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Biomedical subjects

S J Webb

Publications and source records attributed to S J Webb.

At least 19 recordsLinked to original sources
PubMed2002

Regulation of TNF-alpha-induced IL-6 production in MG-63 human osteoblast-like cells.

Tumor necrosis factor-alpha (TNF-alpha) stimulates osteoblast production of interleukin-6 (IL-6), an inflammatory cytokine implicated in osteoclastic bone resorption. Therefore, we tested the hypothesis that TNF-alpha-induced IL-6 production in MG-63 osteosarcoma cells occurs via the p38 mitogen-activated protein kinase (MAPK) pathway. TNF-alpha activated p38 MAPK and stimulated IL-6 secretion by MG-63 cells, and pre-incubation of cells with the p38 MAPK inhibitor abrogated TNF-alpha-dependent IL-6 secretion. Transfection of IL-6 full-length and 5-deletion gene promoter reporter constructs indicated that p38 MAPK activation by TNF-alpha enhanced IL-6 gene expression, and that the p38 MAPK-responsive region resided in the proximal 260-bp segment. Transfection of NFkappaB and C/EBPbeta-sensitive reporter promoter constructs demonstrated that NFkappaB activity was enhanced and that constitutive C/EBPbeta was inhibited by TNF-alpha, with both effects being p38 MAPK-dependent. In conclusion, although p38 MAPK activation by TNF-alpha stimulates IL-6 secretion by MG-63 cells, it has opposing effects on c/EBPbeta and NFkappaB activity.

Analysis of Variance↗
PubMed2001

DNA adduct levels and absence of tumors in female rapid and slow acetylator congenic hamsters administered the rat mammary carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b] pyridine.

N-acetyltransferases (EC 2.3.1.5) catalyze O-acetylation of heterocyclic amine carcinogens to DNA-reactive electrophiles that bind and mutate DNA. An acetylation polymorphism exists in humans and Syrian hamsters regulated by N-acetyltransferase-2 (NAT2) genotype. Some human epidemiological studies suggest a role for NAT2 phenotype in predisposition to cancers related to heterocyclic amine exposures, including breast cancer. 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a heterocyclic amine carcinogen prevalent in the human environment and induces a high incidence of mammary tumors in female rats. PhIP-induced carcinogenesis was examined in female rapid and slow acetylator Syrian hamsters congenic at the NAT2 locus. In both rapid and slow acetylators, PhIP-DNA adduct levels were highest in pancreas, lower in heart, small intestine, and colon, and lowest in mammary gland and liver. Metabolic activation of N-hydroxy-PhIP by O-acetyltransferase was highest in mammary epithelial cells, lower in liver and colon, and lowest in pancreas. Metabolic activation of N-hydroxy-PhIP by O-sulfotransferase was low in liver and colon and below the limit of detection in mammary epithelial cells and pancreas. Unlike the rat, PhIP did not induce breast or any other tumors in female rapid and slow acetylator congenic hamsters administered high-dose PhIP (10 doses of 75 mg/kg) and a high-fat diet.

Acetylation↗
PubMed2001

Perceptual priming for upright and inverted faces in infants and adults.

Based on recent models of the ontogeny of memory (Nelson, 1995), we hypothesize that 6-month-old infants should show evidence of repetition priming. Event-related potentials were recorded from 11 scalp sites to novel and primed upright and inverted faces. In Experiment 1 (n = 24), 6-month-old infants viewed faces that were repeated after 6 to 12 images. Overall, repeated faces demonstrated greater negativity than novel faces and upright faces demonstrated greater negativity than inverted faces. In order to ground these results in an adult model, a group of adults (n = 30) was tested in a similar experiment. Here we observed effects of repetition at an early positive component labeled the P150 as well as at the P300, with repeated images being more positive than novel images. These data support the idea that infants at 6 months are capable of revealing electrophysiological evidence of perceptual priming.

Adolescent↗
PubMed2001

Oral administration of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) yields PhIP-DNA adducts but not tumors in male Syrian hamsters congenic at the N-acetyltransferase 2 (NAT2) locus.

