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Biomedical subjects

J Abbotts

Publications and source records attributed to J Abbotts.

At least 19 recordsLinked to original sources
PubMed2001

Morbidity and Irish Catholic descent in Britain. Relating health disadvantage to socio-economic position.

In common with some other ethnic and religious minorities whose forebears migrated from their country of origin, Irish Catholics in Britain are less well off than the host population in terms of socio-economic position and health. Results are presented from a Scottish study, where Catholic religion of origin mainly indicates Irish ancestry, and it is estimated that about one-third of the population is of significant Irish descent. In this study, excess of physical and mental health problems and disability have previously been reported for those of Catholic background, particularly in the eldest cohort (aged 56 in 1988), and have not been fully explained by health-related behaviour. In this paper, we examine a number of key health measures, namely self-assessed health, number of symptoms in the month prior to interview, sadness or depression, disability and lung function, and various indicators of socio-economic position (head of household social class, main source of income, car ownership, housing tenure and school-leaving age), which all show Catholic disadvantage. Using longitudinal results from the 723 respondents who completed interviews both at sweeps one (1988) and three (1995), it is estimated that about half of the morbidity excess amongst middle-aged Catholics in Glasgow can be explained by socio-economic disadvantage. The health and socio-economic position of white minorities and disadvantaged religious minorities like Catholics in Scotland should be monitored by a co-ordinated information strategy.

Aged↗
PubMed2001

Poor but healthy? The youngest generation of Irish catholics in west Scotland.

OBJECTIVE: Catholic adults in the West of Scotland, who are mainly of Irish origin, have been shown to suffer excess morbidity and mortality compared to the general population. A major contributing factor to this inequality is socio-economic disadvantage. This paper investigates the health and socio-economic position of Catholics in the youngest generation. DESIGN: Secondary analysis of baseline data from the West of Scotland 11-16 STUDY: Teenage Health, which is a longitudinal school-based survey. SETTING: One hundred and thirty five primary schools in Glasgow and surrounding districts. SUBJECTS: Two thousand five hundred and eighty six final-year pupils (average age eleven years and three months), born in 1983/1984. RESULTS: Comparing Catholics and non-Catholics on a range of indicators of general health, recent acute symptoms, chronic conditions, mental health and physical measures, we found no evidence of any systematic health inequality. A few indicators did show statistically significant differences at the five percent level, but these were not in any consistent direction. In terms of household socio-economic position, though, we found strong evidence of disadvantage for Catholics. Catholic children were more likely to have parents of manual social class, without any formal qualifications, who were less likely to own their home or a car, more likely to express difficulty 'making ends meet', and more likely to live in a deprived area. CONCLUSIONS: We discuss the prospects for diminishing socio-economic inequality over time between Catholics and non-Catholics in this cohort, which will depend on Catholic social mobility. We consider the likelihood of enduring health equality for Catholics, which will depend on the effects of different influences on health over the life course.

Catholicism↗
PubMed1999

Morbidity and Irish Catholic descent in Britain: relating health disadvantage to behaviour.

OBJECTIVES: This paper critically evaluates the evidence for two health-related stereotypes of the Irish, namely that behaviours such as smoking and heavy drinking explain their excess morbidity in Britain, and secondly that, in illness, this ethnic group behaves more stoically. DESIGN: Data are reported on over 850 respondents from each of three cohorts (aged 18, 39 and 58 in 1990/91) of the West of Scotland 20-07 Study, in which a small but pervasive excess of morbidity has been observed in those of Catholic background (in this area associated with Irish descent). Logistic regression was used to investigate any differences in drinking, smoking and participation in sport between those of Catholic and non-Catholic heritage, whilst controlling for sex and social class. Where a difference was observed, we looked for an association between health-related behaviour and the Catholic morbidity excess for six measures of physical and mental health. Finally, illness behaviour at age 39 and 58 was investigated for those experiencing one of a number of common symptoms in the month prior to interview, by noting whether a general medical practitioner (GP) was consulted. RESULTS: The only difference in health-related behaviour was in the eldest cohort, where an excess of smoking was observed for the Catholics. However, except for lung power, smoking was not able to explain very much, if any, of the Catholic morbidity disadvantage. For most of the symptoms studied, GP consultation rates were similar, although there was a tendency towards Catholic over-consulting. CONCLUSION: This paper finds minimal evidence in favour of either stereotype: behaviours such as smoking and excess drinking were not strongly associated with the poor morbidity status of the Irish in the population we have studied; neither have the Irish been found to be more stoic in illness. Therefore the stereotypes are not an adequate explanation, nor a necessary correlate, of the frequent finding of raised morbidity in communities of Irish Catholic origin.

