Managing smoking cessation.
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Family Practice↗
Biomedical subjects
T Coleman
Publications and source records attributed to T Coleman.
Cloning and expression in Escherichia coli of an azoreductase gene from Clostridium perfringens and comparison with azoreductase genes from other bacteria.
A genomic library of Clostridium perfringens ATCC 3626 was constructed in phage lambda gt11 and screened with an antibody against the C. perfringens azoreductase, which catalyzes the reduction of azo dyes to aromatic amines. A positive recombinant phage, containing a 3.8 kb DNA fragment insert was selected and purified. Lytic and lysogenic Escherichia coli cultures infected with the recombinant phage had higher azoreductase activity than cultures infected only with the vector lambda gt11. The 3.8 kb DNA fragment was amplified by PCR and found to hybridize with one band from C. perfringens DNA digested with EcoR1, indicating the presence of a single copy of the azoreductase gene. The fragment also hybridized with DNA from other azoreductase-producing Clostridium species, a Eubacterium sp., Enterobacter cloacae, Citrobacter amalonaticus and E. coli, but not with DNA from some other species of anaerobic bacteria capable of reducing azo dyes. The data indicate that the sequence of the azoreducatse gene of C. perfringens is conserved in some anaerobes and facultative anaerobes, but not in others, and that different types of azoreductase genes must be found in other anaerobic bacteria.
Bacteria↗
Diet-induced diabetes activates an osteogenic gene regulatory program in the aortas of low density lipoprotein receptor-deficient mice.
Vascular calcification is common in people with diabetes and its presence predicts premature mortality. To clarify the underlying mechanisms, we used low density lipoprotein receptor-deficient (LDLR -/-) mice to study vascular calcification in the ascending aorta. LDLR -/- mice on a chow diet did not develop obesity, diabetes, atheroma, or vascular calcification. In contrast, LDLR -/- mice on high fat diets containing cholesterol developed obesity, severe hyperlipidemia, hyperinsulinemic diabetes, and aortic atheroma. A high fat diet without cholesterol also induced obesity and diabetes, but caused only moderate hyperlipidemia and did not result in significant aortic atheroma formation. Regardless of cholesterol content, high fat diets induced mineralization of the proximal aorta (assessed by von Kossa staining) and promoted aortic expression of Msx2 and Msx1, genes encoding homeodomain transcription factors that regulate mineralization and osseous differentiation programs in the developing skull. Osteopontin (Opn), an osteoblast matrix protein gene also expressed by activated macrophages, was up-regulated in the aorta by these high fat diets. In situ hybridization showed that peri-aortic adventitial cells in high fat-fed mice express Msx2. Opn was also detected in this adventitial cell population, but in addition was expressed by aortic vascular smooth muscle cells and macrophages of the intimal atheroma. High fat diets associated with hyperinsulinemic diabetes activate an aortic osteoblast transcriptional regulatory program that is independent of intimal atheroma formation. The spatial pattern of Msx2 and Opn gene expression strongly suggests that vascular calcification, thought to be limited to the media, is an active process that can originate from an osteoprogenitor cell population in the adventitia.
Animals↗
Comparison of video-recorded consultations with those in which patients' consent is withheld.
BACKGROUND: Video-recorded consultations are widely used for research in general practice. Recently, video recordings have begun to be used for the purposes of general practitioner (GP) registrar assessment. It is unknown, however, whether consultations in which patients withhold consent for recording differ from those that are recorded. AIM: To compare clinical problems and demographic characteristics of adult patients who consent to the video recording of consultations with those who withhold consent. METHOD: This was prospective study of 538 adult patients consulting 42 GPs, based in practices throughout Leicestershire. Each patient attended a surgery session with one of the 42 GPs between April 1995 and March 1996. Clinical presentations and demographic characteristics of patients consenting and withholding consent to the video recording of their consultations were compared. GPs' perceptions of whether patients in these two groups were distressed/upset or embarrassed were also compared. RESULTS: A total of 85.9% (462/538) of adults consented to video recording, and 14.1% (76/538) withheld consent. Multiple logistic regression revealed that patients who presented with a mental health problem were more likely to withhold consent to recording (odds ratio 2.5, 95% confidence interval 1.4-4.6). Younger patients were also more likely to withhold consent to video recording. Additionally, where patients' consent was withheld, GPs perceived patients to be more distressed or embarrassed. CONCLUSION: Younger patients and those suffering from mental health problems are more likely than others to withhold consent to being video recorded for research purposes in general practice. The implications of this study for the assessment of registrar GPs using video-recorded consultations are discussed.
