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Biomedical subjects

A Wilkins

Publications and source records attributed to A Wilkins.

At least 19 recordsLinked to original sources
PubMed2001

Small GTPases in Dictyostelium: lessons from a social amoeba.

Although the process of sequencing the Dictyostelium genome is not complete, it is already producing surprises, including an unexpectedly large number of Ras- and Rho-subfamily GTPases. Members of these families control a wide variety of cellular processes in eukaryotes, including proliferation, differentiation, cell motility and cell polarity. Comparison of small GTPases from Dictyostelium with those from higher eukaryotes provides an intriguing view of their cellular and evolutionary roles. In particular, although mammalian Ras proteins interact with several signalling pathways, the Dictyostelium pathways appear more linear, with each Ras apparently performing a specific cellular function.

Animals↗
PubMed2000

A novel Dictyostelium RasGEF is required for normal endocytosis, cell motility and multicellular development.

BACKGROUND: Dictyostelium possesses a surprisingly large number of Ras proteins and little is known about their activators, the guanine nucleotide exchange factors (GEFs). It is also unclear, in Dictyostelium or in higher eukaryotes, whether Ras pathways are linear, with each Ras controlled by its own GEF, or networked, with multiple GEFs acting on multiple Ras proteins. RESULTS: We have identified the Dictyostelium gene that encodes RasGEFB, a protein with homology to known RasGEFs such as the Son-of-sevenless (Sos) protein. Dictyostelium cells in which the gene for RasGEFB was disrupted moved unusually rapidly, but lost the ability to perform macropinocytosis and therefore to grow in liquid medium. Crowns, the sites of macropinocytosis, were replaced by polarised lamellipodia. Mutant cells were also profoundly defective in early development, although they eventually formed tiny but normally proportioned fruiting bodies. This defect correlated with loss of discoidin Igamma mRNA, a starvation-induced gene, although other genes required for development were expressed normally or even precociously. RasGEFB was able to rescue a Saccharomyces CDC25 mutant, indicating that it is a genuine GEF for Ras proteins. CONCLUSIONS: RasGEFB appears to be the principal activator of the RasS protein, which regulates macropinocytosis and cell speed, but it also appears to regulate one or more other Ras proteins.

Amino Acid Sequence↗
PubMed2000

Dictyostelium RasD is required for normal phototaxis, but not differentiation.

RasD, a Dictyostelium homolog of mammalian Ras, is maximally expressed during the multicellular stage of development. Normal Dictyostelium aggregates are phototactic and thermotactic, moving towards sources of light and heat with great sensitivity. We show that disruption of the gene for rasD causes a near-total loss of phototaxis and thermotaxis in mutant aggregates, without obvious effects on undirected movement. Previous experiments had suggested important roles for RasD in development and cell-type determination. Surprisingly, rasD(-) cells show no obvious changes in these processes. These cells represent a novel class of phototaxis mutant, and indicate a role for a Ras pathway in the connections between stimuli and coordinated cell movement.

Animals↗
PubMed2000

Purification and cloning of phosphatidylinositol transfer proteins from Dictyostelium discoideum: homologues of both mammalian PITPs and Saccharomyces cerevisiae sec14p are found in the same cell.

Soluble phosphatidylinositol transfer proteins (PITPs) have important roles in lipid-mediated signalling as well as in membrane traffic. Two PITPs (alpha and beta) have been cloned from mammalian cells, which are unrelated in sequence to yeast PITP (the product of the SEC14 gene). However, all three PITPs can perform interchangeably to reconstitute function in mammalian cells. We have now purified the major PITP from the cytoplasm of Dictyostelium discoideum and cloned the gene. This protein, DdPITP1, is homologous with mammalian PITPalpha and PITPbeta. We have also cloned a second gene (DdPITP2) related in sequence to DdPITP1. In addition, an independently cloned cDNA encodes a relative of the SEC14 family of yeast PITPs. DdPITP1, DdPITP2 and DdSec14 proteins were all able to mediate the transfer of PtdIns from one membrane compartment to another; they thus exhibited the hallmark of PITPs. Secondly, all three PITPs were able to rescue phospholipase C-mediated phosphoinositide hydrolysis in PITP-depleted HL60 cells, indicating that all three PITPs were capable of stimulating phosphoinositide synthesis. The identification of PITPs related to both mammalian PITPs and yeast Sec14p in a single organism will provide a unique opportunity to examine the functions of this class of protein with genetic approaches.

