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Biomedical subjects

G D Smith

Publications and source records attributed to G D Smith.

At least 253 records · Page 14Linked to original sources
PubMed1996

Birthweight, body-mass index in middle age, and incident coronary heart disease.

BACKGROUND: Several studies have shown a relation between fetal development, as shown by birthweight, and later coronary heart disease. This study investigated whether this relation is predominantly the consequence of early life exposures, or can best be explained in terms of an interaction between influences in early life and in adulthood. METHODS: This prospective study in Caerphilly, South Wales, included 1258 men, aged 45-59 at initial screening, who were able to provide birthweight data. These men are from an initial cohort of 2512 men, from whom information has been obtained in a series of examinations since 1979 on health-related behaviours, incidence of coronary heart disease, and risk factors. The main outcome measure was fatal and non-fatal coronary heart disease during 10 years of follow-up. FINDINGS: Higher birthweight was related to lower risk of coronary heart disease during the follow-up period: coronary heart disease occurred in 46 (11.6%) men in the lowest birthweight tertile, 44 (12.0%) of those in the middle tertile, and 38 (9.1%) of those in the highest tertile (p = 0.03). Stratification of the cohort by body-mass index (BMI) revealed a significant interaction such that the inverse association between birthweight and risk of coronary heart disease was restricted to men in the top tertile of BMI (interaction test p = 0.048 adjusted for age, and p = 0.012 fully adjusted). Within the top BMI tertile, coronary heart disease occurred in 19 (16.4%) of men in the lowest birthweight tertile, 13 (12.6%) of those in the middle tertile, and 13 (7.5%) of those in the highest tertile (p = 0.0005). These associations were not changed substantially by adjustment for age, father's social class, own social class, marital status, fibrinogen and cholesterol concentrations, systolic blood pressure, and smoking history. INTERPRETATION: The association between birthweight and risk of coronary heart disease cannot be explained by associations with childhood or adulthood socioeconomic status. Nor do conventional risk factors for coronary heart disease in adulthood account for the association. However, there is an important interaction between birthweight and BMI such that the increased risk of coronary heart disease associated with low birthweight is restricted to people who have high BMI in adulthood. Risk of coronary heart disease seems to be defined by the combined effect of early-life and later-life exposures.

Birth Weight↗
PubMed1996

Life expectancy in men who have never smoked and those who have smoked continuously: 15 year follow up of large cohort of middle aged British men.

OBJECTIVE: To estimate the life expectancy in a representative sample of men who have never smoked and of those who have smoked all their adult lives. DESIGN: 15 year follow up of a large representative cohort of British men in the British regional heart study and use of national mortality statistics for 1992. SUBJECTS: 7735 middle aged British men aged 40-59 at the time of screening (between 1978 and 1980). MAIN OUTCOME MEASURES: Mortality from all causes and from smoking related causes. RESULTS: 1624 men had never smoked at the time of screening and did not take up smoking during the study. 127 of them died during follow up. 3151 men began smoking before they were 30 and were still smoking at the time of screening. Of these, 751 had stopped smoking five years after screening; they were excluded from the analysis five years after the date they had stopped. 560 of the lifelong smokers died during follow up. When study estimates were combined with those from national mortality statistics for men aged 20-40, only an estimated 42% (95% confidence interval 36% to 50%) of lifelong smokers alive at the age of 20 would be alive at 73, compared with 78% (74% to 82%) of lifelong non-smokers. CONCLUSION: These estimates present the effects of smoking on mortality in a way that is easily communicated to patients and the general public in health promotion initiatives.

Adult↗
PubMed1996

Will we ever know when to treat HIV infection?

Confidence in the efficacy of using antiretroviral drugs to treat HIV infection has grown in the past year as a result of the prolonged survival of those randomly allocated to receive an additional drug in comparative controlled trials. HIV remains, however, the only serious infectious disease for which antimicrobial treatment is deliberately delayed. This is because infected subjects can often be symptomless for more than a decade in the absence of any treatment, and results from trials with the nucleoside analogue reverse transcriptase inhibitor zidovudine have failed to show any evidence for extended survival in those beginning treatment early compared with those who deferred treatment. The new confidence in currently available treatments, and in the prospects for new ones, inevitably leads to renewed questioning of the current strategy of waiting for signs of immune deficiency before electing to intervene. A new randomised controlled trial comparing strategies of early and deferred treatment is required to assess whether the time has come for intervention immediately after HIV has been diagnosed.

Antiviral Agents↗
PubMed1996

Low levels of sex hormone-binding globulin and testosterone predict the development of non-insulin-dependent diabetes mellitus in men. MRFIT Research Group. Multiple Risk Factor Intervention Trial.

