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Biomedical subjects

J Walker

Publications and source records attributed to J Walker.

At least 109 records · Page 6Linked to original sources

Il-1-related cytokine responses of nonimmune skin cells subjected to CEES exposure with and without potential vesicant antagonists.

Sulfur mustard provokes an acute inflammatory response in skin. To determine if keratinocytes regulate this response and whether three potential vesicant antagonists can counteract adverse changes, specimens of EpiDerm (MatTek Corp., Ashland, MA), a human skin model of differentiating keratinocytes, were exposed 2 h to humidified air with or without 2-chloroethyl ethyl sulfide (CEES, 1.72-1.73 mg/L/min) with or without 10 mM niacinamide, a poly (ADP-ribose) polymerase (PARP) inhibitor, 25 microM CGS9343B (calmodulin antagonist), or 8.4 mM leupeptin (cysteine protease inhibitor). After a 22-h incubation, levels of interleukin-1 alpha (IL-1alpha), its receptor antagonist (IL-1Ra), soluble type II receptor (sIL-1RII) and prostaglandin-E(2) (PGE(2)) were determined. Methylthiazole tetrazolium (MTT) viability tests and histological observations were also conducted. PGE(2) levels were abundant but unaffected by CEES regardless of antagonist presence. Total amounts (media plus lysate) of IL-1alpha, IL-1Ra, and sIL-1RII were reduced with CEES irrespective of antagonist. CEES promoted the release of IL-1Ra. Exposure of EpiDerm to CEES in the presence of the vesicant antagonists did not improve viability or counteract histological damage. We conclude CEES depresses total IL-1alpha and related cytokines, does not affect PGE(2) release, and adverse changes associated with CEES-exposed EpiDerm are not ameliorated by these particular antagonists. Dramatically increased (5- to 10-fold) release of IL-1Ra may provide a useful marker for cytotoxicity. The high level of IL-1Ra and increased release with injury suggest a primary function in down-regulating IL-1 inflammatory responses in skin.

Benzimidazoles↗

Rapid discrimination between methicillin-sensitive and methicillin-resistant Staphylococcus aureus by intact cell mass spectrometry.

Rapid, accurate discrimination between methicillin-sensitive Staphylococcus aureus (MSSA) and methicillin-resistant S. aureus (MRSA) strains is essential for appropriate therapeutic management and timely intervention for infection control. A rapid method involving intact cell mass spectrometry (ICMS) is presented that shows promise for identification, discrimination of MSSA from MRSA and typing. In ICMS, cells from a bacterial colony are emulsified in a chemical matrix, added to a sample slide, dried and analysed by matrix-assisted laser desorption ionisation time-of-flight mass spectrometry (MALDI-TOF-MS). This technique examines the chemistry of the intact bacterial cell surface, yielding spectra consisting of a series of peaks from 500 to 10000, which represent the mass:charge (m:z) ratios. Each peak corresponds to a molecular fragment released from the cell surface during laser desorption. Specimens can be prepared in a few seconds from plate cultures and a spectrum can be obtained within 2 min. ICMS spectra for 20 staphylococcal isolates showed characteristic peaks, some of which were conserved at species level, some at strain level and some were characteristic of the methicillin susceptibility status of the strain. ICMS may have potential for MRSA identification and typing, and may improve infection control measures.

Cluster Analysis↗

Growth of primary school children: a validation of the 1990 references and their use in growth monitoring.

AIMS: To determine whether the British 1990 growth charts are valid for cross sectional and longitudinal use in primary school children. METHODS: A total of 694 children aged 7-10 years from 10 Leeds primary schools were weighed and measured annually over three years by an expert auxologist. SD scores were calculated using both the Tanner-Whitehouse (TW) and the revised British 1990 growth references. RESULTS: The growth of this sample of children approximated the 1990 growth reference, with mean (SD) scores for height 0.12 (1.01), weight 0.20 (1.07), and body mass index (BMI) 0. 19 (1.12). By comparison, the TW standards exaggerated the height and weight centiles. There was minimal channel crossing for height in either direction with 1.0% crossing up at least one channel width (0.67 SD scores), and 0.2% down for height. However, there was clear evidence of weight and particularly BMI increasing with age between and within subjects, at rates of up to 0.1 SD scores per year. CONCLUSIONS: This study supports the adoption of the new growth references, and their use longitudinally for height monitoring. It also highlights the increasing weight of the school age population as a public health issue.