Amino Acid Sequence↗
PubMed2000

Maternal HIV-1 and HIV-2 infection and child survival in The Gambia.

OBJECTIVE: To compare the survival of children born to HIV-1 or HIV-2 seropositive mothers with that of children born to HIV-seronegative mothers and to evaluate risk factors for mortality. DESIGN: Physician-blinded prospective study. METHODS: One hundred and one HIV-1-seropositive, 243 HIV-2-seropositive pregnant women, and 468 HIV-seronegative women (control group) matched by age, parity, and health centre, were followed up in a study of mother-to-child transmission of HIV. Mothers and children were seen at 2 and 6 months of age and subsequently followed at 3-monthly intervals up to 18 months of age. HIV infection in children was diagnosed by polymerase chain reaction at 2, 9 or 18 months and by antibody assays at 18 months. RESULTS: Fifteen per cent of children born to HIV-1-infected mothers died compared with 7% of children born to HIV-2-infected mothers [hazard ratio, 2.3; 95% confidence interval (CI), 1.1-4.7; P = 0.02], and 6% of HIV-seronegative mothers (hazard ratio, 2.6; 95% CI, 1.4-5.0; P = 0.003). Six of the 17 children known to be HIV-1 infected died compared with none among the eight HIV-2-infected children (P = 0.13). High proviral load in the babies, high antenatal maternal RNA plasma viral load, and maternal death increased child mortality significantly. CONCLUSIONS: More children born to HIV-1-infected mothers died in comparison with those born to HIV-2-infected mothers or to mothers from the control group. This effect was due to excess death in HIV-1-infected infants which was associated with a high viral load in the affected mother and child.

Female↗
PubMed2000

Tropisetron reduces postoperative vomiting in children undergoing tonsillectomy.

In this patient, parent and investigator blinded, randomized, placebo-controlled study, children undergoing tonsillectomy (mean age 6.4 years) received either intravenous placebo (n=36) or tropisetron 0.2 mg.kg-1 up to 5 mg (n=35) at induction of anaesthesia with halothane, nitrous oxide and oxygen. Morphine and paracetamol were given in theatre for postoperative pain. Episodes of vomiting were recorded during the first 24 h after surgery. Intravenous tropisetron was significantly (P<0.001, chi-squared) more effective than placebo in controlling the incidence and frequency of emesis during the first 24 h: vomiting was reduced from 89% to 46% and the mean number of vomits from 4.6 to 2.4. Minor side-effects occurred equally in both the placebo and active groups. Intravenous tropisetron is an effective and safe antiemetic for reducing postoperative vomiting in children undergoing tonsillectomy or adenotonsillectomy.

Anesthesia, Inhalation↗
PubMed2000

The Dictyostelium RasS protein is required for macropinocytosis, phagocytosis and the control of cell movement.

Endocytosis and cell migration both require transient localised remodelling of the cell cortex. Several lines of evidence suggest a key regulatory role in these activities for members of the Ras family of small GTPases. We have generated Dictyostelium cells lacking one member of this family, RasS, and the mutant cells are perturbed in endocytosis and cell migration. Mutant amoebae are defective in phagocytosis and fluid-phase endocytosis and are impaired in growth. Conversely, the rasS(-)cells show an enhanced rate of cell migration, moving three times faster than wild-type controls. The mutant cells display an aberrant morphology, are highly polarised, carry many elongated actin protrusions and show a concomitant decrease in formation of pinocytic crowns on the cell surface. These morphological aberrations are paralleled by changes in the actin cytoskeleton, with a significant proportion of the cortical F-actin relocalised to prominent pseudopodia. Rapid migration and endocytosis appear to be mutually incompatible and it is likely that RasS protein is required to maintain the normal balance between these two actin-dependent processes.

Animals↗
PubMed1999

Serotonergic dysfunction in women with pure premenstrual dysphoric disorder: is the fenfluramine challenge test still relevant?