Adolescent↗
PubMed1999

Association of medical, physiological, behavioural and socio-economic factors with elevated mortality in men of Irish heritage in West Scotland.

BACKGROUND: Men with patrilineal Irish descent from the immigrations of the nineteenth and twentieth centuries have higher death rates from 'all-causes' and, specifically, cardiovascular disease (CVD) than the general population of the West of Scotland. METHODS: A total of 5766 male employees from 27 workplace settings were examined between 1970 and 1973. Surname analysis identified 15 per cent of these men as of patrilineal Irish heritage. For those who have since died, the date and cause of death was obtained. Cox's proportional hazards model was used to compare the mortality risk of those with Irish and non-Irish surnames, and to investigate established medical, physiological, behavioural and socio-economic risk factors (acting in early and later life) as possible explanations for this excess mortality. RESULTS: The relative risk of death from all causes for the Irish of 1.26 (95 per cent confidence interval (CI) (1.12, 1.43)) was reduced to 1.12 (95 per cent CI (0.99, 1.26)) by including established risk factors in the model. The relative risk of CVD mortality of 1.51 (95 per cent CI (1.29, 1.77)) for the Irish was reduced to 1.35 (95 per cent CI (1.14, 1.58)) by the same adjustments. The elevated all-cause mortality of the Irish was mainly attributable to cardiovascular deaths. CONCLUSIONS: Cigarette smoking was only able to 'explain' a small amount of the excess all-cause and CVD mortality of men with patrilineal Irish descent. Relative deprivation during childhood and adulthood contributed to the high Irish mortality. However, there remains a substantial excess of premature deaths among Irish men which is unaccounted for by established risk factors.

Adult↗
PubMed1998

Mortality in men of Irish heritage in West Scotland.

Britons of Irish parentage have been found to exhibit poorer health and to die at a younger age than the general population. This paper expands the investigation of Irish mortality patterns in Britain, to include men with patrilineal Irish descent from the immigration of the 19th and 20th centuries. Five thousand, seven hundred and sixty-six male employees aged between 35 and 64 y were examined in 27 workplace settings in Glasgow, Grangemouth and Clydebank between 1970 and 1973. Twenty-one years' mortality follow-up was analysed from a survey involving a health questionnaire and medical examination, using name analysis to identify those of patrilineal Irish descent. Fitting Cox's proportional hazards model to date of death, using date of birth and Irish names as covariates, resulted in the patrilineal Irish showing elevated mortality from all cases (relative risk 1.22; 95% CI [1.08, 1.38]) and coronary heart disease (relative risk 1.53; 95% CI [1.27, 1.83]). Mortality risk for men with an Irish surname was also elevated for cerebrovascular disease (relative risk 1.30; 95% CI [0.86, 1.95]), respiratory disease (relative risk 1.17; 95% CI [0.73, 1.86]) and injury or poisoning (relative risk 1.42; 95% CI [0.78, 2.61]), although the low numbers of men dying from these causes, meant that differences did not reach statistical significance at the 5% level. No differences were observed for cancer or other causes. Previous work has shown high mortality for second generation Irish, whereas this study indicates high all-cause mortality and an excess of deaths for coronary heart disease in the much larger group of men with patrilineal Irish descent from the immigration of the 19th and 20th centuries.

