Search PubMed⌕ Search

Biomedical subjects

M Wheeler

Publications and source records attributed to M Wheeler.

At least 19 recordsLinked to original sources
PubMed2007

Maternal testosterone in pregnancy and atopic outcomes in childhood.

BACKGROUND: In mice, androgens downregulate Th2 cytokine responses, but whether androgen levels during pregnancy might influence the development of allergy in the offspring has not been studied. METHODS: In the Avon Longitudinal Study of Parents and Children (ALSPAC), a population-based birth cohort of 14 541 pregnancies, we related maternal blood total testosterone during pregnancy, measured in a subset of the cohort, to allergic outcomes in the offspring, including asthma, hayfever, eczema (n=543) and wheezing (n=532) at 69-81 months, and atopy (positive skin prick test to Dermatophagoides pteronyssinus, cat or grass, n=386) and blood total immunoglobulin E (IgE; n=314) at 7 years. We used logistic and linear regression to analyse binary outcomes and log-transformed IgE, respectively, controlling for potential confounders. RESULTS: Maternal testosterone was negatively associated with total IgE in boys [adjusted geometric mean ratio (GMR), per doubling of testosterone, 0.33 (0.20-0.55), P=0.000038 (n=168)], but not in girls [GMR 1.04 (0.53-2.06), P=0.91 (n=146)], P-value interaction 0.0086. The effect in boys was even stronger in the absence of maternal atopic disease. Testosterone was not associated with skin test positivity or atopic disease in either sex. CONCLUSIONS: Higher testosterone levels in pregnancy are associated with lower IgE production in boys.

Adolescent↗
PubMed2006

Gamma-aminobutyric acid up- and downregulates insulin secretion from beta cells in concert with changes in glucose concentration.

AIMS/HYPOTHESIS: The role of gamma-aminobutyric acid (GABA) and A-type GABA receptors (GABA(A)Rs) in modulating islet endocrine function has been actively investigated since the identification of GABA and GABA(A)Rs in the pancreatic islets. However, the reported effects of GABA(A)R activation on insulin secretion from islet beta cells have been controversial. METHODS: This study examined the hypothesis that the effect of GABA on beta cell insulin secretion is dependent on glucose concentration. RESULTS: Perforated patch-clamp recordings in INS-1 cells demonstrated that GABA, at concentrations ranging from 1 to 1,000 micromol/l, induced a transmembrane current (I(GABA)) which was sensitive to the GABA(A)R antagonist bicuculline. The current-voltage relationship revealed that I(GABA) reversed at -42+/-2.2 mV, independently of glucose concentration. Nevertheless, the glucose concentration critically controlled the membrane potential (V (M)), i.e., at low glucose (0 or 2.8 mmol/l) the endogenous V (M) of INS-1 cells was below the I(GABA) reversal potential and at high glucose (16.7 or 28 mmol/l), the endogenous V (M) of INS-1 cells was above the I(GABA) reversal potential. Therefore, GABA dose-dependently induced membrane depolarisation at a low glucose concentration, but hyperpolarisation at a high glucose concentration. Consistent with electrophysiological findings, insulin secretion assays demonstrated that at 2.8 mmol/l glucose, GABA increased insulin secretion in a dose-dependent fashion (p<0.05, n=7). This enhancement was blocked by bicuculline (p<0.05, n=4). In contrast, in the presence of 28 mmol/l glucose, GABA suppressed the secretion of insulin (p<0.05, n=5). CONCLUSIONS/INTERPRETATION: These findings indicate that activation of GABA(A)Rs in beta cells regulates insulin secretion in concert with changes in glucose levels.

Animals↗
PubMed2006

The influence of premenopausal hormones on severity of climacteric symptoms and use of HRT.