The fenfluramine (FEN) neuroendocrine challenge paradigm, which involves measuring the response of prolactin (PRL) release to an oral challenge dose of FEN, provides a means of assessing serotonin (5-HT) function. The purpose of this study was to ascertain the role of 5-HT in premenstrual dysphoric disorder (PMDD) by measuring: (1) PRL and cortisol (CORT) responses to FEN; and (2) platelet 3H-imipramine binding levels, in females with pure PMDD (without a past or present comorbid mood disorder) in comparison to healthy controls. FEN challenge tests were administered to nine female patients with pure PMDD and nine healthy female controls during the follicular and late luteal phases of a menstrual cycle. There were no differences in the PRL response to FEN for women with PMDD compared to healthy controls. However, the trend toward a delayed response to FEN and a significant negative correlation between delta(max) PRL and basal CORT in patients but not in controls during both phases of the menstrual cycle suggest an underlying 5-HT dysfunction in patients as compared to controls. This is further supported by the finding of significantly lower Bmax 3H-imipramine binding levels in the patients during the late luteal phase.

Journal Article↗
PubMed1999

An evaluation of the informed consent procedure used during a trial of a Haemophilus influenzae type B conjugate vaccine undertaken in The Gambia, West Africa.

It has recently been debated whether it is possible or desirable to have one internationally recognised standard of "informed consent" or whether research ethics should be adapted to the culture and educational level of the study population. This study examined the attitudes of the Gambian people to consent to medical research, and evaluated the informed consent process used in a major efficacy trial of a Haemophilus influenzae vaccine. Consent was requested after parents had received a verbal explanation and an information sheet which described the vaccine trial in a local language. A semi-structured interview was conducted with 137 acceptors and 52 refusers. Certain points of knowledge were recalled well by the acceptors; 90% knew the purpose of the vaccine was to prevent disease, but the placebo control design was understood by only 10%. The prime motive for consenting was to receive the HIB vaccine (93%) and that for refusing was that the vaccine was experimental (35%) and might have unknown side effects (29%). Although parents took advice from researchers (50%), health workers (24%), friends (16%) and family (12%), in all cases the decision was made by one of the child's parents. Only 1% of parents sought the opinion of traditional or religious leaders. The principles of informed consent, that it should be free, autonomous and informed were affirmed by this community. Therefore, in The Gambia, the international code of informed consent is appropriate.

Adult↗
PubMed1999

Medical technology assessment photic stimulation--standardization of screening methods.

RATIONALE: In many EEG laboratories in Europe, intermittent photic stimulation (IPS) is not performed routinely, and consequently, great variation exists in the type of photo stimulator used, the methodology employed, and the interpretation of the EEG curves, thus leading to different outcomes. METHODOLOGY: It was decided to hold a consensus meeting with experts in the field of photic stimulation from various European countries. This meeting was held at the Stichting Epilepsie Instellingen Nederland, Heemstede, the Netherlands. The consensus reached was presented and discussed at the 9th European Congress of Clinical Neurophysiology in Ljubjana in June 1998. RESULTS: Patients should be positioned at a distance of 30 cm from the photic stimulator (nasion to lamp) with dim surrounding lights, just enough to see the patient. Flashes should be delivered in separate trains of 10 s for each frequency, with intervals of 7 s minimum. First stimulation occurs with eyes open followed after 5 s by eye closure, while starting at 1 Hz progressing to 20 Hz, unless generalised epileptiform discharges are evoked at a lower frequency. Then, frequencies should start at 60 Hz decreasing to 25 Hz. The following frequencies should be used: 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 60, 50, 40, 30 and 25 Hz. The total duration is a maximum of 6 min (patients without a reaction to IPS). In interpreting the evoked responses, a clear distinction should be made between epileptiform responses confined to the occipital area (OSW), starting occipitally and spreading to frontal regions (OGSW), or generalised from the start (GSW). Other responses include generalised spikes (OR). CONCLUSION: This standard is safe, relatively quick, simple and reliable. Comparison of data within patients and between patients of various laboratories will also be possible. This will improve the quality of the care of the individual patient and make collaborative research possible.

Electroencephalography↗
PubMed1999

Both coloured overlays and coloured lenses can improve reading fluency, but their optimal chromaticities differ.

