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Biomedical subjects

C Sharpe

Publications and source records attributed to C Sharpe.

At least 19 recordsLinked to original sources
PubMed2001

Wnt signalling: a theme with nuclear variations.

Wnt proteins are involved in a large number of events during development and disease. The crucial element in the transduction of the signal elicited by Wnt is the state and activity of beta-catenin. There are two pools of beta-catenin, one associated with cadherins at the cell surface and a soluble one in the cytolasm, whose state and concentration are critical for Wnt signalling. In the absence of Wnt, the cytoplasmic pool is low due to targetted degradation of beta-catenin. Upon Wnt signalling, beta-catenin is stabilized. As a consequence, it can access the nucleus where it interacts with members of the Tcf family of transcription factors to modulate the expression of defined targets. Recent reports indicate that, in addition to Tcfs, beta-catenin can interact with other nuclear proteins raising the possibility that Wnt signalling has a wider modulatory effect on transcription than is mediated by its interactions with Tcfs. BioEssays 23:311-318, 2001.

Animals↗
PubMed2001

Characterization of matrix metalloprotease activities induced in the sea urchin extraembryonic matrix, the hyaline layer.

Hyaline layers, freshly prepared from one-hour-old embryos, were devoid of gelatin-cleavage activity. However, upon storage at 4 degrees C, gelatin-cleavage activities appeared; three species of apparent mol mass 94 --> 117-, 90-, and 45-kDa were seen. All three species required zinc for activity. Using gel-exclusion chromatography we separated the 94 --> 117-, and 90-kDa species from the 45-kDa activity. The two higher mol mass species were inhibited by ethylenebis (oxyethylenenitrilo) tetraacetic acid and the lost activity was restored by calcium. Reconstitution of activity occurred with an apparent dissociation constant (calcium) of 5 microM. The presence of millimolar concentrations of magnesium had a minimal inhibitory effect on activity. The thermal denaturation profile of the higher mol mass gelatin-cleavage activity was significantly different in the presence and absence of calcium. Stabilization of these activities against thermal denaturation at 60 degrees C occurred with an apparent dissociation constant (calcium) of 0.6 mM. Magnesium had no significant effect on the thermal denaturation profile. Collectively, these results suggest at least two different modes of interaction between calcium and the higher mol mass gelatinases. These conclusions are discussed in the context of the high calcium and magnesium concentrations present in the sea water environment of the sea urchin embryo.

Animals↗
PubMed2000

The control of Xenopus embryonic primary neurogenesis is mediated by retinoid signalling in the neurectoderm.

In Xenopus, the primary neurons form in three domains either side of the midline in the posterior neurectoderm. At the late neurula stage there are approximately 120 primary sensory neurons on each side of the embryo. Co-injecting synthetic mRNA encoding retinoic acid receptor alpha (NR1B1) and retinoid X receptor beta (NR2B2) results in an increase in the number of primary neurons and this is further enhanced by the addition of retinoic acid indicating that elevated retinoid signalling promotes an increase in the number of cells undergoing primary neurogenesis. However, primary neurogenesis remains confined to the three domains that normally give rise to primary neurons indicating that not all regions of the neurectoderm respond equivalently to elevated retinoid signalling. The inhibition of retinoid signalling with a dominant negative retinoid receptor or treatment with citral, an inhibitor of retinoid metabolism, inhibits the formation of primary neurons. However, the lateral extent of the neurectoderm does not differ following these experimental manipulations suggesting that changes in primary neuron cell number, in response to changes in retinoid signalling, cannot be accounted for by significant gains or losses of neurectoderm. In addition, two lines of evidence are presented to suggest that retinoid signalling affects primary neurogenesis by acting directly on the neurectoderm. First, animal caps neuralized by noggin undergo primary neurogenesis in response to retinoid signalling and second primary neurogenesis is elevated in neural conjugates in which the ectodermal, but not the mesodermal, component has been co-injected with RAR/RXR mRNA.

