percentage of parents who smoked. Children living with mothers or fathers who smoked experienced little reduction in exposure. CONCLUSIONS: Exposure to passive smoking among children in England has approximately halved since the late 1980s. This reduction is partly explained by the fall in the percentage of both mothers and fathers who smoke and is also likely to reflect reductions of smoking in public places. However, there is only limited evidence that children from smoking households have experienced a reduction in exposure through parents' avoidance of smoking in their presence.

Adolescent↗
PubMed2000

Mitogenic phospholipase D activity is restricted to caveolin-enriched membrane microdomains.

Phospholipase D (PLD) activity is elevated in response to the oncogenic stimulus of several signaling oncogenes. PLD activity is also elevated in response to peptide growth factors, indicating that PLD likely plays an important role in mitogenic signaling. Many proteins that mediate mitogenic signaling are localized in caveolin-enriched membrane microdomains (CEMMs). We report here that the elevated PLD activity in NIH 3T3 cells transformed by activated oncogenic forms of Src, Ras, and Raf is largely restricted to the CEMMs. Likewise, the PLD activity stimulated by epidermal growth factor is also restricted to the CEMMs. Although both PLD1 and PLD2 were found in CEMMs, neither was particularly enriched in the CEMMs of the transformed relative to the parental cells, indicating that it is the specific activity of PLD that is increased in the CEMMs. An apparent PLD substrate specificity in transformed cells for phosphatidylcholine lacking arachidonate acyl groups is also explained by the localization of activity in the CEMMs where [(3)H]arachidonate-labeled PC was excluded. These data indicate that mitogenic signals through PLD are initiated in CEMMs where many signaling molecules colocalize.

3T3 Cells↗
PubMed2000

The gold rush.

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Biotechnology↗
PubMed2000

Genetic characterization of gram-positive homologs of the XerCD site-specific recombinases.

Homologs of the XerCD enzymes, which in Escherichia coli have been shown to be responsible for resolving chromosomal multimers prior to chromosome segregation, were identified in the genomes of Staphylococcus aureus and Streptococcus pneumoniae. Phylogenetic and conservation pattern analysis suggests that the S. aureus gene products are orthologs of XerC and D. A S. aureus xerC null mutant displayed in vitro characteristics consistent with the segregation defect reported for E. coli xer mutants, and was found to be attenuated in a murine infection model. Strikingly, the S. aureus xerD gene appears to be absolutely required for viability, and may therefore be the first example of an essential gene of the lambda integrase family. In contrast, phylogenetic and conservation pattern analysis show that the S. pneumoniae gene products are more closely related to phage integrases than to XerCD. S. pneumoniae xer1, 2 and 3 null mutants were each found to be attenuated in a murine infection model, suggesting that they may control processes which affect virulence.

Alleles↗
PubMed1999

Comparison of the reliability of plantar pressure measurements using the two-step and midgait methods of data collection.

The reliability of plantar pressure measurements obtained using the traditional midgait method compared with the two-step method was investigated. Using an EMED-SF system, the parameters of contact area, contact time, maximum force, and peak pressure at seven sites of the foot were assessed for reliability of measurement in 10 normal subjects. The results of the study indicate that the two-step method is as reliable as the midgait method and may be preferred for use in both research and clinical settings.

Adult↗
PubMed1998

Composition of peripheral blood lymphocyte populations during different stages of chronic infection with hepatitis B virus.