Few prospective data are available regarding the association of sex hormone-binding globulin (SHBG), testosterone, and the risk of developing diabetes. Stored fasting serum samples from participants enrolled in the Multiple Risk Factor Intervention Trial (MRFIT) at 22 centers throughout the United States from December 1973 through February 1976 were used to perform a nested case- control study. For 176 initially nondiabetic men who had developed diabetes during 5 years of follow-up, two controls were selected, one matched only for randomization date, treatment group, and clinic ("loose controls") and the other matched additionally for fasting glucose and body mass index ("tight controls"). When cases were compared with lose controls, higher levels of fasting insulin and lower levels of total and free testosterone and SHBG were significantly associated with increased development of diabetes. However, when cases were compared with tightly matched controls, these associations weakened considerably. Low SHBG and testosterone may constitute part of the prediabetic state in men along with previously reported variables, such as higher glucose and insulin levels and obesity.

Adult↗
PubMed1996

Deprivation and cause specific morbidity: evidence from the Somerset and Avon survey of health.

OBJECTIVE: To investigate the association between cause specific morbidity and deprivation in order to inform the debates on inequalities in health and health services resource allocation. DESIGN: Cross sectional postal questionnaire survey ascertaining self reported health status, with validation of a 20% sample through general practitioner and hospital records. SETTING: Inner city, urban, and rural areas of Avon and Somerset. SUBJECTS: Stratified random sample of 28,080 people aged 35 and over from 40 general practices. MAIN OUTCOME MEASURES: Age and sex standardised prevalence of various diseases; Townsend deprivation scores were assigned by linking postcodes to enumeration districts. Relative indices of inequality were calculated to estimate the magnitude of the association between socioeconomic position and morbidity. RESULTS: The response rate was 85.3%. The prevalence of most of the conditions rose with increasing material deprivation. The relative index of inequalilty, for both sexes combined, was greater than 1 for all conditions except diabetes. The conditions most strongly associated with deprivation were diabetic eye disease (relative index of inequality 3.21; 95% confidence interval 1.84 to 5.59), emphysema (2.72; 1.67 to 4.43) and bronchitis (2.27; 1.92 to 2.68). The relative index of inequality was significantly higher in women for asthma (P < 0.05) and in men for depression (P < 0.01). The mean reporting of prevalent conditions was 1.07 for the most deprived fifth of respondents and 0.77 in the most affluent fifth (P < 0.001). CONCLUSIONS: Material deprivation is strongly linked with many common diseases. NHS resource allocation should be modified to reflect such morbidity differentials.

Adult↗
PubMed1996

Molecular structure and mechanisms of action of cyclic and linear ion transport antibiotics.

Ionophores are antibiotics that induce ion transport across natural and artificial membranes. The specific function of a given ionophore depends upon its selectivity and the kinetics of ion capture, transport, and release. Systematic studies of complexed and uncomplexed forms of linear and cyclic ionophores provide insight into molecular mechanisms of ion capture and release and the basis for ion selectivity. The cyclic dodecadepsipeptide valinomycin, cyclo[(-L-Val-D-Hyi-D-Val-L-Lac)3-], transports potassium ions across cellular membrane bilayers selectively. The x-ray crystallographic and nmr spectroscopic data concerning the structures of Na+, K+, and Ba+2 complexes are consistent and provide a rationale for the K+ selectivity of valinomycin. Three significantly different conformations of valinomycin are observed in anhydrous crystals, in hydrated crystals grown from dimethylsulfoxide, and in crystals grown from dioxane. Each of these conformations suggests a different mechanism of ion capture. One of the observed conformations has an elliptical structure stabilized by four 4<--1 intramolecular hydrogen bonds and two 5<--1 hydrogen bonds. Ion capture could be readily achieved by disruption of the 5<--1 hydrogen bonds to permit coordination to a potassium ion entering the cavity. The conformation found in crystals obtained from dimethyl sulfoxide is an open flower shape having three petals and three 4<--1 hydrogen bonds. Complexation could proceed by a closing up of the three petals of the flower around the desolvating ion. In the third form, water molecules reside in the central cavity of a bracelet structure having six 4<--1 hydrogen bonds. Two of these bracelets stack over one another with their valine-rich faces surrounding a dioxane molecule. The stacked molecules form a channel approximately 20 A in length, suggesting that under certain circumstances valinomycin might function as a channel. A series of analogues of valinomycin differing in ring composition and size have been synthesized and their transport properties tested. Peptide substitution and chiral variation in the dodecadepsipeptide can result in stabilization or modification of the different conformers. While contraction of the ring size results in loss of ion transport properties, expansion of the ring size permits complexation of larger ions and small positively charged molecules. Gramicidin A is a pentadecapeptide that functions as a transmembrane channel for transporting monovalent cations. Crystal structures of the cesium chloride complex and two uncomplexed forms of gramicidin A have been reported. In all three structures the gramicidin A molecule is a left-handed, antiparallel, double-stranded helical dimer. In the cesium complex the beta 7.2-helix has 6.4 residues per turn with an internal cavity large enough to accommodate cesium ions. In the uncomplexed structures the channel is 31 A long and has 5.6 amino acids per turn. Because the helix is too tightly wound to permit ion transport, ion transport would require breaking and reforming of hydrogen bonds.