2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a heterocyclic amine carcinogen present in well-done meat. PhIP must undergo host-mediated bioactivation to exert its mutagenic and carcinogenic effects. Following N-hydroxylation, N-acetyltransferases catalyze the O-acetylation (activation) of N-hydroxy-PhIP to an electrophile causing DNA damage. A well-defined genetic polymorphism in N-acetyltransferase 2 (NAT2) activity exists in humans and the Syrian hamster. Since some human epidemiological studies suggest an association between acetylator genotype and cancer susceptibility in individuals who consume well done meats, this study was designed to investigate the specific role of acetylator genotype in PhIP-induced tumors using a Syrian hamster model congenic at the NAT2 locus. Following oral administration of PhIP to male rapid and slow acetylator Syrian hamsters, DNA adducts were identified in each tissue examined with levels in the relative order: pancreas > heart and urinary bladder > prostate, small intestine and transverse colon > ascending colon, liver, cecum, descending colon, and rectum. However, no tumors were observed in male rapid and slow acetylator congenic hamsters administered 11 oral doses of PhIP (75 mg/kg) and maintained on a high fat diet for one year.

Acetylation↗
PubMed2001

Mechanisms of postnatal neurobiological development: implications for human development.

This review focuses on the postnatal neuroanatomical changes that arise during the first years of human life. Development is characterized by 2 major organizational periods. The first period begins at conception and includes the major histogenetic events such as neurulation, proliferation, migration, and differentiation. It has been proposed that these events may be controlled by genetic and epigenetic events, which give rise to neural structures that are amenable to external influence. The second period is a time of reorganization in the human cortex. These events occur during gestation and continue postnatally, possibly through the 2nd decade of life. This stage is characterized by dendritic and axonal growth, synapse production, neuronal and synaptic pruning, and changes in neurotransmitter sensitivity. Although the initiation of these events is influenced by endogenous signals, further neural maturation is primarily influenced by exogenous signals. To illustrate both the progressive and regressive events during the postnatal period, we use examples from the development of the human cortex.

Axons↗
PubMed2001

Prenatal neurobiological development: molecular mechanisms and anatomical change.

During prenatal development, the central nervous system is transformed from a thin layer of unspecified tissue into a complex system that can process information and organize actions. There are 8 general mechanisms that permit this transformation: neural induction, neurulation, proliferation, migration, axonal outgrowth, synaptogenesis, differentiation, and apoptosis. These processes as well as the anatomical changes they cause are described. Future research with humans, such as in utero MRI as well as behavioral and electrophysiological testing of infants following specific prenatal perturbations, is suggested to link the findings from molecular approaches to developmental neuropsychology.

Apoptosis↗
PubMed2000

Synthesis and recognition properties of a ruthenium(II)-bis(zinc) cyclic porphyrin trimer.

A series of cyclic metalloporphyrin trimers containing one Ru(II)-CO porphyrin center are synthesized. A stepwise convergent route is used to synthesize Ru(CO)Zn(2)2.Py3T, where tripyridyltriazine (Py3T) templates the formation of the trimer and forces the CO group to the outside of the cavity. Three mixed-metal trimers, Ru(CO)Zn(2)2, Ru(CO)Ni(2)2, and Ru(CO)Mg(2)2, are synthesized from Ru(CO)Zn(2)2.Py3T and are characterized by NMR, UV-visible, and fluorescence spectroscopy. The Ru(CO)Zn(2)2 trimer is found to bind Py3T very tightly (K approximately 10(12) M-1), the resultant complex dissociating very slowly (kdissoc approximately 3 x 10(-7) s-1) in CDCl3 at 60 degrees C. During the course of these studies, the binding selectivity of a ruthenium porphyrin monomer, Ru(CO)3, for pyridine over THF is estimated to be ca. 7 x 10(4):1.

Indicators and Reagents↗
PubMed2000

A tin(IV)-ruthenium(II)-tin(IV) cyclic porphyrin trimer with replaceable chiral linings.

A series of cyclic metalloporphyrin trimers, Ru(CO)(py)[Sn(carboxylate)2](2)2, having cavities lined with different carboxylate groups are synthesized by adding the appropriate carboxylic acids to the mixed trimer Ru(CO)(py)-[Sn(OH)2](2)2. This methodology provides ready access to a wide range of cavities lined with substituents possessing chirality or hydrogen-bonding groups. The potential of such systems is illustrated by synergistic binding of a hydroxypyridine to the Ru(II)-CO center and to the hydroxyl groups of a D-quinate-lined cavity. The effect of changing the carboxylate lining of the cavity on the course of epoxidation reactions catalyzed by these trimers is also reported.

Carboxylic Acids↗
PubMed2000

Molecular genetics and epidemiology of the NAT1 and NAT2 acetylation polymorphisms.

