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Biomedical subjects

L A Kelly

Publications and source records attributed to L A Kelly.

At least 19 recordsLinked to original sources
PubMed2005

Effect of socioeconomic status on objectively measured physical activity.

BACKGROUND: A socioeconomic gradient in childhood obesity is known to be present by the age of school entry in the UK. The origin of this gradient is unclear at present, but must lie in socioeconomic differences in habitual physical activity, sedentary behaviour, or dietary intake. AIMS: To test the hypothesis that habitual physical activity and/or sedentary behaviour are associated with socioeconomic status (SES) in young Scottish children. METHODS: Observational study of 339 children (mean age 4.2 years, SD 0.3) in which habitual physical activity and sedentary behaviour were measured by accelerometry over six days (study 1). In a second study, 39 pairs of children of distinctly different SES (mean age 5.6 years, SD 0.3) were tested for differences in habitual physical activity and sedentary behaviour by accelerometry over seven days. RESULTS: In study 1, SES was not a significant factor in explaining the amount of time spent in physical activity or sedentary behaviour once gender and month of measurement were taken into account. In study 2, there were no significant differences in time spent in physical activity or sedentary behaviour between affluent and deprived groups. CONCLUSION: Results do not support the hypothesis that low SES in young Scottish children is associated with lower habitual physical activity or higher engagement in sedentary behaviour.

Body Mass Index↗
PubMed2005

Low physical activity levels and high levels of sedentary behaviour are characteristic of rural Irish primary school children.

There is increasing public health concern that levels of physical activity in children are extremely low. This study aimed to describe objectively levels of physical activity and sedentary behaviour during the waking hours in a sample of 4-5 year old (median 5.4 years range 4.3, 6.0) rural Irish children (n=41) and to test for gender differences in patterns of physical activity and sedentary behaviour. There were significant gender differences in physical activity (Boys (median) 834 accelerometer counts per minute (cpm), girls (median) 628cpm; p = 0.0015), sedentary behaviour (Boys 74% of waking time, girls 81% of waking time, p=0.0011) and moderate-vigorous physical activity (Boys 4% of waking time, girls 2% of waking time; p=0.0175). This study that suggests young rural Irish children lead sedentary lifestyles.

Anthropometry↗
PubMed2004

Total energy expenditure and physical activity in young Scottish children: mixed longitudinal study.

Childhood obesity has been attributed to a decline in total energy expenditure (TEE). We measured TEE, physical activity, and sedentary behaviour in a representative sample of young children from Glasgow, UK, at age 3 years (n=78), and we did a follow-up study at age 5 years (n=72). Mean physical activity level (TEE/resting energy expenditure) was 1.56 (SD 0.39) at age 3 years and 1.61 (0.22) at age 5 years. Median time in sedentary behaviour was 79% of monitored hours at age 3 years (IQR 74-84) and 76% (71-80) at age 5 years. Median time spent in moderate to vigorous physical activity represented only 2% of monitored hours at age 3 years (IQR 1-4) and 4% at age 5 years (2-6). Modern British children establish a sedentary lifestyle at an early age.

Age Factors↗
PubMed2001

Nucleotide oxidation mediated by naphthalimide excited states with covalently attached viologen cosensitizers.

The ground- and excited-state interactions of polymethylene-linked 1,8-naphthalimide-viologen dyads with calf-thymus DNA have been investigated. By virtue of the covalently attached viologen, the compounds represent the first example of linked chromophore/cosensitizer systems in the photooxidation of duplex DNA. The compounds associate strongly with DNA. Analysis of ground-state spectral changes yield binding constants of 0.7-2.5 x 10(6) M-1. Upon 355 nm pulsed irradiation of the compounds in the presence of calf-thymus DNA, reduced viologen is observed within the laser pulse. Photoproducts are not observed on this time scale in the absence of DNA. Since ground-state bleaching of the naphthalimide was not observed, the results suggest that DNA nucleobases are the species being oxidized. The quantum efficiency of radical production increases with the extent of binding to DNA. Under conditions where the compounds are bound predominantly to DNA, the quantum efficiencies were found to range from 0.02 to 0.03. Although small, the values represent a substantial increase in charge-separation yield compared to 1,8-naphthalimide compounds that lack the covalently attached viologen. The mechanism of radical production and effect of number of intervening methylenes are discussed.