Amino Acid Sequence↗
PubMed1996

A novel complex of a phenolic derivative with insulin: structural features related to the T-->R transition.

The structure of a symmetric T3R3f insulin hexamer, complexed with 4-hydroxybenzamide, has been determined using X-ray crystallographic techniques. Data were measured from six crystals grown in microgravity to a resolution of 1.4 A and the structure has been refined including the contributions from hydrogen atoms. The crystals are isomorphous with T3R3f complexes of phenolic derivatives as well as with uncomplexed forms. Unlike the structures of complexes with phenol, m-cresol, resorcinol, 4'-hydroxyacetanilide, and methylparaben, which bind one phenolic derivative molecule per R- or Rf-state monomer, two molecules of 4-hydroxybenzamide are bound by each Rf-state monomer. The presence of the second guest molecule results in an extensive hydrogen bonding network, mediated by water molecules, between the T- and Rf-state trimers and adds stability to the formation of the hexamer. The only access to these second sites is through three symmetry-related, narrow channels that originate on the surface of the T-state trimer. Although the conformation of the backbone atoms of the monomers is nearly identical to that of other T3R3f hexamers, significant changes are observed in the conformations of side chains in the vicinity of the second binding site. The side chain of the T-state A11 Cys residue, which forms a disulfide bond to A6 Cys in the same monomer, is observed in two discrete conformations; two discrete conformations are also present for the entire A8 Thr residue in the Rf-state monomer. A procedure is also described for an alternate method of interframe scaling and merging intensity data from an image plate detector.

Benzamides↗
PubMed1996

Determination of half-reaction equilibrium in a ping-pong enzyme mechanism.

Substituted enzyme (or ping-pong) mechanisms usually involve enzymes that exist in two forms that alternate during the catalytic reaction. A method is described here for determining the position of the equilibrium of a half reaction in a ping-pong enzyme mechanism that is based on the kinetics of the burst reaction which occurs upon addition of reactants that recycle the enzyme from one form to another. The theoretical basis for the analysis is developed, and the method is applied to the half reaction of the aldimine form of aspartate transaminase with difluoro-oxaloacetate.

Animals↗
PubMed1996

Neurohumoral, peptidergic and biochemical responses to supine exercise in two groups with primary autonomic failure: Shy-Drager syndrome/multiple system atrophy and pure autonomic failure.

The neurohumoral, peptidergic and biochemical responses to supine leg exercise were studied in two groups with primary autonomic failure: Shy-Drager syndrome (SDS, n = 15) and pure autonomic failure (PAF, n = 15), to determine if these accounted for exercise-induced hypotension and the greater blood pressure (BP) fall in PAF. Responses were compared to normal subjects (controls, n = 15), in whom BP rose with exercise. Resting plasma noradrenaline (NA) was higher in controls than SDS, and was lowest in PAF. With exercise, NA increased in controls, with a small rise in SDS, but no change in PAF. Resting plasma adrenaline (A) was higher in controls and SDS than PAF, with no change during exercise. Plasma dopamine was unrecordable at all stages in all groups. Resting plasma renin activity (PRA) was higher in controls than SDS and PAF, and was unchanged with exercise in all groups. Plasma insulin, C-peptide and serum growth hormone (GH) were similar at rest and with exercise in the three groups. Plasma glucose was higher at rest in SDS and PAF, and increased with exercise in all three groups. In conclusion, neither exercise-induced hypotension, nor the differences between SDS and PAF could be related to abnormalities in the release of A, PRA, insulin, glucose or GH. The abnormal NA response to exercise was consistent with the BP fall being due to inadequate compensatory sympathetic activity. In SDS, the small NA increase, in the presence of supersensitivity, may have reduced their BP fall as compared to PAF. These results suggest that impaired sympathetic neural activity is a key factor in exercise-induced hypotension.

Autonomic Nervous System Diseases↗
PubMed1996

Analytical steady-state solution to the rapid buffering approximation near an open Ca2+ channel.

We derive an analytical steady-state solution for the Ca2+ profile near an open Ca2+ channel based on a transport equation which describes the buffered diffusion of Ca2+ in the presence of rapid stationary and mobile Ca2+ buffers (Wagner and Keizer, 1994). This steady-state rapid buffering approximation gives an upper bound on local Ca2+ elevations such as Ca2+ puffs or sparks when conditions for the validity of the rapid buffering approximation are met and is an alternative to approximations that assume that mobile buffers are unsaturable. This result also provides an analytical estimate of the cytosolic Ca2+ domain concentration ([Ca2+]d) near a channel pore and shows the dependence of [Ca2+]d on moderate concentrations of endogenous mobile buffer, Ca2+ indicator dye, and bulk cytosolic Ca2+. Assuming a simple relationship between [Ca2+]d and the lumenal depletion domain of an intracellular Ca2+ channel, lumenal and cytosolic Ca2+ profiles are matched to give an implicit analytical expression for the effect of bulk lumenal Ca2+ on [Ca2+]d.

