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Biomedical subjects

L Smith

Publications and source records attributed to L Smith.

At least 73 records · Page 4Linked to original sources
PubMed2001

Allele-specific quantification of tumor necrosis factor alpha (TNF) transcription and the role of promoter polymorphisms in rheumatoid arthritis patients and healthy individuals.

Interindividual variation in the expression of tumor necrosis factor alpha (TNF) suggests the existence of functionally distinct TNF alleles that could play a role in susceptibility to TNF associated diseases such as rheumatoid arthritis (RA). To determine whether differential expression of TNF alleles exists, the relative contribution of TNF alleles in total TNF RNA production in peripheral blood mononuclear cells (PBMC) of healthy individuals and synovial tissue of RA patients was analyzed. By using a Tai I restriction fragment length polymorphism (RFLP) located at position +489 in the first intron of the gene, the relative contribution of each allele in precursor transcript production in heterozygous individuals could be measured. By means of this method we studied whether differences exist between TNF alleles in TNF pre-mRNA production. The relative contribution of TNF alleles to the non-spliced RNA pool was measured in PBMC of healthy individuals which were stimulated with LPS, PMA and anti-CD3 and anti-CD28 monoclonal antibodies for different time periods. Moreover, synovial biopsy material of RA patients was analyzed. The results of this study do not reveal a difference in the contribution of distinct TNF alleles in TNF pre-mRNA production upon in vitro and physiological stimulation conditions in healthy individuals and RA patients. Since some of the individuals whose PBMC were tested were also heterozygous for either -308, -1031, -863, -857 TNF promoter/enhancer single nucleotide polymorphisms (SNPs), the data argue against functional relevance of these TNF promoter/enhancer SNPs in the regulation of transcription. In conclusion, the data do not provide evidence for the existence of transcriptionally distinct TNF alleles to explain interindividual variation in TNF expression.

Alleles↗
PubMed2001

Segmental mandibular reconstruction by microincremental automatic distraction osteogenesis: an animal study.

We investigated the reconstruction of a surgically created critical size mandibular defect in sheep using a newly developed automatic distraction device. The device has an implantable component, which is fixed to the mandible to allow the transfer of the transport disc across the created defect, and an external component which is mounted on the activation pump and secured away from the site of bone distraction. Compression of the bellows in the external component causes fluid to be forced through the connecting tube into the distraction component. Distraction at a rate of 1 mm over 24 h was achieved in six sheep. New bone generated at the site of the created defects both anterior (compression side) and posterior (tension side) to the transport disc and had similar radiodensity to the adjacent mandibular bone eight weeks after the completion of distraction.

Angiography↗
PubMed2001

In vitro human tissue models in risk assessment: report of a consensus-building workshop.

Advances in the technology of human cell and tissue culture and the increasing availability of human tissue for laboratory studies have led to the increased use of in vitro human tissue models in toxicology and pharmacodynamics studies and in quantitative modeling of metabolism, pharmacokinetic behavior, and transport. In recognition of the potential importance of such models in toxicological risk assessment, the Society of Toxicology sponsored a workshop to evaluate the current status of human cell and tissue models and to develop consensus recommendations on the use of such models to improve the scientific basis of risk assessment. This report summarizes the evaluation by invited experts and workshop attendees of the current status of such models for prediction of human metabolism and identification of drug-drug interactions, prediction of human toxicities, and quantitative modeling of pharmacokinetic and pharmaco-toxicodynamic behavior. Consensus recommendations for the application and improvement of current models are presented.

Cell Culture Techniques↗
PubMed2001

Hyperbaric oxygen therapy for severe ulcerative colitis.

Hyperbaric oxygen therapy has been used to successfully treat perineal Crohn's disease. We describe the first successful use of hyperbaric oxygen therapy in the treatment of ulcerative colitis, refractory to conventional therapies. Therapy consisted of 30 courses of 100% oxygen at a pressure of 2.0 atm absolute. Clinical remission was achieved on the basis of the Truelove-Witts and disease activity index scores. Corticosteroids were successfully tapered off once remission was achieved.

Adult↗
PubMed2001

Creatine supplementation and health variables: a retrospective study.