Adolescent↗
Effects of heterozygous lipoprotein lipase deficiency on diet-induced atherosclerosis in mice.
Heterozygous lipoprotein lipase deficiency (LPL+/-) is common and has been implicated in premature atherosclerosis in epidemiologic studies. However, in vitro data suggest that LPL deficiency in the vascular wall may be antiatherogenic. To address the role of LPL in atherosclerosis, LPL+/- mice in the C57BL/6J background were fed an atherogenic diet for 8 months. LPL+/- mice were more dyslipidemic than +/+ animals due to increased concentrations of non-HDL lipoproteins. There was no difference in aortic origin atherosclerosis between LPL+/- (n=56) and +/+ (n=55) mice. LPL+/- mice in the low density lipoprotein receptor knockout (LDLR-/-) background were fed the same atherogenic diet for 3 months. LPL+/-LDLR-/- mice were more dyslipidemic than LPL+/+LDLR-/- animals. There was no difference in atherosclerosis assayed for the entire aorta and no difference in aortic sterol content between LPL+/-LDLR-/- (n=28) and LPL+/+LDLR-/- (n=15) mice. LPL protein was detected in murine lesions in a consistent layered pattern. More luminal, lipid-laden macrophages generally did not stain for LPL, but deeper, lipid-poor macrophages as well as necrotic core regions contained immunoreactive LPL. LPL protein was more abundant in lesions from LPL+/+ LDLR-/- than LPL+/-LDLR-/- mice. After eating an atherogenic diet, LPL+/- as compared to LPL+/+ mice have more dyslipidemia, but no more atherosclerosis, and less LPL protein in atherosclerotic lesions. These data suggest that lipoprotein lipase deficiency in the vascular wall could prevent the retention of atherogenic lipoproteins.
Animals↗
Effect of schedule on reactogenicity and antibody persistence of acellular and whole-cell pertussis vaccines: value of laboratory tests as predictors of clinical performance.
The performance of four acellular pertussis vaccines containing between two and five pertussis antigens combined with diphtheria and tetanus toxoids was compared with that of British whole-cell diphtheria/tetanus/pertussis (DTP) vaccine both in laboratory assays for potency, toxicity and immunogenicity, and for reactogenicity and immunogenicity in infants. Clinical responses were evaluated in double blind randomized Phase II trials using 3/5/9 month and 2/3/4 month schedules. The acellular DTPs had much lower toxicity than whole-cell DTP in laboratory tests and were significantly less pyrogenic than whole-cell DTP under both schedules. Local reactions were not consistently lower in acellular than whole-cell vaccinees and varied with the source of the diphtheria and tetanus antigens used. Differences in endotoxin level and content of active pertussis toxin (PT) between acellular DTP vaccines were not clinically significant. The reactogenicity advantage of the acellular vaccines was substantially reduced under the 2/3/4 month schedule due to the reduced reactogenicity of the whole-cell DTP vaccine when given at a younger age. There was no relationship between antigen content measured in micrograms per dose and ELISA antibody responses to filamentous haemagglutinin (FHA) and PT in infants, nor was murine immunogenicity predictive of immunogenicity in humans. Antibody response to PT was attenuated in the whole-cell group under the 2/3/4 month schedule but was unaffected in the group receiving acellular vaccines with individually purified components; antibody response to pertactin (69 kDa antigen) was similar in recipients of the whole-cell and component acellular vaccines under the 2/3/4 month schedule. PT antibody persistence until 4-5 years of age was significantly better in recipients of the component acellular than either the whole-cell vaccine or the co-purified acellular vaccine under the 3/5/9 month schedule. However, diphtheria antitoxin levels were reduced in acellular vaccine recipients under both schedules. Despite significantly lower tetanus potencies of the acellular vaccines in laboratory tests, no differences were found in tetanus anti-toxin responses in children.
Antibodies, Bacterial↗
Correction of hypertriglyceridemia and impaired fat tolerance in lipoprotein lipase-deficient mice by adenovirus-mediated expression of human lipoprotein lipase.