To characterize the immunological populations associated with different stages of chronic infection with hepatitis B virus (HBV), we performed flow cytometric analyses on the peripheral blood leucocytes of 29 patients with various forms of chronic hepatitis B. The clinical spectrum of the patients ranged from asymptomatic infections, in the presence of high virus production, to intermittent or recurrent exacerbations of liver injury alternating with relatively normal liver function. Patients with partial resolution of disease who experienced an initial acute flare followed by prolonged seroconversion showed decreased percentages of CD3+ cells during the seroconversion phase when levels of serum alanine transferase (ALT) had normalized. These CD3+ cells were predominantly CD4+ cells bearing the alpha beta+ T-cell receptor (TCR). In addition, we saw an increase in CD4+ and CD8+ cells bearing the gamma delta TCR in those patients who had seroconverted. No significant differences were seen between any of the groups with respect to percentage of cells with a naive (CD45RA) or memory (CD45RO) phenotype, or of cells displaying the activation markers CD38, HLA-DR or CD57. Longitudinal analyses of 15 patients failed to show any consistent pattern of changes in the immunophenotypic profile during acute flares and their resolution. Our results indicate that the turnover of circulating T lymphocytes during the apparent quiescent phase of chronic infections is higher than that during acute exacerbations, suggesting an active immunosurveillance role of T-cell subpopulations in maintaining low virus levels during seroconversion.

Adolescent↗
PubMed1997

Validity of adolescents' report of maternal age.

Examined the validity of adolescents' reports of their mother's age. Most research on the validity of self-report focuses on personal behaviors such as alcohol and substance use, or response bias due to social desirability. Few studies investigate the validity of adolescents reporting of nonsensitive information. Data from 80 mother-adolescent pairs were collected. The sample included 9th graders from four high school English classes, equal numbers of males and females, and 15% African Americans. The correlation between mothers' reports and youths' reports of mother's age was .99, and 95% of the youth were within a year of their mother's correct age. No race or gender differences were found. These results allow researchers to examine adolescent outcomes for youth born to teen mothers without the expense of also collecting data from their mothers. Results also suggest that adolescents' self-reports of other nonsensitive familial data may also be valid.

Adolescent↗
PubMed1996

Antitumour evaluation of dolastatins 10 and 15 and their measurement in plasma by radioimmunoassay.

Dolastatins 10 and 15 are small peptides isolated from the marine sea hare Dolabella auricularia that have been shown to interact with tubulin. Their growth-inhibitory properties were compared using panels of human ovarian and colon-carcinoma cell lines. Both agents were very potent inhibitors of cell growth, with dolastatin 10 being an average of 9.1-fold more potent than dolastatin 15 [mean 50% inhibitory concentrations (IC50 values) 2.3 x 10(-10) and 2.1 x 10(-9) M, respectively; P < 0.05] and more potent than paclitaxel or vinblastine. While neither dolastatin exhibited marked cross-resistance in cisplatin- or etoposide-resistant cell lines, contrasting effects were observed using an acquired doxorubicin-resistant (CH1doxR, 100-fold resistant, P-glycoprotein overexpressing) cell line. Resistance was significantly higher to dolastatin 15 (12.7-fold) than to dolastatin 10 (only 3.2-fold; P < 0.05) and was reversible in both cases by verapamil. In vivo, using a s.c. advanced-stage human ovarian carcinoma xenograft and equitoxic doses, greater activity was observed with dolastatin 10 (6.1-day growth delay) versus 0.4 days for dolastatin 15. A radioimmunoassay for dolastatin 10 (limit of detection in mouse plasma 5 ng/ml) was developed. The rabbit antiserum aslo cross-reacted by 65% with dolastatin 15. Comparative mouse pharmacokinetics following i.v. administration of 1 mg/kg showed that both compounds are rapidly eliminated, but with a shorter second-phase half-life (t1/2 beta) being observed for dolastatin 15 (being detectable for only up to 4 h post-administration), the t1/2 beta being 3 times longer for dolastatin 10. In addition, areas under the plasma concentration-time curve (AUC values) were 1.6-fold higher for dolastatin 10 (333 versus 208 ng ml-1 h). Plasma binding of dolastatin 10 exceeded 90%. The highly sensitive RIA will be useful for pharmacokinetic studies in conjunction with the planned phase I clinical trials of these novel, extremely potent, tubulin-binding agents, of which dolastatin 10 appears to possess the more promising preclinical features.