Adult↗
PubMed1997

Morbidity and Irish Catholic descent in Britain: an ethnic and religious minority 150 years on.

Ethnic and religious minorities often suffer disadvantages both in socio-economic status and in health. Data from the West of Scotland Twenty-07 study suggest some differences in morbidity between those descended from Irish Catholic migrants of the great emigration from 1840 onwards and others. Catholic religion of at least one parent or at birth is used here as a proxy measure to indicate Irish Catholic descent, on the basis of estimates of sensitivity and specificity in the local area. Higher proportions of "Catholics" are in manual social classes. Differences between "Catholics" and "non-Catholics" in one or more age cohorts are observed for the following aspects of health and physical development: general and physical health (self-assessed health, number of symptoms, accidents), psychological distress (depression, anxiety, number of psychosomatic symptoms), impairments and disabilities (sight, hearing, wearing dentures, disability), and physical measures (height, waist-to-hip ratio, lung function). Furthermore, for all aspects except hearing, wearing dentures and number of psychosomatic symptoms, significant differences remain after accounting for sex and social class. For each measure where a difference is observed, it is those respondents with a Catholic parent or who were born Catholic who experience poorer health or physical development. This suggests that those of Irish Catholic descent are at some disadvantage compared with the rest of the population, with respect to health as well as social class, 150 years after the start of the main migration.

Adolescent↗
PubMed1993

Mechanism of HIV-1 reverse transcriptase. Termination of processive synthesis on a natural DNA template is influenced by the sequence of the template-primer stem.

During processive DNA synthesis in vitro, the human immunoefficiency virus, type 1 (HIV-1) reverse transcriptase encounters template nucleotide positions at which continued synthesis is difficult. At these positions, the enzyme has a relatively high probability of dissociating from the template, and product molecules of corresponding length accumulate as the incubation proceeds. These positions, which are known as termination sites, could be associated with template secondary structures in some cases, but many termination sites appear to be template sequence-related rather than secondary structure-related. Mechanisms producing these blocks in processive DNA synthesis are not well understood. In this study, to examine further the effects of template sequence on termination, we engineered selected single-base changes in the M13mp2 template, and we found that such changes can influence termination. Several general trends emerged from the study. First, strong termination sites rarely correspond to dATP as the "incoming" substrate opposite template T. Second, the sequence of the template-primer stem is more important for termination than the sequence of the single-stranded template ahead of the primer. Thus, we note the phenomenon of action at a distance: changing sequence at one nucleotide position in the template-primer stem alters termination at other positions, a few nucleotides distant at the primer 3' end. A and C as template bases in the template-primer stem have opposite effects. A is the strongest terminator residue, and C is the weakest terminator residue, followed by G. Since termination sites are produced by reverse transcriptase dissociation from the template-primer, the results suggest that the HIV-1 reverse transcriptase has properties reminiscent of a sequence-specific double-stranded DNA-binding protein in that its binding mechanism can distinguish both base residues and positions in the double-stranded DNA template-primer stem.

Base Sequence↗
PubMed1993

Error-prone polymerization by HIV-1 reverse transcriptase. Contribution of template-primer misalignment, miscoding, and termination probability to mutational hot spots.

