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Biomedical subjects

P Webb

Publications and source records attributed to P Webb.

At least 55 records · Page 3Linked to original sources
PubMed1997

Transcriptional activities of estrogen and glucocorticoid receptors are functionally integrated at the AP-1 response element.

Estrogens and glucocorticoids often act in opposition to regulate physiological responses. We investigated whether this might reflect the opposing actions of hormone-bound receptors on target genes regulated by the AP-1 response element. We performed a series of transfection experiments in which transcriptional activation, mediated by the AP-1 response element, was reflected in reporter gene activity. As previously described, we found that estrogens stimulate, whereas the glucocorticoid dexamethasone (Dex) inhibits, transcription through a model promoter from the collagenase gene (-73 to +63). This promoter bears a consensus AP-1 response element. When HeLa cells were treated with both estradiol and Dex, the steroids counteracted each other's transcriptional effects. The amount of transfected estrogen and glucocorticoid receptors (ER and GR) determined the extent to which Dex blunted estrogen stimulation or estrogen prevented Dex inhibition. The ER/GR interaction was observed both in the presence of estradiol and tamoxifen, which has previously been shown to have estrogen-like action at an AP-1 response element. The AP-1 family member c-Jun enhanced Dex inhibition and estradiol stimulation of transcriptional activation. c-Fos potentiated the effect of cotransfected c-Jun on estradiol stimulation but not Dex inhibition. The pattern of steroid responses was retained in the presence of the c-Jun activator phorbol 12-myristate 13-acetate. However, estradiol stimulation was lost in the presence of the c-Jun activator tumor necrosis factor-alpha. The ER/GR/AP-1 response element interaction was present, not only in a cell line originally derived from a uterine cervical adenocarcinoma (HeLa), but also in a cell line derived from the hypothalamus (GT1-1). Lastly, both progesterone receptor types A and B also interacted with the ER at the AP-1 site. These data indicate that opposing steroid influences can be mediated at the level of transcription through the AP-1 site and suggest that the integration of hormone action at this response element may underlie some of the opposing actions of estrogens and glucocorticoids or progestins on physiological responses.

Dexamethasone↗
PubMed1996

Helicobacter pylori gastritis and serum pepsinogen levels in a healthy population: development of a biomarker strategy for gastric atrophy in high risk groups.

This study aimed to estimate the prevalence and type of chronic gastritis in an asymptomatic working population and to determine whether a combination of serum pepsinogen levels and Helicobacter pylori serology could be used to identify a subgroup with atrophic gastritis at elevated risk of gastric carcinoma. A 10% subsample of 544 male volunteer factory workers aged 18-63 years and participating in a larger study underwent endoscopy and biopsy. Of these men, 29 were seropositive for Helicobacter pylori; all but three (89.7%) had chronic gastritis. Serum pepsinogen A levels increased with progression from a corpus predominant pattern of gastritis through pangastritis to an antral predominant pattern. Nine subjects had corpus atrophy, which was in most cases accompanied by fasting hypochlorhydria and hypergastrinaemia. A combination of pepsinogen A below 80 ng ml-1 and Helicobaceter pylori seropositivity detected corpus atrophy with sensitivity 88.9% and specificity 92.3%. A second screening stage, using a pepsinogen A/C ratio of below 2.5 as a cut-off, resulted in a reduction in numbers requiring further investigation but with some loss of sensitivity (77.8%). Application of this two-stage screening programme to the original sample of 544 workers would have resulted in 11 (2.2%) men being selected for follow-up, excluding 25 (5.1%) false negatives. Our results suggest that a combination of serum pepsinogen levels and Helicobacter pylori serology could be useful as a biomarker strategy for detection of individuals at increased risk of gastric carcinoma and for non-invasive investigation of the natural history of Helicobacter pylori gastritis.

Adolescent↗
PubMed1996

Mild overcooling increases energy expenditure during endurance exercise.

Intensive cooling has been shown to increase energy expenditure (EE) during work as well as to decrease physical performance. Two different levels of moderate cooling (10 degrees C vs 15 degrees C) were studied during light endurance exercise in order to examine the effect of the increased heat loss on EE. Twelve subjects performed a 90-min low intensity exercise (100 W) on a cycle ergometer, wearing a water-cooled calorimeter suit for controlled cooling. The lower temperature resulted in a 4.3 +/- 3.8% (mean +/- SD) higher EE, increased total heat loss and lowered skin temperatures. No differences in central core body temperature, heart rate or respiratory quotient (RQ) were recorded. There was a relation between differences in the rate of heat loss and the corresponding increase in EE. Even a small increase in cooling during endurance exercise increased EE which may be a relevant problem in winter sports.