Acyclic Monoterpenes↗
PubMed2000

Retinoid signalling acts during the gastrula stages to promote primary neurogenesis.

Retinoid signalling has been manipulated at different developmental stages to identify a critical period in the gastrula embryo for retinoid-dependent primary neurone formation. The expression of retinoid receptor RARalpha2 in the posterior neuroectoderm of the gastrula embryo is therefore consistent with a role in primary neurogenesis. In addition we show that the expression of neurogenin-1 and XDelta-1, two genes that contribute to the determination of primary neurone cell-fate in the gastrula embryo, respond to retinoid signalling. These results indicate that retinoid signalling is required for an early step in the process of primary neurogenesis. When retinoid signalling is increased, the number of primary neurones increases, but the phenotype is not the same as the neurogenic phenotype that follows the overexpression of a dominant negative form of XDelta-1. Whereas increased retinoid signalling expands the width of primary neurone stripes, dominant negative XDelta-1 increases the density of primary neurones within the stripes. When retinoid signalling is increased and the primary neurone stripes expand, the expression domain of a floorplate marker contracts. Conversely, when retinoid signalling is inhibited, the expression patterns of floorplate markers widen. These results indicate that retinoid signalling acts at an early stage in primary neural development when the fates of different regions of the neuroectoderm are being determined.

Basic Helix-Loop-Helix Proteins↗
PubMed1999

Colorectal cancer prevention by non-steroidal anti-inflammatory drugs: effects of dosage and timing.

Epidemiological studies show that non-steroidal anti-inflammatory drugs (NSAIDs) reduce colorectal cancer incidence. We measured the rate ratio for colorectal adenocarcinoma according to dosage and the timing of exposure by means of a case-control study, nested in a non-concurrent cohort linkage study, using the population of beneficiaries of the Saskatchewan Prescription Drug Plan from 1981 to 1995 with no history of cancer since 1970 as the source population. Four controls per case, matched on age and gender and alive when the case was diagnosed, were randomly selected. Dispensing rates, calculated over successive time periods, characterized NSAID exposure. We accrued 3844 cases of colon cancer and 1971 cases of rectal cancer. For colon cancer a significant trend towards a decreasing rate ratio was associated with increasing exposure during the 6 months preceding diagnosis (P-trend = 0.002). For both cancers, significant trends were associated with exposure 11-15 years before diagnosis (colon: P-trend = 0.01; rectum: P-trend = 0.0001). At the highest exposure levels the rate ratio for colon cancer was 0.57 (95% confidence interval (CI) 0.36-0.89); for rectal cancer it was 0.26 (95% CI 0.11-0.61). No protection was associated with exposure during other periods. The timing of NSAID use must be considered in planning intervention trials to prevent colorectal cancer. There may be a 10-year delay before any preventive effect will appear.

Aged↗
PubMed1999

Cellulite treatment: a myth or reality: a prospective randomized, controlled trial of two therapies, endermologie and aminophylline cream.

Cellulite is a common phenomenon that particularly affects the thighs and buttocks of women. Little scientific evidence exists to support any of the many advertised treatments for it. A total of 52 of 69 women, who were divided into three groups, completed a 12-week, randomized, controlled trial in which the effectiveness of two different treatments for cellulite was assessed. The patients acted as their own controls. The treatments investigated were twice-daily application of aminophylline cream and twice-weekly treatment with Endermologie ES1. Group 1 (double blind) received aminophylline to one thigh/buttock and a placebo cream to the other. Group 2 (singly blind) received Endermologie to one thigh/buttock. Group 3 received Endermologie to both sides and used the same cream regimen as group 1. Results were assessed subjectively by the patient and by clinical examination and photographic assessment by the surgeon (before and after the trial). Morphologic assessment included body mass index, thigh girth at two points, and thigh fat depth measurement by ultrasound. No statistical difference existed in measurements between legs for any of the treatment groups (paired t test, p > 0.4). The best subjective assessment, by the patients themselves, revealed that only 3 of 35 aminophylline-treated legs and 10 of 35 Endermologie-treated legs had their cellulite appearance improved. The authors do not believe that either of these two treatments is effective in improving the appearance of cellulite.