We have observed previously that DNA template-directed polymerization by the type 1 human immunodeficiency virus reverse transcriptase is error-prone for single-nucleotide substitution, addition and deletion errors at homopolymeric sequences. We have also noted strong termination of processive synthesis at these positions (Bebenek, K., Abbotts, J., Roberts, J. D., Wilson, S. H., and Kunkel, T. A. (1989) J. Biol. Chem. 264, 16948-16956). Here we have tested three models to explain errors at these hot spots: template-primer misalignment for deletion errors, and dislocation and direct miscoding for substitution errors. The approach involves introducing single-nucleotide changes within or flanking the homopolymeric hot spots and examining the effects that these changes have on human immunodeficiency virus type 1 (HIV-1) reverse transcriptase error rate, error specificity, and termination probability. The results obtained suggest that single-nucleotide deletion errors in homopolymeric runs result from template-primer misalignment and that both direct miscoding and template-primer dislocation contribute to the base substitution hot spots. The data also suggest that base substitution errors at one position can be templated by the preceding nucleotide or either of the next two nucleotides. Frameshift error rates at homopolymeric sites were affected by changes in the sequences flanking the runs, including single-nucleotide differences in the single-stranded template strand and in the double-stranded primer region as many as six nucleotides distant from the hot spot. Both increases and decreases in frameshift fidelity were observed, and most of these correlated with concomitant increases or decreases in the probability that HIV-1 reverse transcriptase terminated processive synthesis within the run. These data provide further support for a relationship between the frameshift fidelity and the processivity of DNA-dependent DNA synthesis by HIV-1 reverse transcriptase.

Base Sequence↗
PubMed1992

Inhibitors of HIV-1 reverse transcriptase and fidelity of in vitro DNA replication.

Mechanisms of the effects of the dTTP analogues 3'-azido-3'-deoxythymidine 5'-triphosphate (AZTTP) and 3'-amino-3'-deoxythymidine 5'-triphosphate (NH2 TTP) upon the HIV-1 reverse transcriptase (RT) are discussed. These compounds block the RT in vitro and do so by different kinetic mechanisms. Infidelity of replication is a hallmark of the HIV-1 RT, and replication errors by the enzyme on RNA and DNA templates are discussed. The enzyme's infidelity has ramifications for inhibition: On the one hand, the propensity to produce mutations enhances the ability of the virus to escape inhibitors whereas on the other hand, the infidelity of the reverse transcriptase may allow the development of imaginative inhibitor strategies.

DNA Replication↗
PubMed1991

Protein-protein interactions of HIV-1 reverse transcriptase: implication of central and C-terminal regions in subunit binding.

Human immunodeficiency virus 1 reverse transcriptase (RT) purified from virions is composed of a approximately 51,000 Mr polypeptide and a approximately 66,000 Mr polypeptide that are thought to be in heterodimer structure (Chandra et al., 1986; Hansen et al., 1988; Starnes & Cheng, 1989) and are identical except for a 15,000 Mr C-terminal truncation in the smaller species (Di Marzo-Veronese et al., 1986). We prepared individual bacterial-recombinant RTs as the approximately 66,000 Mr polypeptide (p66) or as the approximately 51,000 Mr polypeptide (p51) and then conducted various in vitro protein-protein binding experiments. Analytical ultracentrifugation studies in 0.25 M NaCl at pH 6.5 revealed that p66 was in monomer-dimer equilibrium with KA of 5.1 x 10(4) M-1. p51 failed to dimerize and behaved as a monomer under these conditions. Mixing of the p66 and p51 polypeptides resulted in a 1:1 heterodimer with KA of 4.9 x 10(5) M-1. These results on formation of the p66/p66 homodimer and p66/p51 heterodimer were confirmed by gel filtration analysis using FPLC Superose-12 columns. Binding between p66 and individual p66 segment polypeptides also was observed using an immunoprecipitation assay. Binding between p51 and p66 in this assay was resistant to the presence of approximately 1 M NaCl, suggesting that the binding free energy has a large hydrophobic component. C-Terminal truncation of p66 to yield a 29-kDa polypeptide eliminated binding to p66, and N-terminal truncation of p66 to yield a 15-kDa peptide also eliminated binding to p66. The results indicate that purified individual RT peptides p51 and p66 are capable of binding to form a 1:1 heterodimer and suggest that the central region of p66 is required for this subunit binding; the C-terminal region (15,000 Mr) of p66 appears to be required also, as p51 alone did not dimerize.

Blotting, Western↗
PubMed1991

Thermodynamics of A:G mismatch poly(dG) synthesis by human immunodeficiency virus 1 reverse transcriptase.