Animals↗
PubMed1995

Synthesis and in vitro and in vivo antitumor activity of a series of trans platinum antitumor complexes.

The synthesis of a series of platinum complexes of trans coordination geometry [centered around the general formula, trans-ammine(amine)dichlorodihydroxoplatinum(IV) plus corresponding tetrachloroplatinum(IV) or Pt(II) counterparts] is described as part of a drug discovery program to identify more effective platinum-based anticancer drugs, particularly targeted toward the circumvention of resistance to cisplatin. Complexes have been evaluated for antitumor activity using in vitro and in vivo tumor models. In vitro against a panel of cisplatin-sensitive and -resistant human tumor cell lines (predominantly ovarian), many of the trans platinum complexes studied (e.g., 1, R = cyclohexyl) exhibited comparable potency to cisplatin and also overcame acquired cisplatin resistance, where resistance was due mainly to either reduced drug uptake or enhanced platinum-DNA adduct removal. Moreover, 14 trans complexes showed significant in vivo antitumor activity against the subcutaneous murine ADJ/PC6 plasmacytoma model; all were platinum(IV) complexes, 13/14 possessing axial hydroxo ligands the other possessing axial ethylcarbamato ligands. Where tested, all of their respective platinum(II) or tetrachloroplatinum(IV) counterparts were inactive. Notably, three dihydroxoPt(IV) complexes (18, 29, 34) (R = c-hexyl, c-heptyl, and 1-adamantyl) retained some efficacy against a cisplatin-resistant variant of the ADJ/PC6. Compounds 18 (trans-[PtCl2(OH)2NH3-(RNH2)]) R = c-C6H11, 22, R = Me3C, 27, R = n-C6H13, 28, R = PhCH2, and 36 (trans-[PtBr2(OH)2NH3(c-C6H11NH2)]) also produced evidence of antitumor activity (> 5 days growth delay) against subcutaneously grown advanced stage human ovarian carcinoma xenografts. These data demonstrate that a series of trans-ammine(amine)dichlorodihydroxoplatinum(IV) complexes are active in vivo against both murine and human subcutaneous tumor models and represent potential leads to a new generation of platinum-based anticancer drug.

Animals↗
PubMed1994

A novel trans-platinum coordination complex possessing in vitro and in vivo antitumor activity.

As part of a drug discovery program to discover more effective platinum-based anticancer drugs, a series of platinum complexes of trans coordination geometry centered on trans-ammine(cyclohexylaminedichlorodihydroxo)platinum(IV) (JM335) has been evaluated in vitro against a panel of cisplatin-sensitive and cisplatin-resistant human tumor cell lines (predominantly ovarian). In vitro, against 5 human ovarian carcinoma cell lines, JM335 was comparably cytotoxic to cisplatin itself and over 50-fold more potent than transplatin (mean 50% inhibitory concentrations: JM335, 3.1 microM; cisplatin, 4.1 microM; transplatin, 162 microM). With the use of seven pairs of human tumor cell lines (parent and subline with acquired resistance to cisplatin and encompassing all of the known major mechanisms of resistance to cisplatin) JM335 exhibited a different cross-resistance pattern to that of its cis isomer (JM149). JM335 showed non-cross-resistance in six of the seven resistant lines, cross-resistance in the A2780cisR line possibly being associated with high levels of glutathione. Preliminary intracellular DNA binding studies showed that in contrast to transplatin, JM335 was efficient at forming DNA-DNA interstrand cross-links. In vivo, JM335 produced growth delays in excess of 15 days against 4 of 6 human ovarian carcinoma xenografts and was unique among the complexes studied in retaining some efficacy against a cisplatin-resistant subline of the murine ADJ/PC6 plasmacytoma. JM335 is the first trans-platinum complex to demonstrate marked antitumor efficacy against both murine and human s.c. tumor models and represents a significant structural lead to complexes capable of circumventing cross-resistance to cisplatin.

Animals↗