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Biomedical subjects

G D Smith

Publications and source records attributed to G D Smith.

At least 289 records · Page 16Linked to original sources
PubMed1996

The effects of caring for a spouse with Parkinson's disease on social, psychological and physical well-being.

BACKGROUND: Several previous studies have examined the health of carers, but they have usually focused on elderly subjects and have often not had representative control samples. AIM: To determine whether caring for a partner with Parkinson's disease is associated with a worsening social, psychological and physical well-being than people with partners who do not suffer with Parkinson's disease. METHOD: One hundred and fifty-four carer spouses of subjects with Parkinson's disease, and 124 non-carer spouses of randomly selected population controls recruited from a national case-control study of early-onset Parkinson's disease in the Republic of Ireland, between 1992-1994, were studied. Outcome was measured along three dimensions: social functioning, assessed by the frequency of social contacts, outings and holidays; psychological well-being, measured by the General Health Questionnaire; and physical health, measured by the career's use of medical services, medications and episodes of chronic illness. RESULTS: Carer spouses were less likely to get out of the house once a week at least (odds ratio 1.79, 95% confidence intervals 1.00-3.20) or to have had a holiday in the last year (odds ratio 1.71, 95% confidence intervals 1.01-2.90). Contact with friends and neighbours decreased with increasing care provision. For spouses providing a lot of care, there was an almost fivefold increase in psychiatric morbidity (odds ratio 4.86, 95% confidence intervals 1.5-15.9) after adjusting for other variables. Most of the medical outcomes were less favourable among carers, but only the use of tranquilizers (odds ratio 3.73, 95% confidence intervals 1.18-11.8) and episodes of chronic illness (odds ratio 2.96, 95% confidence intervals 1.27-6.94) were significant. CONCLUSIONS: Overall, career spouses have slightly worse social, psychological and physical profiles. For social outcomes, increasing care provision is associated with fewer contacts, outings and holidays. For psychological and physical measures, carers providing a lot of care experience worse health. These results have implications for targeting appropriate interventions.

Caregivers↗
PubMed1995

A thyrotropin-releasing hormone analogue: pGlu-Phe-D-Pro-psi [CN4]-NMe at 293 and 107 K.

Data have been measured at two temperatures, 293 K and 107 K, for a crystal of a thyrotropin-releasing hormone analogue, pGlu-Phe-D-Pro-psi [CN4]-NMe, C20H25N7O3, and the structures solved and refined. The tripeptide contains a tetrazole ring which mimics a cis-peptide bond at the C terminus. An intermolecular hydrogen bond exists between two molecules related by the twofold screw axis, resulting in infinite chains of hydrogen-bonded peptide molecules. Because of the folding and packing of the molecules, there are no intermolecular contacts of less than 4 A to the N atom of the phenylalanine residue.

Amino Acid Sequence↗
PubMed1995

Health effects of anticipation of job change and non-employment: longitudinal data from the Whitehall II study.

OBJECTIVE: To assess the effect of anticipating job change or non-employment on self reported health status in a group of middle aged male and female white collar civil servants. DESIGN: Longitudinal cohort study (Whitehall II study). Questionnaire data on self reported health status and health behaviour were obtained at initial screening and four years later, during the period when employees of the department facing privatisation were anticipating job change or job loss. SETTING: London based office staff in 20 civil service departments. SUBJECTS: 666 members of one department threatened with early privatisation were compared with members of the 19 other departments. MAIN OUTCOME MEASURES: Self reported health status measures and health related behaviours, before and during anticipation of privatisation. RESULTS: In comparison to the remainder of the cohort, the profile of health related behaviours of cohort members who faced privatisation was more favourable, both before and during anticipation of privatisation. There were no significant differences in the changes in health behaviours between cohort members moving into a period of job insecurity and the remainder of the cohort. Self reported health status, however, tended to deteriorate among employees anticipating privatisation when compared with that of the rest of the cohort. CONCLUSIONS: The application of a longitudinal design, allowing the same individuals to be followed from job security into anticipation, provides more robust evidence than has previously been available that anticipation of job loss affects health even before employment status has changed.

Adaptation, Psychological↗
PubMed1995

Chloroquine augments the binding of insulin to its receptor.