Humans homozygous or heterozygous for mutations in the lipoprotein lipase (LPL) gene demonstrate significant disturbances in plasma lipoproteins, including raised triglyceride (TG) and reduced HDL cholesterol levels. In this study we explored the feasibility of adenovirus-mediated gene replacement therapy for LPL deficiency. A total of 5 x 10(9) plaque-forming units (pfu) of an E1/E3-deleted adenovirus expressing either human LPL (Ad-LPL) or the bacterial beta-galactosidase gene (Ad-LacZ) as a control were administered to mice heterozygous for targeted disruption in the LPL gene (n = 57). Peak expression of total postheparin plasma LPL activity was observed at day 7 in Ad-LPL mice versus Ad-LacZ controls (834 +/- 133 vs 313 +/- 89 mU/mL, P < .01), and correlated with human-specific LPL activity (522 +/- 219 mU/mL) and mass (9214 +/- 782 ng/mL), a change that was significant to 14 and 42 days, respectively. At day 7, plasma TGs were significantly reduced relative to Ad-LacZ mice (0.17 +/- 0.07 vs 1.90 +/- 0.89 mmol/L, P < .01) but returned to endogenous levels by day 42. Ectopic liver expression of human LPL was confirmed by in situ hybridization analysis and from raised LPL activity and mass in liver homogenates. Analysis of plasma lipoprotein composition revealed a marked decrease in VLDL-derived TGs. Severely impaired oral and intravenous fat-load tolerance in LPL-deficient mice was subsequently corrected after Ad-LPL administration and closely paralleled that observed in wild-type mice. These findings suggest that liver-targeted adenovirus-mediated LPL gene transfer offers an effective means for transient correction of altered lipoprotein metabolism and impaired fat tolerance due to LPL deficiency.
Adenoviridae↗
Summative assessment in general practice. Content validity of video recorded consultations needs to be proved.
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Education, Medical, Graduate↗
Sampling for qualitative research using quantitative methods. 1. Measuring GPs' attitudes towards discussing smoking with patients.
BACKGROUND: Interview studies which employ qualitative methodology are often concerned with classifying behaviours or attitudes and an ideal sample of research subjects displays variety in the attitudes or behaviours under scrutiny. OBJECTIVE: This paper describes the development of a questionnaire which measures GPs' attitudes towards discussing smoking with patients with the intention of using this instrument to select GPs with diverse views for a qualitative interview study. METHOD: Thirteen attitude statements with an accompanying Likert-type scale were completed by 327 GPs in one FHSA area. Factor analysis of responses produced two subscales: 'perceived efficacy' and 'enthusiasm'. Reliability and validity of these were examined. RESULTS: Each subscale had good internal reliability and preliminary exploration of construct validity supported the notion that the subscales were valid. CONCLUSION: The use of this type of instrument in sampling GPs for qualitative studies could be effective for selecting subjects with a diversity of views towards the research topic.
Attitude of Health Personnel↗
Sampling for qualitative research using quantitative methods. 2. Characteristics of GPs who agree to video-taping of consultations.
BACKGROUND AND OBJECTIVES: Studies using video-recordings of GPs' consultations have been important in investigating GPs' clinical behaviour. Unfortunately, the characteristics of participating GPs are rarely described, making it difficult to assess how representative they are or how generalizable the studies' results can be. This paper documents the recruitment of 53 GPs to a research project which involved video-recording their consultations to determine how GPs approach the topic of smoking cessation with patients. METHODS: The Attitudes to Smoking Advice Questionnaire was used to select GPs with diverse attitudes towards discussing smoking with patients. RESULTS: Out of 123 GPs who were eligible to take part, 53 (43.1%) agreed. GPs who agreed to become research subjects were younger, more likely to work in teaching or training practices and more likely to be current members of the RCGP. CONCLUSIONS: When planning studies which utilize video-recordings of GPs' consultations, researchers should give consideration to how this apparent self-selection by participating GPs could influence research results.