The focus of this review is the molecular genetics, including consensus NAT1 and NAT2 nomenclature, and cancer epidemiology of the NAT1 and NAT2 acetylation polymorphisms. Two N-acetyltransferase isozymes, NAT1 and NAT2, are polymorphic and catalyze both N-acetylation (usually deactivation) and O-acetylation (usually activation) of aromatic and heterocyclic amine carcinogens. Epidemiological studies suggest that the NAT1 and NAT2 acetylation polymorphisms modify risk of developing urinary bladder, colorectal, breast, head and neck, lung, and possibly prostate cancers. Associations between slow NAT2 acetylator genotypes and urinary bladder cancer and between rapid NAT2 acetylator genotypes and colorectal cancer are the most consistently reported. The individual risks associated with NAT1 and/or NAT2 acetylator genotypes are small, but they increase when considered in conjunction with other susceptibility genes and/or aromatic and heterocyclic amine carcinogen exposures. Because of the relatively high frequency of some NAT1 and NAT2 genotypes in the population, the attributable cancer risk may be high. The effect of NAT1 and NAT2 genotype on cancer risk varies with organ site, probably reflecting tissue-specific expression of NAT1 and NAT2. Ethnic differences exist in NAT1 and NAT2 genotype frequencies that may be a factor in cancer incidence. Large-scale molecular epidemiological studies that investigate the role of NAT1 and NAT2 genotypes and/or phenotypes together with other genetic susceptibility gene polymorphisms and biomarkers of carcinogen exposure are necessary to expand our current understanding of the role of NAT1 and NAT2 acetylation polymorphisms in cancer risk.

Acetylation↗
PubMed1999

Caspase-mediated cleavage of APC results in an amino-terminal fragment with an intact armadillo repeat domain.

During the effector phase of apoptosis, caspase activation appears to be responsible for the distinctive structural changes of apoptosis and perhaps for some of the changes in function of the doomed cells. There is therefore interest in identifying caspase substrates and the details of the cleavage events. Here we define precisely the event responsible for generation of a stable 90 kDa fragment from the oncosuppressor protein adenomatous polyposis coli (APC). Using synthetic radiolabeled APC peptides as substrate, we demonstrate cleavage by cytosolic extracts from preapoptotic cells. This cleavage was reproduced by recombinant caspase-3 and blocked by a tetrapeptide inhibitor Ac-DEVD-CHO, which is specific for caspase-3 family members. Inhibitors specific for caspase-1 and -8 however, were less effective in blocking APC cleavage. Mutation of a candidate DNID caspase-3 target site completely abolished cleavage. This cleavage may be of biological importance since the 90 kDa fragment consists of a sequence that is highly conserved in the human, rat, mouse, Xenopus, and Drosophila APC, although wide sequence divergence is observed in Drosophila immediately carboxy-terminal to the DNID site. Furthermore, cleavage at this site separates two significant functional domains: an amino-terminal armadillo repeat and an adjacent series of beta-catenin binding sites. Further circumstantial evidence for the significance of APC-related pathways in apoptosis is provided by the observation that apoptosis also induces cleavage of beta-catenin itself, a protein known to accumulate in cells depleted in functional APC and that appears to link cell-cell signaling to changes in transcription and cell movement.

Adenomatous Polyposis Coli↗
PubMed1999

Cytochrome P-450 mRNAs are modulated by dehydroepiandrosterone, nafenopin, and triiodothyronine.

Dehydroepiandrosterone (DHEA) is the only known naturally occurring compound that promotes peroxisome proliferation in rodent liver, and stimulates transcriptional induction of genes involved in lipid metabolism and peroxisomal beta-oxidation. Therefore, we examined mRNA for several such genes in rat liver, specifically acyl-CoA oxidase and the cytochromes P-450 (CYP4A1, CYP4A3, and CYP3A23), after 5 to 6 day treatments with either DHEA, or nafenopin, a known peroxisome proliferator. Acyl-CoA oxidase and CYP4A1 were induced nearly identically by DHEA and nafenopin, with induction being more pronounced in female rats. However, CYP3A23 was induced only by DHEA, suggesting an induction mechanism independent of the peroxisome proliferator activated receptor. Previously, we observed triiodothyronine (T3) suppression of peroxisome proliferator induced CYP4As and we sought to determine whether CYP3A23 might be regulated in a different manner. T3 was found to also suppress DHEA-dependent induction of CYP3A23. CYP4A2 expression in kidney was also negatively regulated by T3. To characterize a putative negative thyroid hormone response element (nTRE) in the 5' flanking region of this gene, a luciferase reporter gene containing a rat CYP4A2 flanking sequence extending to -1865 bp was transfected into HepG2 cells along with human thryroid hormone receptor expression vector. Expression of luciferase activity was unaffected by T3, suggesting the absence of a functional nTRE within this portion of CYP4A2. These data demonstrate gene regulatory activity by DHEA different from that of nafenopin, and a suppressive effect of T3, consistent with indirect regulatory mechanisms not involving an nTRE.