Animals↗
PubMed2001

Mechanisms of photoinitiated cleavage of DNA by 1,8-naphthalimide derivatives.

Using water-soluble 1,8-naphthalimide derivatives, the mechanisms of photosensitized DNA damage have been elucidated. Specifically, a comparison of rate constants for the photoinduced relaxation of supercoiled to circular DNA, as a function of dissolved halide, oxygen and naphthalimide concentration, has been carried out. The singlet excited states of the naphthalimide derivatives were quenched by chloride, bromide and iodide. In all cases the quenching products were naphthalimide triplet states, produced by induced intersystem crossing within the collision complex. Similarly, the halides were found to quench the triplet excited state of the 1,8-naphthalimide derivatives by an electron transfer mechanism. Bimolecular rate constants were < 10(5) M-1 s-1 for quenching by bromide and chloride. As expected from thermodynamic considerations quenching by iodide was 6.7 x 10(9) and 8.8 x 10(9) M-1 s-1 for the two 1,8-naphthalimide derivatives employed. At sufficiently high ground-state concentration self-quenching of the naphthalimide triplet excited state also occurs. The photosensitized conversion of supercoiled to circular DNA is fastest when self-quenching reactions are favored. The results suggest that, in the case of 1,8-naphthalimide derivatives, radicals derived from quenching of the triplet state by ground-state chromophores are more effective in cleaving DNA than reactive oxygen species or radicals derived from halogen atoms.

1-Naphthylamine↗
PubMed2001

Prognostic value of quantitative reverse transcription-polymerase chain reaction in lymph node-negative esophageal cancer patients.

PURPOSE: In esophageal cancer, lymph node metastases are the strongest predictor of recurrence and poor outcome. However, many node-negative patients still recur despite a potentially curative resection. This is probably the result of microscopically occult metastases missed by histological examination. In this study, we used both standard, gel-based reverse transcription-PCR (RT-PCR) and Taqman quantitative RT-PCR (QRT-PCR) for carcinoembryonic antigen (CEA) mRNA to detect occult micrometastases in 387 lymph nodes from 30 histologically node-negative esophageal cancer patients. EXPERIMENTAL DESIGN: CEA expression was compared with clinical outcomes to determine correlation with disease recurrence. For quantitative data, an optimum CEA expression level cutoff value was defined as the value that most accurately classified patients on the basis of disease recurrence. Kaplan-Meier survival curves were generated, and multivariate analyses were performed to evaluate the prognostic value of QRT-PCR. RESULTS: CEA expression levels were above the optimum cutoff level in 12 tissue blocks, resulting in the identification of 11 CEA-positive patients. Of these patients, 9 suffered disease recurrence and 2 remain disease free. Of the 19 CEA-negative patients, there was 1 disease recurrence. The sensitivity and specificity for predicting disease recurrence were 90 and 90%, respectively. Kaplan-Meier analysis showed that CEA positivity resulted in significantly lower disease-free and overall survival (P <0.0001 and 0.0006 respectively). In multivariate analyses, CEA positivity measured by QRT-PCR was the strongest independent predictor of disease recurrence among other clinical and pathological factors examined. CONCLUSIONS: QRT-PCR offers significant benefits over standard RT-PCR and identifies node-negative patients at high risk for recurrence.

Aged↗
PubMed2000

Retinoic acid-induced tissue transglutaminase and apoptosis in vascular smooth muscle cells.