OBJECTIVES: There is wide variation in the severity of climacteric symptoms and we hypothesized that this could be a reflection of premenopausal hormone levels. METHODS: As part of a long-term cohort study of endocrine risk factors for breast cancer, blood had been collected between 1986 and 1990 from 1882 premenopausal women aged >or=35 years. Questionnaires on menopausal symptom severity were sent to 1,843 surviving women in 2001, of whom 1,434 replied. Estradiol, progesterone and testosterone levels were measured by radioimmunoassay in 680 women who reported a natural menopause and completed the symptom severity section in full. RESULTS: Symptom severity fell with rising premenopausal estradiol levels and women with higher premenopausal testosterone levels had more severe vasomotor symptoms. Over 70% of women with above-median severity of symptoms had used hormone replacement therapy (HRT). Those with higher testosterone levels were less likely to take HRT. CONCLUSIONS: Premenopausal hormone levels may predict risk of severe menopausal symptoms, which in turn influences use of HRT. Paradoxically, a high testosterone level was associated with more vasomotor symptoms but reduced use of HRT. Those at greatest risk of climacteric symptoms may be at lower risk of breast cancer because of premenopausal reduced estrogen exposure.

Adult↗
PubMed2004

The relationship of sex hormones and cortisol with cognitive functioning in Schizophrenia.

Gonadal as well as stress hormones have recently been implicated in pathophysiology and sex differences in onset, prognosis and treatment of schizophrenia. The present study investigated the effects of serum levels of oestrogen, progesterone, testosterone and cortisol on neuropsychological functioning and psychopathology in a group of 37 patients (17 women, 20 men) with schizophrenia. Neuropsychological measures included tests of attention, verbal abilities, language, memory, executive functioning, motor and speed of information processing. The results showed that oestrogen and age was associated with low positive symptom scores, and within gender, cortisol predicted poor performance on the information processing domain in men. These findings demonstrate that cortisol, in addition to the commonly reported effects of oestrogen, influences neuropsychological functioning in schizophrenia with differential effects on specific domains of cognitive functioning and underscore the need for further investigation of the modulating role of hormones on neuropsychological functioning in schizophrenia.

Adolescent↗
PubMed2003

Deletion of GABAA receptor alpha 1 subunit-containing receptors alters responses to ethanol and other anesthetics.

GABA(A) receptors have been implicated in mediating several acute effects of ethanol including anxiolysis, ataxia, sedation/hypnosis, and anticonvulsant activity. Ethanol sensitivity of neurons has been associated with expression of alpha1 subunit-containing receptors. The objective of this study was to determine the contribution of alpha1 subunit containing receptors to ethanol responses in comparison to neurosteroids and other anesthetics using GABA(A) receptor alpha1 subunit knockout mice. Deletion of alpha1 subunit-containing receptors did not alter the anxiolytic, ataxic, anticonvulsant, or hypnotic effects of ethanol or acute functional tolerance to ethanol but did increase sensitivity to the locomotor-stimulating effects of ethanol. The ability of ethanol to potentiate muscimol-stimulated chloride uptake and ethanol clearance was also not altered following alpha1 subunit deletion. The anticonvulsant and hypnotic effects of neurosteroids as well as their potentiating effect on GABA-mediated Cl(-) uptake were unaltered in alpha1(-/-) mice. The hypnotic effect of pentobarbital, etomidate, and midazolam were reduced, whereas the effect of ketamine was enhanced in alpha1(-/-) mice. Thus, GABA(A) receptor alpha1 subunit-containing receptors appear to influence the motor-stimulating effect of ethanol and the sedative/hypnotic effects of some anesthetics, but not ethanol. These receptors do not appear to be necessary for most ethanol responses, suggesting involvement of other GABA(A) receptor subtypes or other targets altogether.

Anesthetics↗
PubMed2002

Microfluidic technology for assisted reproduction.

The physical tools used in assisted reproduction have changed little over several decades. Microfluidics is an emerging technology that allows a fresh examination of the way assisted reproduction is performed. Here we review our work to develop microfluidic devices to perform the functions required in assisted reproduction. These functions include loading/unloading, culture, chemical manipulation, and mechanical manipulation of embryos and oocytes. Basic microfluidic theory and microfluidic device design and operation are discussed. Results are presented for mechanical removal of cumulus cells and for embryo culture. Results suggest that microfluidic systems will lead to improved efficiencies in assisted reproduction.