Attitude of Health Personnel↗
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is N-demethylated by cytochromes P450 2D6, 1A2 and 3A4--implications for susceptibility to Parkinson's disease.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces a Parkinson-like syndrome through biotransformation by monoamine oxidase B to the neurotoxic metabolite 1-methyl-4-phenylpyridine. Neuroprotection may be provided by parallel N-demethylation and N-oxidation pathways mediated by the microsomal cytochrome P450 and flavin monooxygenase systems, respectively. The aims of this study were to characterise the N-demethylation of MPTP by human liver microsomes over a wide range of concentrations, and to identify the cytochrome P450 enzymes involved in this reaction. The kinetics of the N-demethylation of MPTP (1 microM - 3 mM) by microsomes from the liver of an extensive metabolizer with respect to cytochrome P4502D6 (CYP2D6) activity were biphasic (apparent Km1 and Km2 values = 48 and 2882 microM). The high affinity activity was abolished in the presence of quinidine (1 microM) and was absent in microsomes from a genotypically poor metabolizer with respect to CYP2D6. Yeast microsomes containing heterologously expressed CYP2D6 N-demethylated MPTP (Km = 39 microM), and there was a high correlation between the quinidine-inhibitable N-demethylation of MPTP (50 microM) (0.7-91%, mean 44%, of total activity) and the alpha-hydroxylation of metoprolol in microsomes from 11 human livers (rs = 0.92; P < .001). At 50 microM MPTP, N-demethylase activity in human liver microsomes was also inhibited by furafylline (10 microM) and ketoconazole (2 microM) (mean inhibition 39 and 13%, respectively; n = 11 livers). Yeast microsomes containing heterologously expressed human CYP1A2 N-demethylated MPTP with a Km of 2246 microM. These findings indicate that CYP2D6, CYP1A2 and, to a lesser extent CYP3A4, may have a role in protecting against Parkinson's disease induced by MPTP and other potential environmental neurotoxins. The data provide some biochemical support for the proposition that genotypically poor metabolizers with respect to CYP2D6 are overrepresented in some populations of Parkinson's patients, and that smokers (induced CYP1A2?) are underrepresented.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
Anti-smoking advice in general practice consultations: general practitioners' attitudes, reported practice and perceived problems.
BACKGROUND: Anti-smoking advice from general practitioners has proven efficacy. However, general practitioners do not exploit a large proportion of opportunities to discuss smoking with patients. AIM: A study aimed to explore general practitioners attitudes towards discussing smoking with patients and to assess how these influence the quantity of anti-smoking advice that general practitioners report giving during routine consultations. It also aimed to determine the extent to which general practitioners report using evidence-based interventions against smoking and to discover the problems they experience when discussing smoking with patients. METHOD: A postal survey of all 468 general practitioners on the Leicestershire Family Health Services Authority list was conducted. General practitioners' attitudes were assessed by scoring 13 attitude statements using a six-point Likert-type scale. They were also asked to rank (from a list of 12 items) the five approaches that they found most productive and (from a list of 11 items) the five problems that they most commonly encountered when giving anti-smoking advice to patients. RESULTS: A total of 327 questionnaires (70%) were returned. Most respondents (97%) thought that their advice was more effective when linked to patients' presenting problems and 65% reported that linking their anti-smoking advice to patients' presenting complaints was one of their three most preferred approaches to discussing smoking. Advising all presenting smokers to quit was considered by 40% of respondents to be an appropriate use of time but 76% reported that patients' lack of motivation was one of the three most commonly encountered problems. An analysis of the ratings of the 13 statements suggested that general practitioners who reported the greatest smoking cessation activity during routine consultations held more positive attitudes towards discussing smoking with patients. CONCLUSION: This study suggests that general practitioners believe that their anti-smoking advice is more effective when linked to patients' presenting complaints, and this belief appears to be reflected in the way in which general practitioners approach smoking cessation with patients. The findings may indicate that general practitioners are unlikely to accept a role in a population-based anti-smoking strategy which demands that they discuss smoking with all presenting smokers.
Attitude of Health Personnel↗
Video-recorded consultations.
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Family Practice↗
Influence of patient's age on GPs' definition of hypertension. Patients aged over 80 may not benefit from antihypertensive treatment.
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Aged↗
COOH-terminal disruption of lipoprotein lipase in mice is lethal in homozygotes, but heterozygotes have elevated triglycerides and impaired enzyme activity.