Aging↗

Human granulosa cells are a site of sulphatase activity and are able to utilize dehydroepiandrosterone sulphate as a precursor for oestradiol production.

Dehydroepiandrosterone sulphate (DHEAS) is the most abundant androgen in the circulation and in ovarian follicular fluid. A steroid sulphatase accepting DHEAS as a substrate has been identified in the follicle, but the cellular location has not been determined. As DHEAS is also a potential source of oestrogen for endocrine-dependent tumours, a potent steroid sulphatase inhibitor oestrone-3-O-sulphamate (EMATE) has been developed which inhibits this activity in rat liver and mammary tumour. The aim of this study was to investigate human granulosa cells as a site of steroid sulphatase activity, to determine whether DHEAS can be utilized as a precursor for oestrogen synthesis and to investigate the inhibitory capacity of EMATE in these cells. Conversion of DHEAS to DHEA was assessed in luteinized granulosa cells by tritiated steroid assay following incubation with or without LH or insulin and steroid accumulation in the medium measured by RIA. The effects of EMATE were assessed by addition of a range of doses during the measurement of conversion of DHEAS to DHEA. Cells from three sizes of small follicles from an unstimulated ovary were also assessed for their ability to produce oestradiol from DHEAS. Sulphatase enzyme activity was present in all cells; the mean conversion of tritiated DHEAS to DHEA was 50% (range 4-65%). LH and EMATE inhibited and insulin stimulated this activity. Addition of DHEAS to granulosa cells caused a dose-dependent increase in oestradiol and androstenedione production with no change in progesterone concentration. LH increased the accumulation of oestradiol in the medium. DHEAS also stimulated oestradiol production by granulosa cells from small follicles. This is the first demonstration that granulosa cells are a site of sulphatase activity and that DHEAS can be utilized as a substrate for androstenedione and oestrogen production. This may be of physiological importance for both normal folliculogenesis and oestrogen-dependent tumour growth.

Androstenedione↗

Effect of gender on anti-inflammatory and analgesic actions of two kappa-opioids.

The higher incidence of inflammatory and painful disorders in women and recent reports that have emphasized the importance of gender in nociceptive sensitivity and responsiveness to analgesics prompted us to investigate gender as a factor in the variability in response to opioids. We studied the anti-inflammatory and antinociceptive effects of two kappa-opioid agonists in adjuvant-induced arthritis, one that acts both peripherally and centrally (PNU50488H; 20 mg/kg/day), the other which is peripherally selective (asimadoline; 5 mg/kg/day). Both drugs had equally powerful anti-inflammatory effects in both male and female rats (reducing measures by 60-80%). In contrast, there were gender-based heterogeneities in their analgesic actions, contingent on the method of stimulation (mechanical or thermal); males were insensitive to the analgesic effects of asimadoline with thermal but not mechanical nociceptive stimuli. We also sought evidence for gender influences on the joint content of Substance P (SP), a peptide suggested to have a role in producing inflammation and found that levels were higher in the untreated arthritic females, although there were no gender differences in disease sensitivity or nociception in arthritic animals receiving no drugs. Paradoxically, both drugs elevated SP concentrations in the joints, perhaps as a consequence of an action of kappa-opioids to suppress SP release from peripheral nerves, but the gender differences remained. Further experiments are required to determine exact mechanisms responsible for the gender distinction in analgesic response to kappa-opioids that may involve differential activation of primary afferents.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

K-ras point mutation detection in lung cancer: comparison of two approaches to somatic mutation detection using ARMS allele-specific amplification.

BACKGROUND: The use of sensitive molecular techniques to detect rare cells in a population is of increasing interest to the molecular pathologist, but detection limits often are poorly defined in any given molecular assay. We combined the approaches of real-time quantitative PCR with ARMS(TM) allele-specific amplification in a novel assay for detecting mutant K-ras sequences in clinical samples. METHODS: ARMS reactions were used to detect seven commonly occurring mutations in the K-ras oncogene. These mutations produce amino acid changes in codon 12 (Gly to Ala, Arg, Asp, Cys, Ser, or Val) and codon 13 (Gly to Asp). A control reaction was used to measure the total amount of amplifiable K-ras sequence in a sample so that the ratio of mutant to wild-type sequence could be measured. Quantitative data were confirmed for a selection of samples by an independent cloning and sequencing method. The assay was used to analyze 82 lung tumor DNA samples. RESULTS: The assay detected K-ras mutations in 44% of adenocarcinomas, which is equivalent to frequencies reported in the literature using ultrasensitive techniques. Forty-six percent of squamous carcinomas were also positive. The ratio of mutant sequence in the tumor DNA samples was 0.04-100%. CONCLUSIONS: The assay is homogeneous, with addition of tumor DNA sample being the only step before results are generated. The quantitative nature of the assay can potentially be used to define the analytical sensitivity necessary for any specified diagnostic application of K-ras (or other) point mutation detection.