Animals↗
PubMed1996

Validity of the rapid buffering approximation near a point source of calcium ions.

In the presence of rapid buffers the full reaction-diffusion equations describing Ca2+ transport can be reduced using the rapid buffering approximation to a single transport equation for [Ca2+]. Here we simulate the full and reduced equations, exploring the conditions necessary for the validity of the rapid buffering approximation for an isolated Ca2+ channel or a cluster of channels. Using a point source and performing numerical simulations of different durations, we quantify the error of the rapid buffering approximation as a function of buffer and source parameters as well as the time and spatial scale set by the resolution of confocal microscopic measurements. We carry out simulations of Ca2+ "sparks" and "puffs," both with and without the indicator dye Ca2+ Green-1, and find that the rapid buffering approximation is excellent. These calculations also show that the traditional calculation of [Ca2+] from a fluorescence signal may grossly underestimate the true value of [Ca2+] near a source. Finally, we use the full model to simulate the transient Ca2+ domain near the pore of an open Ca2+ channel in a cell dialyzed with millimolar concentrations of 1,2-bis(2-aminophenoxy)ethane-N,N,N,N-tetraacetic acid or EGTA. In this regime, where the rapid buffering approximation is poor. Neher's equation for the steady-state Ca2+ profile is shown to be a reliable approximation adjacent to the pore.

Biophysical Phenomena↗
PubMed1996

Lifecourse exposure and later disease: a follow-up study based on a survey of family diet and health in pre-war Britain (1937-1939).

There is an increasing interest in the origins of adult disease in early life. The elucidation of such explanations of current morbidity and mortality must depend upon the follow-up of previously established cohorts. This paper describes the design of and background to such a follow-up of one of the richest data sources for this type of research: Sir John Boyd Orr's survey of diet and health in pre-war Britain. 1,352 families from 16 centres in England and Scotland were surveyed; 3,762 children aged up to 19 years from these families were examined. Socio-economic information and detailed one week dietary diary records are available for all families. Detailed medical examinations (including anthropometry) were undertaken on children in 14 of the centres. Most of the information is cross-sectional although 1,322 children were examined on two or more occasions one year apart to assess the effects of dietary supplementation. Dietary records were retrieved for 1,343 (99.3%) of the families. Medical examination records were found for 3,560 (94.6%) of the children who were examined in the survey and attempts have been made to trace 4,973 children who were either examined or whose family participated in the dietary survey. The data demonstrate relationships between family food expenditure and height in childhood and housing conditions. Eighty-five per cent (4211/4973) of the children have been traced and flagged on the National Health Service Central Register, Southport. The characteristics of those traced do not differ significantly from those we have been unable to trace although untraced females were slightly heavier. To date 696 (16.5%) of the cohort have died. The cohort will be used to investigate the relationship between diet, nutritional status (height, weight, cristal height), health and social circumstances in childhood, and mortality and morbidity in adulthood.

Adolescent↗
PubMed1996

Birthweight, adult risk factors and incident coronary heart disease: the Caerphilly Study.

OBJECTIVE: To determine the relationships between birthweight, the incidence of coronary heart disease, and a range of coronary heart disease risk factors that operate during adult life. DESIGN: Cohort study with a 10-year follow-up period. SETTING: The town of Caerphilly, South Wales, and five adjacent villages. SUBJECTS: 1,258 men aged 45-59 at time of recruitment between 1979 and 1983. MAIN OUTCOME MEASURES: All deaths, coronary heart disease deaths, non-fatal CHD events. RESULTS: The validity of the birthweight data was supported by the strong graded associations between birthweight and anthropometric measures in adulthood, particularly height, body mass index, triceps, skinfold thickness and percentage body fat. An inverse relationship was found between birthweight and incident fatal and non-fatal CHD, (P = 0.01), though no relationship was found between birthweight and all-cause mortality. Amongst the major CHD risk factors, only fibrinogen shows a statistically significant relationship with birthweight (P = 0.008), fibrinogen levels being lower among the men with lower birthweights. When social and biological variables are included in models relating incident CHD and birthweight, the relationship between birthweight and incident fatal and non-fatal CHD remains essentially unchanged. CONCLUSION: A graded association between low birthweight and later CHD has been demonstrated in this cohort. This inverse association cannot be explained by the measured social or behavioural variables, or by other risk factors operating in adult life.

Birth Weight↗