Animals↗
PubMed2002

Demonstration of reduced in vivo surface expression of activating mutant thyrotrophin receptors in thyroid sections.

OBJECTIVE: Thyroid function and growth are controlled by TSH. Hyperthyroidism can be due to Graves' Disease (GD), in which thyroid-stimulating antibodies mimic TSH, or gain-of-function mutations in the TSH receptor (TSHR). These activating mutations have poor surface expression when assessed in non-thyroidal cells in vitro but nothing is known of their in vivo behaviour. Several TSHR antibodies have been produced but none has been applied to thyroid paraffin sections. This study aimed to develop a technique suitable for use on paraffin sections and apply it to investigate TSHR expression in thyroids harbouring activating TSHR germline mutations compared with normal and GD thyroids. DESIGN AND METHODS: Immunocytochemistry coupled with antigen retrieval, using a spectrum of antibodies to the TSHR, was applied to paraffin sections of GD thyroid tissue. Subsequently, TSHR immunoreactivity was examined in three normal thyroids, three patients with GD and three patients with familial hyperthyroidism, due to different gain-of-function TSHR germline mutations, using the optimised protocol. RESULTS: Two antibodies, A10 and T3-495, to the extracellular domain (ECD) and membrane spanning region (MSR) of the TSHR respectively, produced specific basolateral staining of thyroid follicular cells. In normal and GD thyroids, basolateral staining with T3-495 was generally more intense than with A10, suggesting a possible surfeit of MSR over ECD. Graves' Disease thyroids have more abundant TSHR than normal glands. In contrast, thyroids harbouring gain-of-function mutations have the lowest expression in vivo, mirroring in vitro findings. CONCLUSIONS: The development of an immunocytochemical method applicable to paraffin sections has demonstrated that different molecular mechanisms causing hyperthyroidism result in the lowest (mutation) and highest (autoimmunity) levels of receptor at the thyrocyte surface.

Adult↗
PubMed2001

Recruitment of the class II phosphoinositide 3-kinase C2beta to the epidermal growth factor receptor: role of Grb2.

Previously we demonstrated that the class II phosphoinositide 3-kinase C2beta (PI3K-C2beta) is rapidly recruited to a phosphotyrosine signaling complex containing the activated receptor for epidermal growth factor (EGF). Although this association was shown to be dependent upon specific phosphotyrosine residues present on the EGF receptor, the underlying mechanism remained unclear. In this study the interaction between PI3K-C2beta and the EGF receptor is competitively attenuated by synthetic peptides derived from each of three proline-rich motifs present within the N-terminal region of the PI3K. Further, a series of N-terminal PI3K-C2beta fragments, truncated prior to each proline-rich region, bound the receptor with decreased efficiency. A single proline-rich region was unable to mediate receptor association. Finally, an equivalent N-terminal fragment of PI3K-C2alpha that lacks similar proline-rich motifs was unable to affinity purify the activated EGF receptor from cell lysates. Since these findings revealed that the interaction between the EGF receptor and PI3K-C2beta is indirect, we sought to identify an adaptor molecule that could mediate their association. In addition to the EGF receptor, PI3K-C2beta(2-298) also isolated both Shc and Grb2 from A431 cell lysates. Recombinant Grb2 directly bound PI3K-C2beta in vitro, and this effect was reproduced using either SH3 domain expressed as a glutathione S-transferase (GST) fusion. Interaction with Grb2 dramatically increased the catalytic activity of this PI3K. The relevance of this association was confirmed when PI3K-C2beta was isolated by coimmunoprecipitation with anti-Grb2 antibody from numerous cell lines. Using immobilized, phosphorylated EGF receptor, recombinant PI3K-C2beta was only purified in the presence of Grb2. We conclude that proline-rich motifs within the N terminus of PI3K-C2beta mediate the association of this enzyme with activated EGF receptor and that this interaction involves the Grb2 adaptor.