PURPOSE: Long-term safety of creatine supplementation has been questioned. This retrospective study was performed to examine markers related to health, the incidence of reported side effects and the perceived training benefits in athletes supplementing with creatine monohydrate. METHODS: Twenty-six athletes (18 M and 8 F, 24.7 +/- 9.2 y; 82.4 +/- 20.0 kg; 176.5 +/- 8.8 cm) from various sports were used as subjects. Blood was collected between 7:00 and 8:30 a.m. after a 12-h fast. Standard clinical examination was performed for CBC and 27 blood chemistries. Testosterone, cortisol, and growth hormone were analyzed using an ELISA. Subjects answered a questionnaire on dietary habits, creatine supplementation, medical history, training history, and perceived effects of supplementation. Body mass was measured using a medical scale, body composition was estimated using skinfolds, and resting heart rate and blood pressure were recorded. Subjects were grouped by supplementation length or no use: Gp1 (control) = no use (N = 7; 3 F, 4 M); Gp2 = 0.8-1.0 yr (N = 9; 2 F, 7 M); and Gp3 = 1(+) (N = 10; 3 F, 7 M). RESULTS: Creatine supplementation ranged from 0.8--4 yr. Mean loading dose for Gp2 and Gp3 was 13.7 +/- 10.0 and the maintenance dose was 9.7 +/- 5.7 g.d(-)1. Group differences were analyzed using one-way ANOVA. CONCLUSIONS: Expected gender differences were observed. Of the comparisons made among supplementation groups, only two differences for creatinine and total protein (P < 0.05) were noted. All group means fell within normal clinical ranges. There were no differences in the reported incidence of muscle injury, cramps, or other side effects. These data suggest that long-term creatine supplementation does not result in adverse health effects.

Adolescent↗
PubMed2001

HLA-B27 expression does not modulate intracellular Chlamydia trachomatis infection of cell lines.

Chlamydia trachomatis is an obligate intracellular pathogen. Infection of susceptible individuals with this bacterium can trigger the development of reactive arthritis, an acute inflammation that is associated with the expression of the class I major histocompatibility antigen, HLA-B27. Other facultative intracellular pathogens, such as Yersinia and Salmonella spp., are also known triggers of reactive arthritis. Previous studies report conflicting results concerning whether the presence of HLA-B27 modulates the infection of cells with these enteric pathogens. In the present study, we have examined whether the expression of HLA-B27 can influence the infection of cell lines with C. trachomatis and also whether the replication of these bacteria is altered in HLA-B27-expressing cell lines. To do this, we have used a sensitive flow cytometric approach. We fixed and permeabilized cells and used fluorescein isothiocyanate-conjugated monoclonal antibody specific for chlamydia lipopolysaccharide to detect intracellular bacteria. The staining pattern obtained closely resembled the intracellular life cycle of chlamydia, with the appearance of brightly staining cells correlating to the microscopic detection of mature inclusion bodies. Moreover, since the percentage of cells that stained with the antibody was proportional to the infectious inoculum used, we were able to use the technique to quantitate the number of infectious organisms recoverable from infected cell lines. An important component of our study was the use of heparin to prevent reinfection of cells and thus enable the infection to be followed from a discrete time point. Our results suggest that HLA-B27 influences neither the infection nor replication of C. trachomatis serovar L2 within cell lines. Consequently, the role of HLA-B27 in the pathogenesis of reactive arthritis may lie downstream of the invasion and replication stages of the triggering pathogenic infection.

Cell Line↗
PubMed2001

Mechanism of endothelial dysfunction in apolipoprotein E-deficient mice.

Endothelium-dependent relaxations mediated by NO are impaired in a mouse model of human atherosclerosis. Our objective was to characterize the mechanisms underlying endothelial dysfunction in aortas of apolipoprotein E (apoE)-deficient mice, treated for 26 to 29 weeks with a lipid-rich Western-type diet. Aortic rings from apoE-deficient mice showed impaired endothelium-dependent relaxations to acetylcholine (10(-)(9) to 10(-)(5) mol/L) and Ca(2+) ionophore (10(-)(9) to 10(-)(6) mol/L) and endothelium-independent relaxations to diethylammonium (Z)-1-(N,N-diethylamino)diazen-1-ium-1,2-diolate (DEA-NONOate, 10(-)(10) to 10(-)(5) mol/L) compared with aortic rings from C57BL/6J mice (P<0.05). By use of confocal microscopy of an oxidative fluorescent probe (dihydroethidium), increased superoxide anion (O(2)(-)) production was demonstrated throughout the aortic wall but mainly in smooth muscle cells of apoE-deficient mice. CuZn-superoxide dismutase (SOD) and Mn-SOD protein expressions were unaltered in the aorta exposed to hypercholesterolemia. A cell-permeable SOD mimetic, Mn(III) tetra(4-benzoic acid) porphyrin chloride (10(-)(5) mol/L), reduced O(2)(-) production and partially normalized relaxations to acetylcholine and DEA-NONOate in apoE-deficient mice (P<0.05). [(14)C]L-Citrulline assay showed a decrease of Ca(2+)-dependent NOS activity in aortas from apoE-deficient mice compared with C57BL/6J mice (P<0.05), whereas NO synthase protein expression was unchanged. In addition, cGMP levels were significantly reduced in the aortas of apoE-deficient mice (P<0.05). Our results demonstrate that in apoE-deficient mice on a Western-type fat diet, impairment of endothelial function is caused by increased production of O(2)(-) and reduced endothelial NO synthase enzyme activity. Thus, chemical inactivation of NO with O(2)(-) and reduced biosynthesis of NO are key mechanisms responsible for endothelial dysfunction in aortas of atherosclerotic apoE-deficient mice.