Human immunodeficiency virus 1 (HIV-1) reverse transcriptase has been found to conduct error-prone synthesis on DNA and RNA templates. We find here that tolerance of an A:G mispair with poly(rA) as template is particularly strong, such that extensive poly(dG) synthesis is conducted. This type of extensive misincorporation is not observed with several reference DNA polymerases. Surprisingly, HIV reverse transcriptase processivity and kcat for dGMP misincorporation and normal dTMP incorporation are about the same. However, the Km value for dGTP in poly(dG) synthesis is approximately 1000-fold higher than the Km for dTTP in poly(dT) synthesis. Comparison of thermodynamic parameters for dGMP misincorporation and normal dNMP incorporation indicates a lower energy of activation for dGMP misincorporation than for normal dNMP incorporation. Entropy of activation (delta S*) for normal dTMP incorporation is positive (approximately 10 cal/kmol), whereas delta S* for dGMP misincorporation is negative (-36 cal/kmol). Since differences in delta S* are usually considered to reflect differences in solvation for the transition state complex, these results are consistent with the interpretation that the active site of HIV reverse transcriptase is flexible enough to misincorporate dGMP without the usual dispersion of water molecules.

Autoradiography↗
PubMed1990

Identification and properties of the catalytic domain of mammalian DNA polymerase beta.

Rat DNA polymerase beta (beta-pol) is a 39-kDa protein organized in two tightly folded domains, 8-kDa N-terminal and 31-kDa C-terminal domains, connected by a short protease-sensitive region. The 8-kDa domain contributes template binding to the intact protein, and we now report that the 31-kDa C-terminal domain contributes catalytic activity. Our results show that this domain as a purified proteolytic fragment conducts DNA synthesis under appropriate conditions but the kcat is lower and primer extension properties are different from those of the intact enzyme. A proteolytic truncation of the 31-kDa catalytic domain fragment, to remove a 60-residue segment from the NH2-terminal end, results in nearly complete loss of activity, suggesting the importance of this segment. Overall, these results indicate that the domains of beta-pol have distinct functional roles, template binding and nucleotidyltransferase, respectively; yet, the intact protein is more active for each function than the isolated individual domain fragment.

Animals↗
PubMed1990

Mechanism of HIV reverse transcriptase: enzyme-primer interaction as revealed through studies of a dNTP analogue, 3'-azido-dTTP.

Primer and dNTP recognition by purified HIV reverse transcriptase have been investigated. Earlier kinetic studies suggested that the reaction pathway for DNA synthesis is ordered, with template-primer and free enzyme combining to form the first complex in the reaction sequence [Majumdar et al. (1988) J. Biol. Chem. 263, 15657-15665], and through use of a particularly high affinity template-primer analogue [r(I)n.Sd(C)28], rate values for formation of the first complex were calculated [Majumdar et al. (1989) Biochemistry 28, 1340-1346]. We now report rate values for first complex formation in the usual model replication system with poly[r(A)].oligo [d(T)] as template-primer. We find that 3'-azido-dTTP (AZTTP) is a linear competitive inhibitor of DNA synthesis against the substrate dNTP (dTTP) in the poly[r(A)].oligo[d(T)] replication system. This suggests that 3'-azido-dTTP and dTTP combine with the same form of the enzyme in the reaction scheme, i.e., the enzyme-primer complex. This is not trivial, since a second analogue, 3'-amino-dTTP, also is an inhibitor against dTTP, but the mechanism in this case is linear noncompetitive. Because the inhibition by 3'-azido-dTTP is linear competitive, the KD for physical binding to the enzyme is assumed to be the same as the Ki for inhibition (20 nM). Substrate kinetic studies of DNA synthesis using 3'-azido-dTTP as substrate revealed that the Michaelis constant is 3 microM. Therefore, the Km for this substrate analogue is 100-fold higher than the KD for binding of the analogue to the enzyme-primer complex.(ABSTRACT TRUNCATED AT 250 WORDS)

Antiviral Agents↗
PubMed1989

Specificity and mechanism of error-prone replication by human immunodeficiency virus-1 reverse transcriptase.