Adaptor Proteins, Signal Transducing↗
PubMed2000

The Fort McMurray Demonstration Project in Social Marketing: theory, design, and evaluation.

CONTEXT: The Fort McMurray Demonstration Project in Social Marketing is a multifaceted program that applies the techniques of social marketing to health and safety. This paper describes the origins of the project and the principles on which it was based. VENUE: Fort McMurray, in the province of Alberta, Canada, was selected because the community had several community initiatives already underway and the project had the opportunity to demonstrate "value added." CONCEPT: The project is distinguished from others by a model that attempts to achieve mutually reinforcing effects from social marketing in the community as a whole and from workplace safety promotion in particular. DESIGN: Specific interventions sponsored by the project include a media campaign on cable television, public activities in local schools, a community safety audit, and media appearance by a mascot that provides visual identity to the project, a dinosaur named "Safetysaurus." The project integrated its activities with other community initiatives. MAIN OUTCOME MEASURES: The evaluation component emphasizes outcome measures. A final evaluation based on injury rates and attitudinal surveys is underway. RESULTS: Baseline data from the first round of surveys have been compiled and published. In 1995, Fort McMurray became the first city in North America to be given membership in the World Health Organization's Safe Community Network.

Adult↗
PubMed2000

Glycine-gated chloride channels in neutrophils attenuate calcium influx and superoxide production.

Recently, it was demonstrated that liver injury and TNF-alpha production as a result of endotoxin (lipopolysaccharide, LPS) were attenuated by feeding animals a diet enriched with glycine. This phenomenon was shown to be a result of, at least in part, activation of a chloride channel in Kupffer cells by glycine, which hyperpolarizes the cell membrane and blunts increases in intracellular calcium concentrations ([Ca(2+)](i)) similar to its action in the neuron. It is well known that hepatotoxicity due to LPS has a neutrophil-mediated component and that activation of neutrophils is dependent on increases in [Ca(2+)](i). Therefore, the purpose of this study was to determine if glycine affected agonist-induced increases in [Ca(2+)](i) in rat neutrophils. The effect of glycine on increases in [Ca(2+)](i) elicited either by the bacterial-derived peptide formyl-methionine-leucine-phenylalanine (FMLP) or LPS was studied in individual neutrophils using Fura-2 and fluorescence microscopy. Both FMLP and LPS caused dose-dependent increases in [Ca(2+)](i), which were maximal at 1 microM FMLP and 100 microgram/ml LPS, respectively. LPS increased intracellular calcium in the presence and absence of extracellular calcium. Glycine blunted increases in [Ca(2+)](i) in a dose-dependent manner with an IC(50) of approximately 0.3 mM, values only slightly higher than plasma levels. Glycine was unable to prevent agonist-induced increases in [Ca(2+)](i) in chloride-free buffer. Moreover, strychnine (1 microM), an antagonist of the glycine-gated chloride channel in the central nervous system, reversed the effects of glycine (1 mM) on FMLP- or LPS-stimulated increases in [Ca(2+)](i). To provide hard evidence for a glycine-gated chloride channel in the neutrophil, the effect of glycine on radioactive chloride uptake was determined. Glycine caused a dose-dependent increase in chloride uptake into neutrophils with an ED(50) of approximately 0.4 mM, an effect also prevented by 1 microM strychnine. Glycine also significantly reduced the production of superoxide anion from FMLP-stimulated neutrophils. Taken together, these data provide clear evidence that neutrophils contain a glycine-gated chloride channel that can attenuate increases in [Ca(2+)](i) and diminish oxidant production by this important leukocyte.

Animals↗
PubMed2000

Biosynthesis and functions of melanin in Sporothrix schenckii.