Animals↗
PubMed2001

Similar effects on infants of n-3 and n-6 fatty acids supplementation to pregnant and lactating women.

OBJECTIVE: There have been indications that high intake of n-3 long-chain polyunsaturated fatty acids (PUFAs) during pregnancy may increase birth weight and gestational length. In addition, n-3 long-chain PUFAs may be important for the neurobiological development of the infants. High levels of docosahexaenoic acid (DHA, 22:6 n-3) are found in the gray matter of the cerebral cortex and in the retina, and it seems as if the availability of long-chain PUFAs may be limiting cerebral development. The fetus and the newborn are dependent on a high supply from their mothers, either via the placenta or via breast milk. We supplemented pregnant and lactating women with n-3 or n-6 long-chain PUFAs to evaluate the effect on birth weight, gestational length, and infant development. DESIGN: We performed a double-blind, randomized study recruiting 590 pregnant, healthy, nulli- or primiparous women (19-35 years old) in weeks 17 to 19 of pregnancy. The women were provided 10 mL of either cod liver oil or corn oil daily until 3 months after delivery. MAIN OUTCOME MEASURES: Primary outcomes were gestational length and birth weight. Electroencephalography (EEG) was done on the second day of life and at 3 months of age. Novelty preference (Fagan test) was used as an indicator of cognitive function at 6 and 9 months of age. The fatty acid pattern in umbilical plasma phospholipids and in breast milk was measured, and dietary assessments were performed, both on the mothers during pregnancy and on the infants at 3 months of age. The growth of the infants was followed up to 1 year of age. RESULTS: Three hundred forty-one mothers took part in the study until delivery. There were no significant differences in maternal body mass index before pregnancy and at birth, or parity between the 2 groups. Smoking habits and parental education were also similar in the 2 groups. The mean age of the mothers receiving cod liver oil was, by chance, 1 year higher than the age of the mothers receiving corn oil (28.6 [3.4] vs 27.6 [3.2] years). The maternal dietary intake in the 2 groups receiving cod liver oil or corn oil was similar, except for the supplementation. There were no differences in gestational length or birth weight between the cod liver oil group and the corn oil group (279.6 [9.2] vs 279.2 [9.3] days; 3609 [493] vs 3618 [527] g, respectively). Birth length, head circumference, and placental weight were also similar in the 2 groups. The concentrations of the n-3 fatty acids eicosapentaenoic acid (20:5 n-3), docosapentaenoic acid (22:5 n-3), and DHA in umbilical plasma phospholipids were higher in the cod liver oil group compared with the corn oil group (10.8 [7.6] vs 2.5 [1.8] microg/mL, 5.0 [2.6] vs 2.9 [1.3] microg/mL, 55.8 [20.6] vs 45.3 [12.8] microg/mL, respectively). Neonates with high concentration of DHA in umbilical plasma phospholipids (upper quartile) had longer gestational length than neonates with low concentration (lower quartile; 282.5 [8.5] vs 275.4 [9.3] days). No differences in EEG scores or Fagan scores were found, but neonates with mature EEG (N = 70) had a higher concentration of DHA in umbilical plasma phospholipids than neonates with immature EEG (N = 51) on the second day of life. Dietary information from 251 infants at 3 months of age was collected and 85% of these infants were exclusively breastfed, in addition to 12% who were partly breastfed. The breast milk of mothers supplemented with cod liver oil contained more n-3 long-chain PUFAs and less n-6 long-chain PUFAs than breast milk of mothers supplemented with corn oil. There were no significant differences in infant growth during the first year of life between the 2 groups. CONCLUSIONS: This study shows neither harmful nor beneficial effects of maternal supplementation of long-chain n-3 PUFAs regarding pregnancy outcome, cognitive development, or growth, as compared with supplementation with n-6 fatty acids. However, it confirms that DHA concentration may be related to gestational length and cerebral maturation of the newborn.

Abnormalities, Multiple↗
PubMed2001

A new module in caring for older adults: problem-based learning and practice portfolios.