5' Untranslated Regions↗
PubMed1996

Regulation of CYP4A expression in rat by dehydroepiandrosterone and thyroid hormone.

Dehydroepiandrosterone (DHEA) is a peroxisome proliferating agent when administered in pharmacological dosages, but it has not been shown to function through the peroxisome proliferator-activated receptor in cell-based assays. Because members of the thyroid hormone/vitamins A and D nuclear receptor subfamily, including PPAR, are known to modulate each other's function in gene expression by heterodimerization, we sought to establish whether DHEA and thyroid hormone interact to regulate several of the hepatic and renal enzymes associated with peroxisome proliferation, i.e., peroxisomal beta-oxidation and microsomal NADPH:cytochrome P450 oxidoreductase and the cytochromes P450 4A. In rats administered exogenous T3 to attain a hyperthyroid state, induction of the three isozymes of CYP4A (4A1, 4A2, and 4A3) by DHEA was suppressed > 60-80% at the mRNA level, with induction of CYP4A2 mRNA being completely inhibited. Nuclear run-on transcription assays indicated that this inhibitory effect was regulated at the level of transcription. Induction of hepatic peroxisomal beta-oxidation by DHEA or the peroxisome proliferator nafenopin was in large part unaffected by treatment of animals with T3 under any condition tested. Microsomal NADPH:cytochrome P450 oxidoreductase activity was induced by either DHEA or T3; cotreatment resulted in an additive induction. When animals were treated with a lower dose of exogenous T3 that rendered the animals slightly hyperthyroid, only induction of hepatic CYP4A2 mRNA by DHEA or nafenopin was significantly inhibited (> 80%) compared with euthyroid control animals. Animals that had been rendered hypothyroid through removal of the thyroid gland showed normal induction of CYP4A genes by DHEA in liver, suggesting that their induction by DHEA was not dependent on the presence of thyroid hormone. The administration of exogenous T3 to thyroidectomized rats in the presence of DHEA potently suppressed hepatic induction of all three genes at the mRNA and protein level. In experiments with cultured rat hepatocytes, physiological concentrations of T3 potently inhibited the induction of CYP4A2 mRNA levels by nafenopin but had little effect on induction of CYP4A1 or 4A3 mRNA. At higher T3 concentrations, the induction of CYP4A1/4A3 mRNA and protein was also inhibited. These results suggest that T3 modulates the expression of CYP4A2 at the level of transcription in physiologically relevant concentrations but that hyperthyroid conditions are required to suppress expression of CYP4A1/4A3 genes. In euthyroid rodent kidney, which only expresses CYP4A2 under either basal or DHEA-induced conditions, near-physiological levels of T3 caused potent suppression of peroxisome proliferator-dependent induction of CYP4A2 mRNA levels by either DHEA or nafenopin. In thyroidectomized rats, basal expression of CYP4A2 mRNA was decreased relative to euthyroid controls, but DHEA was as effective an inducer of this mRNA as it is in euthyroid rats. As seen in euthyroid rats, T3 administration potently suppressed DHEA induction of CYP4A2 mRNA levels under either basal or induced conditions. Although CYP4A expression was not derepressed in liver or kidneys of hypothyroid animals, our results indicated that the thyroid status of the animal did affect basal expression of CYP4A2, suggesting involvement of thyroid hormone or some other factor regulated by the thyroid gland on its constitutive expression.

Animals↗
PubMed1994

Induction of microsomal and peroxisomal enzymes by dehydroepiandrosterone and its reduced metabolite in rats.