The effect of chloroquine on the interaction of insulin with its receptor has been investigated under both equilibrium and non-equilibrium conditions. Chloroquine was found to augment insulin binding in a pH-dependent manner between pH 6.0 and pH 8.5, with the maximum occurring at approximately pH 7.0. Analysis of the equilibrium binding data in terms of independent binding sites gave equivocal results but suggested an increase in the high-affinity component. Analysis using the negative co-operativity binding model of De Meyts, Bianco and Roth [J. Biol. Chem. (1976) 251, 1877-1888] suggested that the affinity at both high and low occupancy was increased equally. The kinetics of association of insulin with the plasma-membrane receptor indicated that, although the net rate of association increased in the presence of chloroquine, this was due to a reduction in the dissociation rate rather than an increase in the association rate. This was confirmed by direct measurement of the rates of dissociation. Dissociation was found to be distinctly biphasic, with fast and slow components. Curve fitting suggested that the decrease in dissociation rate in the presence of chloroquine was not due to a decrease in either of the two dissociation rate constants, but rather to an increase in the amount of insulin dissociating by the slow component. It was also found that the increase in dissociation rate in the presence of excess insulin, ascribed to negative co-operativity, could be accounted for by an increase in the amount of insulin dissociating by the faster pathway, rather than by an increase in the dissociation rate constant. Thus chloroquine appears to have the opposite effect to excess insulin, and evidence was found for the induction of positive co-operativity in the insulin-receptor interaction at high chloroquine concentrations. Evidence was also found for the presence of low-affinity chloroquine binding sites with binding parameters similar to the concentration dependence of the chloroquine-induced augmentation of insulin binding.

Animals↗
PubMed1995

Use of globic scattering factors for protein structures at low resolution.

At 3 to 4 A resolution, the electron density of a protein may be modeled by a continuous chain of 'globs' representing the amide region of the peptide backbone and the side-chain residues. Group scattering factors are derived from a trans planar C alpha C = ONC alpha backbone segment and most favored side-chain conformer for 18 different amino acids. Trial calculations indicate that the phase error and crystallographic residual comparing the atomic and 'globic' models rapidly decrease from high to low resolution. At 3 A resolution, the phase error is approximately 80 degrees. These results indicate that the electron density of a protein composed of N amino acid residues may be adequately modeled by 2N globs at low resolution.

Amino Acids↗
PubMed1995

Role of C-terminal B-chain residues in insulin assembly: the structure of hexameric LysB28ProB29-human insulin.

BACKGROUND: LysB28ProB29-human insulin (Humalog), a fully potent insulin analog in which the prolyl, lysyl sequence at the C-terminal end of the B-chain is inverted, exhibits a decreased association of monomers to dimers leading to rapid in vivo absorption. This provides important benefits for the insulin-requiring diabetic. In spite of its monomeric nature, LysB28ProB29-human insulin can exist as a discrete hexameric structure in the presence of both zinc and phenol. Studies of the crystal structure of LysB28ProB29-human insulin in a hexameric complex were initiated to gain a molecular understanding of the effect of the sequence inversion on the analog's self-association properties and, consequently, its in vivo efficacy. RESULTS: Under the conditions reported, LysB28ProB29-human insulin crystallized as a T3Rf3 hexamer that is isomorphous with the uncomplexed T3Rf3 native human insulin hexamer previously known as '4Zn insulin'. The three-dimensional structure of the T3Rf3 hexamer was determined by X-ray crystallographic methods to a resolution of 2.3 A. The prolyl, lysyl sequence inversion leads to local conformational changes at the C termini of the B-chains which eliminate two critical hydrophobic interactions and weaken two terminal beta-sheet hydrogen bonds that stabilize the dimer. CONCLUSIONS: The loss of these native dimer interactions weakens the hexameric LysB28ProB29-human insulin complex formed in the presence of phenolic ligands. Thus, it is hypothesized that the diffusion of the phenolic ligands from the site of injection results in the dissociation of hexamers directly to monomers, thereby maintaining the rapid time-action of the monomeric analog in spite of the hexameric conformation in therapeutic formulations.

Amino Acid Sequence↗
PubMed1995

Peri-administration of clonidine or MK801 delays but does not prevent the development of mechanical hyperalgesia in a model of mononeuropathy in the rat.