Adult↗
PubMed1995

Transcriptional activators differ in their responses to overexpression of TATA-box-binding protein.

We investigated how overexpression of human TATA-box-binding protein (TBP) affects the action of estrogen receptor (ER) and compared the response with that of other activators. When ER activates a simple promoter, consisting of a response element and either the collagenase or tk TATA box, TBP overexpression potentiates transcription. TBP potentiates only estrogen-induced and not basal transcription and does so independent of spacing between response element and TATA box. TBP overexpression also reduces autoinhibition by overexpressed ER, suggesting that one target of the autoinhibition may be TBP itself. Both AF-1 and AF-2 domains of ER are potentiated by TBP, and each domain binds TBP in vitro. Like ER, chimeric GAL4/VP16 and GAL4/Tat activators are also potentiated by TBP, as is the synergistic activation by ER and GAL4/VP16 on a complex promoter. Unlike ER, GAL4/Sp1 and GAL4/NF-I become less potent when TBP is overexpressed. Furthermore, synergy between ER and Sp1 or between ER and NF-I, whether these are supplied by transfected GAL4 fusions or by the endogenous genes, is inhibited by TBP overexpression. Thus, ER resembles VP16 in response to TBP overexpression and is different from Sp1 and NF-I, which predominate over ER in setting the response on complex promoters.

Animals↗
PubMed1995

The physiology of heat regulation.

Heat regulation is presented as the physiological method of handling metabolic heat, instead of temperature regulation. Experimental evidence of heat regulation from the literature is reviewed, including more than 20 years of calorimetric studies by the author. Changes in heat production are followed by slow exponential changes in heat loss, which produce changes in body heat storage. Heat balance occurs at many levels of heat production throughout the day and night, and at each level there is a related level of rectal temperature. Heat flow can be sensed by the transcutaneous temperature gradient. The controller for heat loss appears to operate like a servomechanism, with feedback from heat loss and possibly feedforward from heat production. Physiological responses defend the body heat content, but heat content varies over a range that is related to heat load. Changes in body heat content drive deep body temperatures.

Body Temperature↗
PubMed1995

Tamoxifen activation of the estrogen receptor/AP-1 pathway: potential origin for the cell-specific estrogen-like effects of antiestrogens.

We find that tamoxifen is a potent activator of estrogen receptor (ER)- mediated induction of promoters regulated by AP-1 sites including the human collagenase gene promoter and constructs in which an AP-1 site is fused to the herpes thymidine kinase promoter. This contrasts with the inability of tamoxifen to activate otherwise identical promoters bearing classical estrogen response elements. Tamoxifen agonism at AP-1 sites is cell type specific, occurring in cell lines of uterine, but not of breast, origin. It thus parallels tamoxifen agonism in vivo. AP-1 proteins such as Jun or Jun/Fos are needed for tamoxifen stimulation, and tamoxifen increases the transcriptional efficiency of these proteins even when they are provided at optimal amounts. The DNA binding domain (DBD) of ER is required for tamoxifen activation at AP-1 sites. In contrast, estrogen activation is partially independent of this domain. This suggests the existence of two pathways of ER action at AP-1: an alpha (DBD-dependent) pathway activated by tamoxifen, and a beta (DBD-independent) pathway activated by estrogen. Fusing VP16 transcriptional activation functions to ER potentiates the beta, but not the alpha, pathway. We discuss models for the two pathways and the possibility that the AP-1 pathway is a major route by which ER affects target tissue growth and differentiation in vivo.

3T3 Cells↗
PubMed1995

Variability in serum pepsinogen levels in an asymptomatic population.

OBJECTIVE: To investigate the variability in serum pepsinogen levels in an asymptomatic population. DESIGN: Cross-sectional survey of 420 men aged 18-63 years, without symptoms or a history of gastric disease, recruited from four factories in Stoke-on-Trent. METHODS: During an interview, data on history of gastric health, 'lifestyle' and occupation were collected, blood samples were taken for measurement of serum pepsinogen and anti-Helicobacter pylori antibody levels and height and weight were measured. RESULTS: Extreme (low/high) levels of pepsinogens A and C, indicative of chronic gastritis, were found in 24 (5.7%) and 61 (14.5%) of the participants, respectively. Low A-C ratios, indicative of moderate or severe gastric atrophy, were found in 13 (3.1%) participants. Of the variables examined, Helicobacter pylori serology had the strongest influence on serum pepsinogen levels. Serum pepsinogen A and C levels were significantly higher in the 33.6% of participants who were seropositive. The effect was more marked for pepsinogen C; thus, A-C ratios were lower in seropositive individuals. In seronegative participants, both pepsinogen A and pepsinogen C levels increased with increasing age; pepsinogen A levels increased with increasing height and were higher in smokers, but decreased with increasing weight. The effect of smoking on pepsinogen A levels was also detectable in seropositive individuals, but was considerably less marked. Among seronegative participants, those employed on the 'shop-floor' in manual jobs had higher serum pepsinogen C levels and lower A-C ratios than office-based workers. CONCLUSION: H. pylori serology was a major source of variation in serum pepsinogen levels, but causes of gastritis other than H. pylori were indicated. Independent of these effects, serum pepsinogen levels may also vary with age, height and weight. Screening of serum pepsinogen levels in the general population may identify 5-15% who require further investigation. Other 'filters' may be required in conjunction with serum pepsinogen levels to identify those needing investigation for significant gastric pathology.