Dehydroepiandrosterone (DHEA) given to rodents in pharmacological doses induces several hepatic enzymes including cytochromes P4504A, NADPH:P450 oxidoreductase, palmitoyl coenzyme A oxidase, and other enzymes associated with the peroxisomal beta-oxidation pathway, leading to peroxisome proliferation and development of hepatocellular carcinoma in rodents. Comparison of the inductive potency of DHEA and other intermediates of the steroid biosynthetic path demonstrated that only DHEA, 5-ene-androstene-3 beta,17 beta-diol (ADIOL), and to a lesser extent, 17 alpha-hydroxypregnenolone, a precursor of DHEA, induce cytochromes P4504A protein and other enzymes associated with the peroxisome proliferative response in vivo. ADIOL exerted its inductive response at a somewhat lower dosage than DHEA, whereas ADIOL and DHEA both induced the microsomal enzymes (P4504A and its oxidoreductase) at somewhat lower dosages than those required to induce peroxisomal enzymes. Northern analysis demonstrated increases in the mRNAs encoding the cytochromes P4504A (> 20-fold) and NADPH:P450 oxidoreductase (> 10-fold) in the livers of DHEA- and ADIOL-treated rats. Run-on transcription analysis demonstrated that DHEA induces CYP4A gene expression 11-fold at the level of transcription initiation. Comparison of the responsiveness of individual rat CYP4A genes (4A1, 4A2, and 4A3) to DHEA and ADIOL in immature versus mature male rats revealed 2-3-fold higher levels of induced CYP4A1 and 4A3 mRNAs in immature rat livers. In contrast, hepatic CYP4A2 mRNA was induced to 6-10-fold higher levels in mature rats. No basal or significant inducible expression of mRNA for CYP4A1 and 4A3 was noted in rat kidney. Significant basal levels of kidney CYP4A2 mRNA were observed only in mature animals, where they were inducible by ADIOL and DHEA to a 3-5-fold greater extent than in the kidneys of immature rats. These studies demonstrate developmental differences in the responsiveness of CYP4A mRNA levels to DHEA and ADIOL in rat kidney and liver. Moreover, the striking inducibility of CYP4A protein and mRNAs, together with the increased rates of synthesis of nascent CYP4A mRNA transcripts in hepatic nuclei from DHEA-treated rats, establish that DHEA increases the expression of these microsomal enzymes at the transcriptional level.

Androstenediol↗
PubMed1991

Survey of general practice audit in Leeds.

OBJECTIVE: To determine general practitioners' attitudes to medical audit and to establish what initiatives are already being undertaken; to define future ideas for audit and perceived difficulties in implementing audit in primary care. DESIGN: Analysis of responses to a self administered postal questionnaire. SETTING: Urban conurbation with a population of about 750,000. PARTICIPANTS: 386 general practitioners on the general medical list of Leeds Family Practitioner Committee. MAIN OUTCOME MEASURES: Extent of recording of practice activity data and outcome measures and clinical data, use of data, and audit performed; ideas for audit and perceived difficulties. RESULTS: 317 doctors responded to the questionnaire (individual response rate 82%) from 121 practices (practice response rate 88%). In all, 206 doctors thought that audit could improve the quality of care; 292 collected practice activity data, though 143 of them did not use it. A total of 111 doctors recorded some outcome measures, though half of them did not use them. Varying proportions of doctors had registers, for various diseases (136 had at least one register), disease management policies (60 doctors), and prescribing policies. In all, 184 doctors met monthly with other members of the primary health care team. CONCLUSIONS: Much poorly focused data collection is taking place. Some doctors have experience in setting up basic information systems and practice policies, and some audit is being performed. The family health services authorities need to take seriously the perceived difficulties of time, organisation, and resources concerned with audit.

Attitude of Health Personnel↗
PubMed1989

Appendicitis and appendicectomy in a Melanesian population.

A prospective study of patients with appendicitis has been conducted over a 3-year period in the Melanesian population of the North Solomons. Patients presented with suspected appendicitis at an annual rate of 39 per 100,000 population. Appendicitis was confirmed at operation at an annual rate of 22 per 100,000 population. The disease was considerably more frequent in male than in female patients. The annual appendicectomy rate was 29 per 100,000 population. Thirty per cent of patients presented with signs of late or complicated appendicitis, while 37 per cent of patients submitted to operation were found to have advanced appendicitis. The incidence and pattern of appendicitis in the North Solomons are quite different from those seen in the urbanized populations of developed countries.

Acute Disease↗
PubMed1988

Skin cancer in the North Solomons.

The Melanesians of the North Solomons are exposed to intense equatorial sunlight and yet have a very low incidence of skin cancer. This study reveals no proven cases of basal cell carcinoma in these people, and demonstrates the rarity of squamous cell carcinoma and melanoma arising in normal pigmented skin. Most, if not all squamous cell carcinomas, arise in skin damaged by tropical ulceration, burns or osteomyelitis. Melanoma arises from the unpigmented skin of the sole of the foot. North Solomon Islanders are very deeply pigmented. Presumably, dense cutaneous melanin in normal undamaged skin provides the highly effective protection against solar carcinogenesis which these people enjoy. Chronic or recurrent skin ulceration with subsequent repair, scarring and loss of pigment is the precursor to almost all non-melanoma skin cancer in these people. Most of these cancers could be prevented by split thickness skin grafting of chronic ulcers, and protection of ulcerated, depigmented and scarred skin from solar radiation.

Australia↗