It is not often that educators have the chance to design a new educational program on the basis of up-to-date and locally relevant research findings. We describe the process by which we designed a new module, aimed at registered nurses who care for older adults in the community. The content of the new module was derived from an analysis of educational needs of the potential student population. The mode of delivery was strongly student-centered, using problem-based learning. Assessment was through the building up by students of a practice portfolio. This paper focuses on a description of the new module and how it relates to the findings of the educational needs analysis. The National Board for Nursing, Midwifery and Health Visiting for Scotland put out a tender in 1995 for a community research project on "Educational Provision for Evolving Roles in Community Health Care" (Nursing Times, June, 9, 1995) with the aim of piloting and evaluating an "innovative program which meets changing needs in community health care." A joint bid by Napier University and the University of Glasgow not only proposed to pilot and evaluate the educational program, but also first to develop the content of the program itself through an educational needs analysis. In this paper, we will first provide an outline of the research that underpinned the educational program. Then, we will describe how the results of the needs analysis were implemented into an innovative educational module. Finally, we will give a brief summary of the new module.

Aged↗
PubMed2001

Predicting shiftwork-related outcomes: shiftwork locus of control and circadian type.

This research discusses the use and viability of the shiftwork locus of control construct alongside circadian type measures as a potential predictor of shiftwork-related outcomes. The shiftwork locus of control (SHLOC) scale, measures of circadian type and shiftwork-related outcome measures were completed by 100 shiftworkers on two occasions separated by seven months. The SHLOC scale measures shiftworkers' generalised beliefs about the levels of personal control they perceive in relation to four major functional domains commonly associated with shiftwork-related disruption. These domains include: sleep, social, health and work problems. The results of multivariate regression analysis showed the SHLOC scale to be predictive of the experience of shiftwork-related sleep and social-life problems while the circadian type measures were predictive of alertness at 7 months. The results suggest that a constellation of personality factors may be an important influence on an individual's tolerance to shiftwork.

Adaptation, Psychological↗
PubMed2001

Reducing night shift exposure: a pilot study of rota, night shift and age effects on sleepiness and fatigue.

The reduction of exposure to longer runs of successive night duties is often one of the aims of 'best practice' intervention. The objective of this pilot study was to examine the effects of a change in rota upon sleepiness and fatigue, and potential age-related issues in relation to the change. Participants were 102 police officers, mean age 33.60 (sd 6.11), mean shiftwork experience = 10.56 years (sd 6.84). Testing occurred at least one month before the change from the existing 'Ottawa' system to a new rota that split a run of 7 consecutive night shifts into blocks of 3 and 4 within the rota cycle, and 6 months after the change. Measures of critical flicker fusion, subjective fatigue and sleepiness, and stimulant intake were taken in relation to selected night shifts on both rotas. Older officers tended to report higher fatigue and sleepiness, and higher caffeine intake than the younger shiftworkers irrespective of rota or shift. The findings tend to suggest that the change of rota had little effect but that age may play a substantial role in responses to night work.

Adult↗
PubMed2001

Shiftwork locus of control effects in police officers.

Personality and experientially-based differences are suggested to moderate the negative effects of shiftworking. This investigation was one of a series of studies aimed at examining the relationship between internal locus of control (internality) and commonly reported outcomes of exposure to shiftworking. The study concentrated on whether or not shiftwork-specific internality appeared to be associated with better experiences for two groups of shiftworkers on different shift rotas. The Shiftwork Locus of Control (SHLOC) scale was completed by each group along with a range of outcome measures (including: sleep disturbance, alertness on shift, psychological well-being, disturbance of social and family life, and fatigue). The analyses controlled for for age, shiftwork experience and years of service effects. The results showed that for the majority of outcome variables, the higher internality was associated with significantly lower levels of shiftwork problems, especially when compared to the low internality group. The findings of this study further support the use of shiftwork-specific locus of control in shiftwork research as an indicator of potentially better tolerance, and possibly as part of an occupational health monitoring process to aid the targeting of interventions.

Adaptation, Psychological↗
PubMed2001

The effect of a change in sleep-wakefulness timing, bright light and physical exercise interventions on 24-hour patterns of performance, mood and body temperature.

Experiments consisting of baseline, bright light and physical exercise studies were carried out to compare the effect of a 9-hour delay in sleep-wakefulness timing, and the effects of bright light and physical exercise interventions on 24-hour patterns of performance, mood and body temperature were examined. Each study comprised a 24-hour constant routine at the beginning followed by 3 night shifts and 24-hour constant routine at the end. Performance on tasks differing in cognitive load, mood and body temperature was measured during each constant routine and the interventions were applied during the night shifts. The 24-hour pattern of alertness and performance on the tasks with low cognitive load in post-treatment conditions followed the change in sleep-wakefulness timing while more cognitively loaded tasks tended to show a reverse trend when compared to pre-treatment conditions. There was a phase delay around 4 hours in circadian rhythms of body temperature in post-treatment conditions.