Following loose ligation of the sciatic nerve, rats develop a persistent hyperalgesia which mimics some of the features of traumatic neuropathy seen in man. Previously, we have shown that administration of MK801 or clonidine prior to and 30 min following loose ligation of the sciatic nerve prevented the development of hyperalgesia up to 30 days following surgery. In the current study, we have extended our observation and examined the effect of administration of clonidine (1 mg/kg, s.c.) or MK801 (0.3 mg/kg, s.c.) 30 min prior to and 6 h following loose ligation of the sciatic nerve on the development of hyperalgesia assessed at 9 time points between 16 and 150 days after loose ligation. We have found that compared with saline treatment, the degree of hyperalgesia apparent in animals receiving MK801 was significantly reduced when tested 16, 28, or 42 days after surgery. No significant difference between the 2 treatment groups was detected at any other time points during the study. Similarly, when compared with saline treated controls, the degree of hyperalgesia measured in animals following peri-administration of clonidine was significantly less when measured 16 and 28 days after surgery, but did not differ significantly at any of the time points tested between 42 and 150 days following surgery. Our results indicate that peri-administration of MK801 or clonidine significantly delay, but do not prevent, the onset of neuropathic hyperalgesia.

Animals↗
PubMed1995

Abnormal cardiovascular and catecholamine responses to supine exercise in human subjects with sympathetic dysfunction.

1. The cardiovascular and catecholamine responses to supine leg exercise were measured in fifteen normal subjects (controls) and in three groups with sympathetic dysfunction: fifteen with central failure (Shy-Drager syndrome; SDS), fifteen with peripheral failure (pure autonomic failure; PAF) and two with isolated dopamine beta-hydroxylase deficiency (DBH deficiency). 2. With exercise, blood pressure increased in controls, fell markedly in SDS and PAF and was unchanged in DBH deficiency. After exercise, blood pressure rapidly returned to baseline in controls, but remained low in SDS and PAF. With exercise, heart rate increased more in controls than SDS or PAF; the response varied in DBH deficiency. 3. With exercise, cardiac output increased similarly in controls, SDS and PAF, with a larger increase in DBH deficiency. Vascular resistance fell less in controls than SDS, PAF and DBH deficiency. 4. With exercise, plasma noradrenaline increased in controls only; plasma adrenaline remained unchanged in all groups. In DBH deficiency, plasma noradrenaline and adrenaline were undetectable, but plasma dopamine was elevated and rose further with exercise. 5. Supine exercise substantially lowered blood pressure in sympathetic failure due to SDS and PAF. In DBH deficiency blood pressure was unchanged; this lack of fall may have been due to vasoconstriction induced by dopamine and other substances released from otherwise intact sympathetic terminals, or to preserved cardiac vagal function.

Adult↗
PubMed1995

Pressor reactions to psychological stress and prediction of future blood pressure: data from the Whitehall II Study.

OBJECTIVE: To examine whether reactions of blood pressure to psychological stress predict future blood pressure. DESIGN: Blood pressure was recorded at a medical screening examination after which pressor reactions to a psychological stress task were determined. Follow up measurement of blood pressure was undertaken, on average, 4.9 years later. SETTING: 20 civil service departments in London. SUBJECTS: 1003 male civil servants aged between 35 and 55 years at entry to the study. MAIN OUTCOME MEASURE: Blood pressure at follow up screening. RESULTS: Reactions of systolic blood pressure to stress correlated positively with systolic blood pressure at follow up screening (r = 0.22, P < 0.01). The dominant correlate of follow up blood pressure was blood pressure at initial screening (r = 0.60; P < 0.01 between initial and follow up systolic blood pressure; r = 0.59, P < 0.01 between initial and follow up diastolic blood pressure). Stepwise multiple regression analysis indicated that reactions to the stressor provided minimal prediction of follow up blood pressure over and above that afforded by blood pressure at initial screening. In the case of follow up systolic blood pressure, systolic reactions to stress accounted for only 1% of follow up variance; systolic blood pressure at initial screening accounted for 34%. With regard to diastolic blood pressure at follow up, the independent contribution from diastolic reactions to stress was less than 1%. CONCLUSION: Pressor reactions to psychological stress provide minimal independent prediction of blood pressure at follow up. Measurement of reactivity is not a useful clinical index of the course of future blood pressure.

Adult↗
PubMed1995

Gene organization in herpesvirus of turkeys: identification of a novel open reading frame in the long unique region and a truncated homologue of pp38 in the internal repeat.