Adipose Tissue↗
PubMed1998

Controlling confounding when studying large pharmacoepidemiologic databases: a case study of the two-stage sampling design.

Large drug databases have been the source of interesting developments for pharmacoepidemiologic research, because they provide relatively accurate drug exposure histories. An important limitation of these databases is the lack of information on potential confounders. One solution, developed more than a decade ago but not widely used, is "two-stage sampling," in which stage 1 is the collection of information on drug exposure and outcomes, and stage 2 is the collection of confounder data on a subset of the stage 1 sample. The balanced design, wherein an equal number of individuals is selected from each drug exposure/disease category, is usually the most efficient strategy by which to select the stage 2 sample. We illustrate the efficiency of the balanced design in two-stage sampling using data from a provincial health organization and a simulation. We also evaluate the relative importance of factors affecting the precision of the effect estimate of the exposure of interest.

Case-Control Studies↗
PubMed1997

Two-stage sampling for etiologic studies. Sample size and power.

Preexisting computerized databases are potentially valuable sources of epidemiologic data. Since such databases are infrequently created specifically for etiologic research, data may be available for the exposure of interest and, through record linkage, for the endpoint of interest, but lacking for potential confounders. Because of the size of these databases, two-stage sampling is an efficient alternative to surveying the entire study population for confounder data. At stage 1, information on exposure and disease status is obtained for the entire study population. Confounder data are collected for probability-selected subsamples at stage 2. Logistic regression is performed on the stage 2 samples, with the parameter estimates and variances appropriately corrected to account for the stage 1 data. In this paper, the authors present methods for determining the required stage 2 sample size in the case of categorical exposure and confounding variables. Sample size tables, power curves, and a computer program have been produced to accommodate a binary exposure and a single binary confounder. With the increasing availability of preexisting yet incomplete databases, the potential for use of two-stage sampling will greatly increase in the future. This investigation provides a basis for estimating the number of participants to sample for the collection of confounder data at the second stage.

Case-Control Studies↗
PubMed1995

Juvenile myoclonic epilepsy: diagnosis, management and outcome.

OBJECTIVES: To study delay in diagnosis, seizure control, seizure-provoking factors, suitable medications and drug side effects in patients with juvenile myoclonic epilepsy. DESIGN: Telephone and personal interview of patients and review of their clinical notes. PARTICIPANTS AND SETTING: Thirty-six patients attending an epilepsy clinic at a tertiary referral hospital. RESULTS: There was a substantial delay in the diagnosis of juvenile myoclonic epilepsy because the symptom of early-morning myoclonus was not specifically sought. Sodium valproate is the drug of choice, producing absolute seizure control in 63% of cases (19/30). Most patients with poor seizure control had provoked seizures only, emphasising the importance of lifestyle in management. Half of the patients taking sodium valproate experienced side effects, such as weight gain. Lamotrigine is the most suitable alternative. CONCLUSIONS: Juvenile myoclonic epilepsy is a common, under-recognised form of epilepsy which is best treated with sodium valproate. If side effects occur, lamotrigine should be used.

Adolescent↗
PubMed1995

An evaluation of the action plans of children with asthma.

OBJECTIVE: To assess the provision and use of action plans in children attending hospital because of asthma. METHODOLOGY: An interviewer administered a structured questionnaire to the parents of 279 children attending the Casualty Department, Outpatient clinics or admitted to hospital because of asthma, at two Level 3 teaching hospitals. RESULTS: Only 82 (29%) of the children attending hospital had a written action plan. The majority (57%) were devised by paediatricians and covered the salient aspects of care. However, indications for steroid use were included in only 28% of plans and only 37% of the action plans in children over 5 years incorporated the use of peak flow meters. CONCLUSIONS: Action plans are still under-utilized in children with asthma. General practitioners should be encouraged to consider the use of action plans for the group of children not already covered.