DNA-dependent DNA synthesis in vitro by human immunodeficiency virus-1 reverse transcriptase is relatively error-prone. The enzyme, whether recombinant or from virus particles, produces errors while replicating M13mp2 DNA at a rate that, if operative in vivo, would produce about five mutations per genome per round of replication. Sequence analysis of mutants resulting from in vitro synthesis demonstrates that errors are nonrandomly distributed. Base substitution and one-base frameshift mutational hot spots are observed. The specificity and position of errors suggest that most of the frameshifts and many of the base substitutions are initiated by template-primer slippage. Processivity analysis for the enzyme on the M13mp2 DNA template reveals strong termination at specific sites. Termination sites within homopolymer sequences correlate with frameshift mutational hot spots. The results suggest that the formation and/or utilization of misaligned template-primers is increased during the dissociation-reinitiation phase of the reaction.

Base Sequence↗
PubMed1988

Studies on the mechanism of human immunodeficiency virus reverse transcriptase. Steady-state kinetics, processivity, and polynucleotide inhibition.

A study of steady-state kinetics of polymerization by purified human immunodeficiency virus DNA polymerase (reverse transcriptase) has been conducted. DNA synthesis was examined using a system of poly(rA) as template, oligo(dT) as primer, and dTTP as nucleotide substrate. The substrate initial velocity patterns point to an ordered mechanism with template-primer adding first. Product inhibition kinetics with either pyrophosphate or phosphonoformate are consistent with this mechanism. The human immunodeficiency virus reverse transcriptase acts processively in this replication system, but exhibits some probability of terminating after each dTMP addition to the nascent chain. The probability of terminating was approximately 20-fold higher after the first dTMP addition than after subsequent additions. With this information on the mode of polymerization, appropriate kinetic models and steady-state rate equations are discussed. In further studies, we found that a heterologous polynucleotide, poly(rC), is a potent inhibitor of the enzyme. The pattern of this inhibition is uncompetitive against template-primer, suggesting that interaction with free enzyme is not the mechanism of the inhibition.

Algorithms↗
PubMed1988

Studies on the mechanism of Escherichia coli DNA polymerase I large fragment. Effect of template sequence and substrate variation on termination of synthesis.

Termination of Escherichia coli DNA polymerase I large fragment after processive synthesis on natural and other well-defined template.primer systems has been examined. We found that after any given deoxynucleoside monophosphate incorporation termination occurs in a nonrandom manner with phi X174 DNA as template: Termination is much more likely at some nucleotide residues along the template than at others. Analysis of these stronger termination sites indicates that the template base:incoming nucleotide combination influences termination. Introduction of a double-stranded region along the phi X174 template induces termination, and reducing dNTP concentrations or substituting 2'-deoxynucleoside 5'-O-(1-thio)triphosphate substrates also increases termination. Observations with the phi X174 DNA template system were extended with a defined template containing 1 inosine residue in an otherwise d(T)n homopolymer. Termination at the I residue is modulated by dCTP and decreases as dCTP concentration increases. A similar relationship is seen with the dCTP (1-thio) derivative, but termination is higher at given concentrations of this derivative than with dCTP. Pyrophosphate decreases general processivity in this system, but does not counteract the effect of increasing dCTP. Hill plot analysis of the dCTP effect in the inosine-containing template system gave a linear plot with Hill coefficient of 0.34, suggesting that dCTP influences termination at several steps in the polymerase reaction scheme. Substituting a methylated template base for I also increased termination, producing very strong blocks to processive synthesis. The results are consistent with a model in which termination occurs with several enzyme forms that are in equilibrium in an ordered catalytic mechanism.

Bacteriophage phi X 174↗