The DNA sequence of a 4.792-kb fragment comprising 3.176 kb of the long unique region (UL) and 1.605 kb of the internal repeat (IRL) flanking UL of herpesvirus of turkeys (HVT) was determined. Three potential open reading frames (ORFs) and an origin of replication have been identified. ORF 1, which maps entirely within UL, has the capacity to code for an 82K protein, 731 amino acids long, which has a counterpart in Marek's disease virus (MDV) but not in other herpesviruses. ORF 2 has the potential to encode a protein consisting of 129 amino acids with a predicted M(r) of 13.5K which appears to be unique to HVT. ORF 3 is encoded entirely within IRL and codes for an 84 amino acids long protein with a predicted M(r) of 8.5K. ORF 3 shows significant homology with the C-terminal region of the MDV-1-specific phosphoprotein pp38 and its recently identified homologue in MDV-2. Northern blot analysis of RNA extracted from HVT-infected chick embryo fibroblasts identified a 5.6-kb RNA transcribed in a leftward direction toward UL scanning ORF 1, ORF 2, and ORF 3 and a 2.8-kb also transcribed leftward toward UL which spanned only ORFs 2 and 3. In addition, a 2.3- to 2.8-kb RNA family was transcribed rightwards through the origin of replication. In vitro transcription and translation of ORF 1 and ORF 3 resulted in the synthesis of polypeptides consistent with their expected M(r), but ORF 2 failed to produce any translation product.

Amino Acid Sequence↗
PubMed1995

Crambin: a direct solution for a 400-atom structure.

The crystal structure of crambin, a 46-residue protein containing the equivalent of approximately 400 fully occupied non-H-atom positions, was originally solved at 1.5 A by exploiting the anomalous scattering of its six S atoms at a single wavelength far removed from the absorption edge of sulfur. The crambin structure has now been resolved without the use of any anomalous-dispersion measurements. The technique employed was an ab initio 'shake-and-bake' method, consisting of a phase-refinement procedure based on the minimal function alternated with Fourier refinement. This method has successfully yielded solutions for a smaller molecule (28 atoms) using 1.2 A data, and a crambin solution was obtained at 1.1 A.

Journal Article↗
PubMed1995

Changes in neuronal markers in a mononeuropathic rat model relationship between neuropeptide Y, pre-emptive drug treatment and long-term mechanical hyperalgesia.

Using the chronic constriction model (CCI) of Bennett and Xie (1988), changes in the lumbar spinal cord in neuropeptides and lectin IB4 were examined at 28 days post-nerve constriction and were compared with the degree of mechanical hyperalgesia. Animals following nerve ligation were significantly more hyperalgesic than sham-operated animals (P < 0.0001). Lectin IB4, a marker of primary afferent C fibres, showed a qualitative decrease in staining intensity in laminae 1-2 with ligation compared with both the unoperated contralateral side and with sham animals. Using fluorescent immunohistochemistry to quantify changes in neuropeptides in the dorsal horn we found that substance P showed significant decreases with ligation compared to sham operation (P < 0.002). CGRP and galanin showed no significant changes in laminae 1-2 compared to sham-operated animals. Neuropeptide Y (NPY) showed no significant changes in intensity in laminae 1-2; however, in laminae 3-4 there was a significant increase with nerve ligation compared to sham (P < 0.005). We examined how pre-emptive drug treatment affected these neuronal markers at 28 days. We used (1) clonidine, an alpha 2-adrenoreceptor agonist (1 mg/kg, i.p.), (2) morphine, a mu-opioid agonist (5 mg/kg, i.p.) or (3) MK-801, an N-methyl-D-aspartate (NMDA) receptor antagonist (0.3 mg/kg, s.c.) administered 30 min prior and 6 h following nerve ligation or sham-operation. Hyperalgesia in the ligated group at 28 days was suppressed by treatment with pre-emptive clonidine (P = 0.003) or MK-801 (P = 0.003) but not morphine. With the exception of NPY there was no effect of pre-emptive drug treatment on any neuronal marker examined. Pre-emptive MK-801 reduced the magnitude of the increase in NPY in laminae 3-4 in the ligated group (P < 0.005) and clonidine showed a similar trend but this did not reach significance. Morphine had no effect on NPY staining. There was a significant correlation between the increase in NPY staining in laminae 3-4 and the degree of hyperalgesia (r = 0.6, P < 0.001). These results suggest that the increased NPY expression in laminae 3-4 of the spinal cord (the territory of the myelinated sensory input) may be crucial to the development of hyperalgesia in this model.

Analgesics↗