Sporothrix schenckii is a human pathogen that causes sporotrichosis, an important cutaneous mycosis with a worldwide distribution. It produces dark-brown conidia, which infect the host. We found that S. schenckii synthesizes melanin via the 1,8-dihydroxynaphthalene pentaketide pathway. Melanin biosynthesis in the wild type was inhibited by tricyclazole, and colonies of the fungus were reddish brown instead of black on tricyclazole-amended medium. Two melanin-deficient mutant strains were analyzed in this study: an albino that produced normal-appearing melanin on scytalone-amended medium and a reddish brown mutant that accumulated and extruded melanin metabolites into its medium. Scytalone and flaviolin obtained from cultures of the reddish brown mutant were identified by thin-layer chromatography, high-performance liquid chromatography, and UV spectra. Transmission electron microscopy showed an electron-dense granular material believed to be melanin in wild-type conidial cell walls, and this was absent in conidial walls of the albino mutant unless the albino was grown on a scytalone-amended medium. Melanized cells of wild-type S. schenckii and the albino grown on scytalone-amended medium were less susceptible to killing by chemically generated oxygen- and nitrogen-derived radicals and by UV light than were conidia of the mutant strains. Melanized conidia of the wild type and the scytalone-treated albino were also more resistant to phagocytosis and killing by human monocytes and murine macrophages than were unmelanized conidia of the two mutants. These results demonstrate that melanin protects S. schenckii against certain oxidative antimicrobial compounds and against attack by macrophages.

Adult↗
PubMed1999

Preoperative pregnancy testing in a tertiary care children's hospital: a medico-legal conundrum.

STUDY OBJECTIVES: To track physician and nursing practice regarding preoperative pregnancy screening and testing in a setting where testing is the established policy. DESIGN: Prospective study. SETTING: University-affiliated, urban, tertiary care pediatric hospital. PATIENTS: 261 menarcheal patients, aged 10 to 34 years, presenting for ambulatory surgery in a 15-month period. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 235 routine pregnancy tests performed, three were positive (1.3%). All patients denied the possibility of pregnancy; all reported last menstrual period less than 3 weeks prior to their scheduled surgery. Two of the three patients whose pregnancy tests were positive were adults. Only two study patients were unsure about the possibility of pregnancy; both patients tested negative. No patient younger than 15 years tested positive (0 of 107). History was an unreliable marker for pregnancy. CONCLUSIONS: Medical history alone may be an unreliable marker for ruling out pregnancy in patients presenting for outpatient surgery in an urban pediatric hospital. The policy for preoperative pregnancy screening adopted by a hospital or health care facility should be predicated on the principle of "best interest of the patient." Considerations must include local law, ethical responsibility, and the balance between cost and risk based on the best and most current scientific information.

Adolescent↗
PubMed1999

A grouping interpretation of the modality effect in immediate probed recognition.

In a series of experiments on immediate probed recognition for eight 3-digit numbers, it was shown that if the target modality involved auditory components and the effect of the similarity of the modality of the probe to that of the targets was controlled, unequivocal evidence was obtained for an auditory superiority effect (modality effect) for hit rates for the final items of the list. Moreover, false-alarm rates were significantly lower following targets with an auditory component than they were following silently seen targets. It is argued that this pattern of hits and false alarms is consistent with the idea that targets that have an auditory component yield memory representations that are better grouped as units than are those for targets that are only silently seen; in particular, if a new probe has a first digit that accidentally matches the first digit of a target item, it is more likely that the subject will mistakenly identify this new probe as old (give a false alarm) if the target has only been partially encoded because it was only silently seen.

Auditory Perception↗
PubMed1999

Home and laboratory pregnancy-testing kits.

Home pregnancy test kits are more sensitive than many pregnancy kits used in laboratories or health centres. Nurses should know the sensitivity of the kit used in their centre or laboratory. A positive home pregnancy test should always be treated as the correct result until sufficient tests have been carried out to prove otherwise.

Female↗