Alleles↗

Identifying local patterns of cross boundary flow and developing socio-economic profiles for general dental practitioners.

OBJECTIVES: The objective of this study was to assess cross-boundary flow in general dental practices in Dudley. DESIGN: Data were collected on NHS patients attending 57 general dental practitioners in Dudley Health District. Socio-economic data were attached to recognised postcodes in order to establish district of residence of patients and the socio-economic (ACORN) status of the neighbourhood in which they lived. SETTING: General dental practices in Dudley. SUBJECTS: General Dental Service patients. RESULTS: Using this methodology a profile of the patient population attending the participating practitioners was drawn up, giving an insight into patterns of dental attendance. CONCLUSION: These profiles will act as indicators of practices in which there are high levels of cross boundary flow and inform discussions on local commissioning.

Adolescent↗

Effect of the worldwide epidemic on HIV prevalence in the United Kingdom: record linkage in anonymous neonatal seroprevalence surveys.

OBJECTIVE: To assess the impact of the worldwide HIV/AIDS epidemic on the prevalence of HIV in women in the United Kingdom (UK), particularly in the large immigrant and ethnic minority communities. METHOD: Unlinked anonymous neonatal seroprevalence survey with electronic record linkage of data from child health computers (maternal age and ethnic status) and birth registration (parent's country of birth). RESULTS: Of a total 137456 samples collected in 1997-1998, 188 (0.14%) were anti-HIV-1 seropositive. Seroprevalence was highest in women born in East Africa (2.3%) and Central Africa (1.9%). 76.4% of seropositive newborns were delivered to mothers born in sub-Saharan Africa; a further 6.0% had fathers from sub-Saharan Africa. However, there was little evidence of HIV in women born in Southern Asia [prevalence 0.0081%; 95% confidence interval (CI) 0-0.04], and none within UK-born Asian communities. Prevalence among the UK-born Black African community was low (0.14%; 95% CI 0-0.6). Among infants with both parents known to be born in the UK, seroprevalence was 0.023% (95% CI 0.01-0.04) in London, and zero (95% CI 0-0.007) in non-Metropolitan areas. Irrespective of mother's region of birth, seroprevalence was 4.2 times higher (95% CI 3.0-5.8) in newborns whose father's details were not recorded at birth registration, a marker for single unsupported mothers. CONCLUSION: The risk of HIV among pregnant women from sub-Saharan Africa has been recognized. However, in southern England, HIV is very rare in women from Southern Asia and in UK-born women in ethnic minority communities, in spite of cultural and travel ties to high-prevalence countries. Data linkage in anonymous surveys assists in monitoring the impact of the worldwide epidemic on prevalence and incidence locally.

Adult↗

Human health implications of environmental contaminants in Arctic Canada: a review.

This paper assesses the impact on human health of exposure to current levels of environmental contaminants in the Canadian Arctic, and identifies the data gaps that need to be filled by future human health research and monitoring. The concept of health in indigenous groups of the Arctic includes social, cultural, and spiritual dimensions. The harvesting, sharing and consumption of traditional foods are an integral component to good health among Aboriginal people influencing both physical health and social well-being. Traditional foods are also an economic necessity in many communities. Consequently, the contamination of country food raises problems which go far beyond the usual confines of public health and cannot be resolved by health advisories or food substitutions alone. The primary exposure pathway for the contaminants considered in this paper is through the traditional northern diet. For the Inuit, the OCs of primary concern at this time from the point of view of exposure are chlordane, toxaphene, and PCBs. Exposures are higher in the eastern than in the western region of the North. For Dene/Metis, exposure to OCs is in general below a level of concern. However, estimated intake of chlordane and toxaphene has been found to be elevated for certain groups and is a cause for concern if exposures are elevated on a regular basis. The developing foetus and breast-fed infant are likely to be more sensitive to the effects of OCs and metals than individual adults and are the age groups at greatest risk in the Arctic. Extensive sampling of human tissues in the Canadian north indicate that a significant proportion of Dene, Cree and Inuit had mean maternal hair mercury levels within the 5% risk-range proposed by the WHO for neonatal neurological damage. Based on current levels, lead does not appear to pose a health threat while cadmium is likely only a major risk factor for heavy smokers or consumers of large amounts of organ meats. Consumers of traditional foods are exposed to an approximately seven-fold higher radiation dose than non-consumers of traditional foods due predominantly to the bioaccumulation of natural radionuclides in the food chain. Risk determination for contaminants in country food involves a consideration of the type and amounts of food consumed and the sociocultural, nutritional, economic, and spiritual benefits associated with country foods. Risk management options that minimize the extent to which nutritional and sociocultural aspects of Aboriginal societies are compromised must always be considered.