Adult↗
PubMed1994

Short TE phosphorus spectroscopy using a spin-echo pulse.

In vivo phosphorus spectroscopy requires very short acquisition delays in order to capture the signal from components with short transverse relaxation times (T2). The echo time typical of standard slice selective spin-echo pulses are too long for this application, so hard pulse, free induction decay (FID) acquisitions have frequently been used instead. With FID, however, there is an interval between the time of coherence and data acquisition (acquisition delay), with resulting baseline distortions. In this paper we describe the design of a new short TE, slice-selective, composite spin-echo pulse with echo times as short as 2.5 ms. With a long TR, fully relaxed, multislice spectra can be collected. This technique will be useful for assessing in vivo, changes in brain phospholipid activity associated with psychiatric and neurological diseases.

Brain↗
PubMed1994

A suit calorimeter for energy balance studies on humans during heavy exercise.

A modification of the suit calorimeter originally developed in 1972 was used in combination with indirect respiratory calorimetry. The modification included increased cooling capacity of the suit by means of an increased density of cooling tubes and a variable water flow pump which permitted higher flow rates. This has made the suit calorimeter a very effective heat exchanger that could be used for studies on high energy turnover during heavy exercise. Furthermore, specially designed absorption clothing made it possible to collect any sweat produced before it evaporated, thus minimizing potential error in measuring evaporative heat loss. The suit calorimeter would seem to offer a valuable tool in the analysis of the specific thermogenic responses to dietary changes and physical activity in studies on energy and protein metabolism and their interaction in humans. It also makes it possible to perform direct calorimetric measurements in metabolic balance studies using continuous parenteral infusion since the subjects do not need to be sealed in a calorimeter chamber.

Adolescent↗
PubMed1994

The genomic organisation, sequence and functional analysis of the 5' flanking region of the chicken estrogen receptor gene.

The cDNA of many members of the nuclear receptor superfamily has been cloned. Recently more effort has been expended on the analysis of these genes at the genomic level and on the factors controlling their expression. The genomic organization of the chicken estrogen receptor gene is presented and compared to the other members of the superfamily of hormone receptor genes with emphasis on the relationship to the functional domains. The results show that the gene is divided into eight exons and that the position of the intron/exon boundaries are as in the human gene but different to the trout estrogen receptor gene. Primer extension and cDNA clone isolation was used to determine the transcription start site and 3.0 kb of 5' flanking sequence was generated. There is striking sequence homology to the human estrogen receptor promoter and there is a well positioned "typical" TATA sequence, with potential candidate CAAT box sequences close to the start site of transcription. In transient transfection assays, subfragments of this region drove CAT expression in chicken embryo fibroblasts, and the level was increased further with the addition of forskolin, but not phorbol myristate acetate. Including sequences more distal to the cap site in promoter constructs, completely abolished the promoter activity and forskolin inducibility, indicating the presence of strong silencing activity.

Animals↗
PubMed1994

Evaluation of the clinical performance of automated proton magnetic resonance spectroscopy in children.

RATIONALE AND OBJECTIVES: Because expeditious neuroimaging is imperative in pediatric patients, we evaluated automated procedures for proton magnetic resonance spectroscopy (1H MRS) of the brain of children. METHODS: 1H MRS was performed on a 1.5-T GE Signa. The protocol included stimulated echo-acquisition mode and spin-echo point resolved spectroscopy. The automated routine included adjustment of first-order gradient shims (x, y, z1) to optimize magnetic field homogeneity, transmit power, center frequency, receiver gain, and water suppression. All spectra were processed with the use of spectroscopy analysis software from General Electric on a Sun workstation. RESULTS: The use of the automated procedures reduced the length of our 1H MRS protocol by 50%. Magnetic field homogeneity was within our accepted standards (7 +/- 2 Hz). Water suppression was within range of our accepted factors (1000-10,000). However, on certain occasions, baseline distortions affected resonances in the 3.22-4.04 ppm range. CONCLUSIONS: Shortening of the time required for clinical 1H MRS will increase its application in evaluating children.

Brain↗