Adult↗
PubMed2001

Age and the subjective experience of shiftwork.

The objective of this study was to examine age related effects of shiftwork albeit difficult to tease apart the natural effects of aging, and lifestyle or behaviour, or job done, over time and the shifts a person works. This is an issue of concern because the numbers of shiftworkers over 45 are increasing. Participants were 306 police officers who had worked a new rota for approximately 6 months. Three age groups were compared (1 = 20-32.9, 2 = 33-39.9, 3 = 40+) using a range of shiftwork-related measures and multivariate analysis of covariance (controlling for shiftwork experience and other individual differences). Younger officers tended to report significantly better attitudes towards their shiftwork, better adjustment to night-bound shifts, greater job satisfaction and organisational commitment, lower fatigue and longer sleep durations. Older shiftworkers reported significantly higher morningness and lower sleep need than the younger officers. This concurred with existing research that implicates such variables in the mechanism(s) involved in age-related tolerance to shiftwork. It was also evident that the older group tended to resort to greater caffeine intake on all shifts. The findings offer tentative support for the position that age can be linked to depleted shiftwork tolerance but the issue of establishing the relative impacts of aging, lifestyle, behaviour, work type and the rota worked remains to be a challenge.

Adaptation, Psychological↗
PubMed2000

Activation of atypical protein kinase C zeta by caspase processing and degradation by the ubiquitin-proteasome system.

Atypical protein kinase C zeta (PKCzeta) is known to transduce signals that influence cell proliferation and survival. Here we show that recombinant human caspases can process PKCzeta at three sites in the hinge region between the regulatory and catalytic domains. Caspase-3, -6, -7, and -8 chiefly cleaved human PKCzeta at EETD downward arrowG, and caspase-3 and -7 also cleaved PKCzeta at DGMD downward arrowG and DSED downward arrowL, respectively. Processing of PKCzeta expressed in transfected cells occurred chiefly at EETD downward arrowG and DGMD downward arrowG and produced carboxyl-terminal polypeptides that contained the catalytic domain. Epitope-tagged PKCzeta that lacked the regulatory domain was catalytically active following expression in HeLa cells. Induction of apoptosis in HeLa cells by tumor necrosis factor alpha plus cycloheximide evoked the conversion of full-length epitope-tagged PKCzeta to two catalytic domain polypeptides and increased PKCzeta activity. A caspase inhibitor, zVAD-fmk, prevented epitope-tagged PKCzeta processing and activation following the induction of apoptosis. Induction of apoptosis in rat parotid C5 cells produced catalytic domain polypeptides of endogenous PKCzeta and increased PKCzeta activity. Caspase inhibitors prevented the increase in PKCzeta activity and production of the catalytic domain polypeptides. Treatment with lactacystin, a selective inhibitor of the proteasome, caused polyubiquitin-PKCzeta conjugates to accumulate in cells transfected with the catalytic domain or full-length PKCzeta, or with a PKCzeta mutant that was resistant to caspase processing. We conclude that caspases process PKCzeta to carboxyl-terminal fragments that are catalytically active and that are degraded by the ubiquitin-proteasome pathway.

Animals↗
PubMed2000

A novel ATPase on mouse chromosome 7 is a candidate gene for increased body fat.

A region of mouse chromosome 7, just distal to the pink-eyed (p) dilution locus, contains a gene or genes, which we have named p-locus-associated obesity (plo1), affecting body fat. Mice heterozygous for the most distally extending chromosomal deletions of this region have nearly double the body fat of mice when the deletion is inherited maternally as when it is inherited paternally. We have physically mapped the 1-Mb critical region, which lies between the Gabrb3 and Ube3a/Ipw genes, and DNA sequencing has localized a new member of the third subfamily of P-type ATPases to the minimal region specifying the trait. This gene, which we have called p-locus fat-associated ATPase (pfatp) is differentially expressed in human and mouse tissues with predominant expression in the testis and lower levels of expression in adipose tissue and other organs. We propose this ATPase as the prime candidate for the gene at the plo1 locus modulating body fat content in the mouse. The unusual inheritance pattern of this phenotype suggests either genomic imprinting, known to occur in other local genes (Ube3a, Ipw), or an effect of maternal haploinsufficiency during pregnancy or lactation on body fat in the progeny.

Adenosine Triphosphatases↗