Adolescent↗
PubMed1994

Clonazepam withdrawal in 13 patients with active epilepsy and drug side effects.

We report the end result of clonazepam (CZP) withdrawal in 13 patients with significant side effects felt to be due to CZP. The present observations supplement the recent report in Seizure by Chataway et al., in proposing a safe CZP withdrawal rate of 0.2 mg/day. Eight of the patients had withdrawal seizures, five had withdrawal symptoms and four patients had no withdrawal problems at all. Ultimately all the patients came off CZP, mainly quite rapidly (3-30 days) with the initial side effects regressing totally in 11 patients.

Adolescent↗
PubMed1992

Mutation in codon 713 of the beta amyloid precursor protein gene presenting with schizophrenia.

Following reports of mutations of codon 717 in exon 17 of the amyloid precursor protein (APP) gene in early-onset familial Alzheimer's disease, we screened exon 17 for new mutations in presenile dementia. The majority of the 105 patients screened had definite or probable Alzheimer's disease, but we also included atypical cases and some chronic schizophrenics. We identified a single abnormal case--a chronic schizophrenic with cognitive defects. Sequencing revealed a C to T nucleotide substitution which produces an alanine to valine change at codon 713. We were unable to detect the mutation in the remaining members of the original cohort nor in a further 100 chronic schizophrenics and 100 non-demented controls. Nonetheless, the position of the mutation in a critical portion of the APP gene suggests that it may well prove to be pathogenic.

Amino Acid Sequence↗
PubMed1991

Hydrogen peroxide is involved in hamster sperm capacitation in vitro.

We have investigated the possibility that the generation of hydrogen peroxide (H2O2) by spermatozoa plays a physiological role during capacitation. Capacitation is defined as the incubation period required for fertilization in mammals. Capacitation culminates in an exocytotic event, the acrosome reaction (AR). Mammalian sperm generate H2O2 during aerobic incubation and do not contain catalase, the enzyme that promotes scavenging of H2O2. In the present work we show that added catalase inhibited the AR, while glucose oxidase (GO), an enzyme that generates H2O2, accelerated the onset of the AR. Direct addition of H2O2 also stimulated the AR; catalase inhibited both the stimulation by GO and by H2O2. The onset of the AR was always preceded by the appearance of hyperactivated motility. The stimulation of the AR by H2O2 was manifest 1-2 h after the addition of H2O2. Catalase added at 3 h of incubation was less effective in inhibiting the AR than catalase added at the beginning. Incubation of sperm with catalase prevented the induction of the AR by the membrane-perturbing lipid, lysophosphatidyl choline. Taken together, these results suggest that H2O2 produced by hamster sperm plays a significant role during capacitation, possibly in membrane reorganization to facilitate the fusion that takes place during exocytosis of the acrosomal contents.

Animals↗
PubMed1989

Genetic analysis of temperature-sensitive lethal mutants of Salmonella typhimurium.

We have isolated 440 mutants of Salmonella typhimurium that show temperature-sensitive growth on complex medium at 44 degrees. Approximately 16% of the mutations in these strains have been mapped to 17 chromosomal locations; two of these chromosomal locations seem to include several essential genes. Genetic analysis of the mutations suggests that the collection saturates the genes readily mutable to a ts lethal phenotype in S. typhimurium. Physiological characteristics of the ts lethal mutants were tested: 6% of the mutants can grow at high temperature under anaerobic conditions, 17% can grow when the medium includes 0.5 M KCl, and 9% of the mutants die after a 2-hr incubation at the nonpermissive temperature. Most ts lethal mutations in this collection probably affect genes required for growth at all temperatures (not merely during high temperature growth) since Tn10 insertions that cause a temperature-sensitive lethal phenotype are rare.

Chromosome Mapping↗