Retinoids exert antiproliferative and prodifferentiating effects in vascular smooth muscle cells (SMCs) and reduce neointimal mass in balloon-injured blood vessels. The mechanisms through which retinoids carry out these effects are unknown but likely involve retinoid receptor-mediated changes in gene expression. Here we report the cloning, chromosomal mapping, and biological activity of the retinoid-response gene rat tissue transglutaminase (tTG). Northern blotting studies showed that tTG is rapidly and dose-dependently induced in a protein synthesis-independent manner after stimulation with the natural retinoid all-trans retinoic acid (atRA). The induction of tTG was selective for atRA and its stereoisomers 9-cis and 13-cis RA, because little or no elevation in mRNA expression was observed with a panel of growth factors. Western blotting and immunofluorescence confocal microscopy showed an accumulation of cytosolic tTG protein after atRA stimulation. Radiolabeled cross-linking studies revealed a corresponding elevation in in vitro tTG activity. The increase in tTG activity was reduced in the presence of 2 distinct inhibitors of tTG (monodansylcadaverine and cystamine). atRA-induced tTG mRNA and protein expression were followed by a significant elevation in SMC apoptosis. Such retinoid-induced programmed cell death could be partially inhibited with each tTG inhibitor and was completely blocked when both inhibitors were used simultaneously. These results establish a role for atRA in the sequential stimulation of tTG and apoptosis in cultured SMCs. atRA-mediated apoptosis in SMCs seems to require the participation of active tTG, suggesting a potential mechanistic link between this retinoid-inducible gene and programmed cell death.

Animals↗
PubMed2000

Up-regulation of prostaglandin EP4 receptor messenger RNA in fetal rabbit skin wound.

BACKGROUND: Scar formation and subglottic stenosis often cause health problems in surgical otolaryngology. However, fetal wounds demonstrate scarless healing. The underlying mechanism remains poorly understood. We isolated differentially expressed genes by comparison between nonwounded with wounded skin of fetal and adult rabbits. METHODS: Skin incisional wounds were made in fetal (21 to 23 days' gestation) and adult rabbits. Nonwounded and wounded skin were harvested 12 hours after surgery. Total RNA was extracted. By means of messenger RNA differential display, differentially expressed complementary DNA fragments were isolated, cloned, and sequenced. The expressed transcripts were verified by reverse RNA dot blot and semiquantitative reverse transcription and polymerase chain reaction. RESULTS: One complementary DNA tag that was induced in fetal skin wounds and repressed in adult skin wounds was isolated. The sequence of this complementary DNA (352 base pairs) encodes the messenger RNA for the E-prostanoid (EP) 4 receptor for prostaglandin E(2) (PGE(2)). The truly differential expression of the transcript was confirmed. In normal skin, the EP4 receptor messenger RNA levels were higher in adults than in fetuses. Twelve hours after wounding, the EP4 receptor transcript was remarkably induced in fetal skin wounds but repressed in adult skin wounds. CONCLUSIONS: Our study demonstrates the differential expression of the EP4 receptor messenger RNA in fetal and adult skin before and 12 hours after wounding. Our results suggest that prostaglandin E(2) is involved in the differential cellular responses and in the regulation of the intracellular signal transduction through its binding to EP4 receptor during fetal wound repair.

Animals↗
PubMed2000

Optimization of the weck-Cel collection method for quantitation of cytokines in mucosal secretions.

Measurement of immune components in mucosal secretions is important for the evaluation of local immunity at the mucosal surfaces. The Weck-Cel ophthalmic sponge provides a method for the collection of these secretions. The sponge absorbs a relatively large volume of material, therefore allowing for quantitation of multiple immune components. Additionally, it provides a method in which the same device may be used to collect specimens from different mucosal sites, such as the genital tract and oral cavity. This sampling technique has successfully been applied for collection and measurement of antibody in oral and genital tract secretions. The purpose of this work was to optimize the extraction of protein from the sponge matrix. Of particular interest was the recovery of cytokines from the sponge. Satisfactory recovery of the cytokines interleukin 1beta (IL-1beta), IL-2, IL-5, IL-12, IL-6, IL-8, IL-10, and granulocyte-macrophage colony-stimulating factor was obtained. However, IL-4 and gamma interferon recovery rates remained low. Using an alteration of the published extraction method, cytokine concentrations were measured in cervical secretions from women using oral contraceptives. The data revealed detectable concentrations of IL-6, IL-10, IL-8, and IL-12 on cycle days 9 and 20. The proposed technique provides an easy, practical, and consistent method for collection of nonconventional body fluids, such as cervicovaginal fluids and saliva, for the assay of immunoglobulins and several cytokines.