The role of the enzyme lipoprotein lipase (LPL) in atherosclerosis is uncertain. To generate an animal model of LPL deficiency, we targeted the LPL gene in embryonic stem cells with a vector designed to disrupt the COOH terminus of the protein and used these cells to generate LPL-deficient mice. Germ line transmission of the disrupted LPL allele was achieved with two chimeric males, and offspring from each of these animals were phenotypically identical. Pups homozygous (-/-) for LPL deficiency died within 48 h of birth with extreme elevations of serum triglycerides (13,327 mg/dl) associated with essentially absent LPL enzyme activity in heart and carcass. Newborn heterozygous (+/-) LPL-deficient pups had lower LPL enzyme activity and higher triglycerides (370 versus 121 mg/dl) than wild type (+/+) littermates. Adult heterozygotes had higher triglycerides than wild type mice with ad libitum feeding (236 mg/dl for +/- versus 88 mg/dl for +/+) and after fasting for 4 h (98 mg/dl for +/- versus 51 for +/+) or 12 h (109 mg/dl for +/- versus 56 mg/dl for +/+). Triglycerides were present as very low density lipoprotein particles and chylomicrons, but high density lipoprotein cholesterol levels were not decreased in +/- animals. Plasma heparin-releasable LPL activity was 43% lower in +/- versus +/+ adult animals. LPL activity, mRNA, and protein were lower in the tissues of +/- versus +/+ mice. Homozygous LPL deficiency caused by disruption of the COOH terminus of the enzyme is lethal in mice. Heterozygous LPL deficiency caused by this mutation is associated with mild to moderate hypertriglyceridemia without affecting static HDL cholesterol levels. Heterozygous LPL-deficient mice could be useful for determining if hypertriglyceridemia, independently or in combination with other discrete defects, influences atherosclerosis.
Animals↗
Novel centrosomal protein reveals the presence of multiple centrosomes in turkey (Meleagris gallopavo) bnbn binucleated erythrocytes.
The phenotype of the bnbn hemolytic anemia mutation in the domestic turkey is manifested as binucleation specifically in the definitive erythrocyte lineage, most likely as the consequence of anomolous centrosomal activity (Bloom et al., 1970; Searle and Bloom, 1979). Here we have identified in turkey two variants of the novel, centrosomally-associated erythroid-specific protein p23. One variant is Ca(2+)-sensitive and is highly homologous to its chick counterpart (Zhu et al., 1995, accompanying paper). The other, p21 is a truncated form resulting from a 62 amino acid deletion from the 3' end and a 40 amino acid insertion at the 5' end, and appears to lack Ca(2+)-sensitivity. These proteins are localized at the marginal band, centrosomes and nuclear membrane of differentiated erythrocytes. Anti-p23/p21 immunofluorescence revealed the presence of multiple centrosomes in bnbn erythrocytes. We therefore undertook a detailed genetic analysis to determine whether the p21 variant represented the bn mutation. Initial tests of normal BnBn and mutant bnbn individuals suggested that the p23/p21 proteins might be encoded by the Bn/bn genes. However, further genetic tests demonstrated independent segregation for these two genetic loci. Thus, these proteins are encoded by the heretofore undescribed genes, p23/p21, mapping to an autosomal locus in the turkey genome.
Amino Acid Sequence↗
Human fatty acid synthase mRNA: tissue distribution, genetic mapping, and kinetics of decay after glucose deprivation.
To better understand the accelerated decay of fatty acid synthase (FAS) message that occurs after glucose deprivation (J. Biol. Chem. 1993. 268: 6961-6970), we characterized the 3' terminus of the human message and the kinetics of FAS mRNA decay in HepG2 cells. The FAS gene was localized to human chromosome 17q24-25 and to syntenic distal mouse chromosome 11. Expression of the FAS message in human tissues was ubiquitous with high levels in liver, lung, and intra-abdominal adipose tissue. The 806 nucleotide 3' untranslated region of the human mRNA contained two regions with the instability pentamer AUUUA. Unlike short-lived messages containing AUUUA motifs, FAS mRNA decay after glucose deprivation was not first order, and there were no detectable changes in the poly(A) tail. Glucose deprivation transiently caused FAS message to sediment more rapidly than control message in density gradients. In vivo treatment with different translational inhibitors showed that translation per se was not necessary for FAS mRNA decay; association of polysomes with FAS message protected it from decay. In cell-free decay experiments, FAS mRNA decay was more rapid using components from glucose-deprived than glucose-treated cells. These data suggest that glucose regulates cytoplasmic HepG2 FAS mRNA stability by partitioning the message between a translated pool not subject to degradation and a decay compartment, features reminiscent of regulated stability for other diet-responsive messages.
Amino Acid Sequence↗