Adult↗

Structural requirements for CD43 function.

The regulation of T cell activation and adhesion by CD43 (leukosialin, sialophorin) has been thought to be mainly a function of the large size and negative charge of the extracellular domain of the protein. In this work, we demonstrate that the cytoplasmic tail is both necessary and sufficient for the negative regulatory effect of CD43 on cell-cell adhesion. Expression of mutant CD43 proteins in primary T cells from CD43-deficient mice demonstrated that the antiproliferative effect of CD43 is also dependent upon the cytoplasmic tail. In contrast, Ab-mediated costimulation through CD43 does not require the intracellular domain of CD43. These data demonstrate that CD43 primarily serves as a negative regulator of T cell activation and adhesion, and that this is mediated not exclusively by passive effects of the extracellular domain, but requires participation of the cytoplasmic tail, perhaps through interactions with the cytoskeleton, or alternatively, active regulation of intracellular signaling pathways.

Animals↗

Electromagnetic fields influence NGF activity and levels following sciatic nerve transection.

Pulsed electromagnetic fields (PEMF) have been shown to increase the rate of nerve regeneration. Transient post-transection loss of target-derived nerve growth factor (NGF) is one mechanism proposed to signal induction of early nerve regenerative events. We tested the hypothesis that PEMF alter levels of NGF activity and protein in injured nerve and/or dorsal root ganglia (DRG) during the first stages of regeneration (6-72 hr). Rats with a transection injury to the midthigh portion of the sciatic nerve on one side were exposed to PEMF or sham control PEMF for 4 hr/day for different time periods. NGF-like activity was determined in DRG, in 5-mm nerve segments proximal and distal to the transection site and in a corresponding 5-mm segment of the contralateral nonoperated nerve. NGF-like activity of coded tissue samples was measured in a blinded fashion using the chick DRG sensory neuron bioassay. Overall, PEMF caused a significant decrease in NGF-like activity in nerve tissue (P < 0.02, repeated measures analysis of variance, ANOVA) with decreases evident in proximal, distal, and contralateral nonoperated nerve. Unexpectedly, transection was also found to cause a significant (P=0.001) 2-fold increase in DRG NGF-like activity between 6 and 24 hr postinjury in contralateral but not ipsilateral DRG. PEMF also reduced NGF-like activity in DRG, although this decrease did not reach statistical significance. Assessment of the same nerve and DRG samples using ELISA and NGF-specific antibodies confirmed an overall significant (P < 0.001) decrease in NGF levels in PEMF-treated nerve tissue, while no decrease was detected in DRG or in nerve samples harvested from PEMF-treated uninjured rats. These findings demonstrate that PEMF can affect growth factor activity and levels, and raise the possibility that PEMF might promote nerve regeneration by amplifying the early postinjury decline in NGF activity.

Animals↗

Cancer mortality in health and science technicians.

BACKGROUND: Nearly one million U.S. women are employed as health or science technicians with various chemical and biological exposures, but few studies have looked at their health outcomes. METHODS: Using 1984-1995 mortality data with coded occupation information, we calculated race- and age-adjusted proportionate cancer mortality ratios (PCMRs) and 95% confidence intervals for two age groups for black and white women with occupations of clinical laboratory (CLT), radiologic, and science technician. RESULTS: For CLTs, the PCMRs for breast cancer were borderline significantly elevated. The PCMRs for leukemia were significantly elevated, particularly for myeloid leukemia. Radiologic technicians had no significantly elevated PCMRs. Science technicians had significantly elevated PCMRs for non-Hodgkin's lymphoma and multiple myeloma in the younger age group. DISCUSSION: The elevated risks for lymphatic and hematopoietic neoplasms in CLTs and science technicians may be associated with occupational exposures.

Adult↗