Adult↗
PubMed2000

Drug resistance and drug combination features of the human immunodeficiency virus inhibitor, BCH-10652 [(+/-)-2'-deoxy-3'-oxa-4'-thiocytidine, dOTC].

The heterosubstituted nucleoside analogue dOTC [( )-2'-deoxy-3'-oxa-4'-thiocytidine, BCH-10652] is a racemic compound structurally related to 3TC (lamivudine), but has the oxygen and sulphur in the furanosyl ring transposed. Both the enantiomers (-)dOTC (BCH-10618) and (+)dOTC (BCH-10619) had equivalent activity against wild-type strains of HIV-1 in C8166 T-cells (EC50 1.0-10.0 microM) and in PBMCs (EC50 0.1-3.0 microM). Investigation of the activity of dOTC and its enantiomers against laboratory strains of HIV-1 with defined resistance to 3TC, AZT (zidovudine), ddl (didanosine), PMEA (adefovir), nevirapine and saquinavir indicated that sensitivity was maintained (<3-fold change in EC50) in all cases, with the exception of HIV-1RF 3TC-resistant viruses. The degree of resistance recorded for dOTC (four- to sevenfold), (-)dOTC (five- to eightfold) and (+)dOTC (five- to >18-fold) against these M1841 or M184V mutants, was significantly less than that recorded for 3TC (>100-fold). In addition, the inhibitory effect of the compounds against clinical isolates of HIV-1 recovered from patients with suspected resistance to 3TC and AZT was investigated. Clinical isolates were genotyped using the Murex Line Probe Assay (LiPA) and subgrouped into wild-type, 3TC-resistant and dual 3TC/AZT-resistant, as well as undefined or mixed genotype populations. Compared with the mean EC50 values obtained with genotypically and phenotypically wild-type clinical isolates, the mean EC50 values calculated for isolates phenotypically resistant to 3TC or 3TC and AZT were only 2.6-, 1.6- and 8.2-fold higher for dOTC, (-)dOTC and (+)dOTC, respectively. When the rate of emergence of virus resistant to dOTC and its enantiomers in vitro was investigated, virus resistant to (+)dOTC was readily selected for (<10 passages), and a methionine (ATG) to isoleucine (ATA) amino acid change at codon 184 was identified. In contrast, virus resistant to dOTC and (-)dOTC took longer to appear (15-20 passages), with a methionine (ATG) to valine (GTG) amino acid change at position 184 identified in both cases. In addition, virus passaged 20 times in the presence of dOTC also had a partial lysine (AAA) to arginine (AGA) exchange at position 65. These viruses showed only low-level resistance to dOTC and its enantiomers, but were highly resistant to 3TC. The antiviral effects of dOTC in combination with the nucleoside RT inhibitors AZT, 3TC, d4T (stavudine) and ddl, the non-nucleoside RT inhibitor nevirapine and the protease inhibitors saquinavir, ritonavir and indinavir was investigated. Two-way drug combination assays were carried out in peripheral blood mononuclear cell (PBMC) cultures by measuring the reduction in p24 viral antigen levels, and data was analysed using the MacSynergy II program. dOTC in combination with 3TC or d4T showed a moderate synergistic effect while all other combinations had an additive interaction.

Anti-HIV Agents↗
PubMed1999

The use of dummy data points when fitting bacterial growth curves.

We consider the problem of fitting mathematical models for bacterial growth and decline to experimental data. Using models which represent the phases of the growth and decline cycle in a piecewise manner, we describe how least-squares fitting can lead to potentially misleading parameter estimates. We show how these difficulties can be overcome by extending a data set to include hypothetical observations (dummy data points) which reflect biological beliefs, and the resulting stabilization of parameter estimates is analysed mathematically. The techniques are illustrated using real and simulated data sets.

Anaerobiosis↗
PubMed1998

all-Trans-retinoic acid reduces neointimal formation and promotes favorable geometric remodeling of the rat carotid artery after balloon withdrawal injury.

BACKGROUND: The multifactorial and unpredictable nature of human restenosis will probably necessitate interventional strategies that target multiple processes involved in acute vascular narrowing. Retinoids (eg, all-trans-retinoic acid, atRA) represent a growing class of pleiotropic biological response modifiers with demonstrable efficacy in managing several pathological conditions. In this report, we have initiated studies to examine the hypothesis that atRA limits neointimal formation after experimental vascular injury. METHODS AND RESULTS: Rats were predosed with atRA (30 mg . kg-1 . d-1 PO) or corn oil 4 days before balloon withdrawal injury (BWI) of the left common carotid artery and continued on this drug regimen for an additional 14 days. High-performance liquid chromatographic analysis documented therapeutic levels of atRA in serum and vascular tissue. atRA depressed peak DNA synthesis in the tunica media of BWI vessels (P<0.05). Histomorphometry revealed atRA-mediated reductions in neointimal area, neointimal cell number, and intimal/medial area ratio as well as significant increases in vessel wall perimeter (P<0. 05). Such changes in vascular architecture contributed to a 35% to 37% increase in the luminal area of BWI vessels exposed to atRA (P<0. 005 compared with controls). CONCLUSIONS: atRA reduces neointimal mass and elicits favorable geometric remodeling of the injured rat carotid artery.

Actins↗
PubMed1998

Preferential fat intake increases adiposity but not body weight in Sprague-Dawley rats.

It is not known whether an inherent preference for dietary fat promotes obesity in animals allowed to self-select the proportions of fat and carbohydrate consumed. To address this question, Sprague-Dawley rats were given a choice between two diets containing either 78% fat (by energy) or 78% carbohydrate; both diets were equicaloric for protein (22%). The entire study lasted 12 weeks. After an adaptation period, macronutrient preferences were determined by measuring 24 h intake of the two diets for 5 days; fat-preferring animals were classified as those that consumed greater than 60% of total energy from the fat/protein source, and carbohydrate-preferring rats as those that consumed less than 40%. Rats with intermediate macronutrient intakes were excluded. Initial body weight was not different between preference groups. Caloric intakes and body weights were then recorded at approximate weekly intervals, and fat depots were weighed at the time of sacrifice. Measures of energy intake and body weight did not differ between the two preference groups over time. In addition, baseline macronutrient preferences remained stable across the study period. Despite similar body weights, mean epididymal fat depot weight was significantly higher in fat-preferring rats than in carbohydrate-preferring rats (12.6 vs. 10.0 g); also, mean inguinal fat depot weight in fat-preferrers was greater although not reliably different compared to carbohydrate-preferring rats (12.9 vs. 10.9 g). Thus, the preferential intake of fat led to a greater deposition of both subcutaneous and visceral fat without an increase in body weight. These data lead us to conclude that the increased fat deposition was due primarily to the ingestion of fat rather than to excess caloric intake.

Adipose Tissue↗
PubMed1983

Hypolipidemic activity and toxicity studies of a styrl-hexahydroindolinol, 34-250.

34-250 evoked hypocholesterolemic activity in the rat (14, 25, 31, 52, 112 mg/kg, po), dog (10, 20, 40 mg/kg, po), and monkey (30 mg/kg, po). Serum triglycerides were lowered in the rat and dog but not in the monkey. 34-250 increased [14C]acetate incorporation into liver cholesterol, but incorporation of 14C-labeled acetate into serum cholesterol was decreased. Desmosterol or 7-dehydro-cholesterol did not accumulate in serum of the three species, suggesting that inhibition of cholesterol biosynthesis by 34-250 possibly does not occur at a late stage. Normal fecal bile acid excretion was observed in rats, suggesting that cholesterol catabolism probably was not enhanced by 34-250. Compound 34-250-induced hypocholesterolemia may result from inhibition of hepatic release of this sterol into blood. The reversible hepatic lipidosis observed in rats is also possibly related to decreased hepatic transport and/or secretion of triglycerides. 34-250 did not cause a proliferation of hepatic microbodies; the lack of an increase in this fatty acid oxidizing organelle suggests that it may also have had a role in increased hepatic lipidosis. In dogs, a high incidence of severe cataracts with an early onset was induced by 20 and 40 mg/kg, po of 34-250 despite the lack of desmosterol or 7-dehydro-cholesterol in serum. The absence of these late stage intermediates of cholesterol biosynthesis in the serum of a test species does not preclude the occurrence of ocular toxicity.

Animals↗