Some individuals read more fluently when the text is coloured: i.e., when coloured sheets of plastic (overlays) are placed upon the page, or when coloured lenses are worn. Overlays provide a surface colour whereas lenses mimic a change in the colour of a light source. The neural mechanisms that underlie colour constancy ensure that the chromaticity of overlays and lenses is processed differently by the visual system. We investigated (1) the relationship between the optimal colours of overlays and lenses, and (2) how reading rate is affected by a particular colour in overlays and lenses. In 100 patients we noted (1) the overlay(s) chosen from among the 29 combinations of the 10 IOO Intuitive Overlays which sample chromaticity systematically and (2) the chromaticity co-ordinates of the lenses subsequently chosen using the intuitive Colorimeter, a device providing a light source that can be adjusted in hue, saturation and luminance independently. The relationship between the chromaticities of the overlays and the lenses showed considerable variation. In a second study, patients attending the Specific Learning Difficulties clinic at the Institute of Optometry, London, were given overlays to use for two months. Seventeen who derived benefit were examined using the Intuitive Colorimeter. Patients were asked to read aloud randomly ordered common words (Wilkins Rate of Reading Test): (1) with no colour, (2) with the chosen overlay, (3) with lenses matching the chosen overlay and (4) with lenses matching the Colorimeter setting. The aids increased reading rate significantly only in conditions (2) and (4). There was no significant improvement when lenses matching the overlay colour were used, and under this condition the reading rate was significantly poorer than in conditions (2) and (4). The colour of a lens will improve reading only if it is selected under conditions that mimic a change in the colour of a light source: coloured overlays give no clinically reliable guide to optimal lens colour.

Color↗
PubMed1999

Coloured overlays, text, and texture.

In four studies children were asked to read aloud a passage of randomly ordered common words with and without a coloured sheet of plastic (overlay) placed upon the page. The children's rate of reading increased with the overlay, for some children more than for others. The children were also asked to undertake a test of texture segmentation in which targets consisting of a structured texture had to be distinguished from within a random background texture. The texture segmentation was improved when the overlay was used, again for some children more than for others. The improvement in texture segmentation was, in general, correlated with the improvement in rate of reading. Slower readers were generally poorer at texture segmentation. The implications for reading, for texture segmentation, and for clinical tests of vision are discussed.

Adolescent↗
PubMed1999

Photic stimulation: standardization of screening methods.

PURPOSE: Differences in methodology of intermittent photic stimulation within and between countries in Europe make collaborative research and interpretation of results difficult. METHOD: Experts in the field of photic stimulation from European countries have given an overview of methods used in routine photic stimulation. A consensus meeting was organized in May 1996 in the Netherlands. RESULTS: Methodology, including specification of a photo stimulator, procedure of photic stimulation, and interpretation of EEG results, has been defined according to available scientific and clinical knowledge. CONCLUSIONS: Consensus was reached in setting up a safe, quick, simple and reliable method to determine whether or not patients are photosensitive. A specification of an international standard for intermittent photic stimulation in the routine EEG examination is given with the purpose of improving patient care and facilitating collaborative research.

Electroencephalography↗
PubMed1999

Pericardial, retroperitoneal, and pleural fibrosis induced by pergolide.

Three patients with Parkinson's disease are described who developed pericardial, retroperitoneal, and pleural fibrosis associated with pergolide treatment. Surgical intervention was required in all three cases, either to reach a tissue diagnosis or for potentially life threatening complications. Symptoms emerged on average 2 years after the institution of treatment, and were sufficiently non-specific to cause significant delays in diagnosis in all cases. The erythrocyte sedimentation rate (ESR) was raised in the two patients in whom it was measured. Serosal fibrosis is a rarely reported adverse effect of pergolide treatment, although it is well described with other dopamine agonists. We suggest that patients with Parkinson's disease who receive pergolide treatment should be regularly monitored for the development of such complications.

Aged↗
PubMed1999

The virtual workplace.

Explore the source record for details and available documents.

Computer Communication Networks↗
PubMed1998

Effects of electroconvulsive therapy and desipramine on neuroendocrine responses to the clonidine challenge test.

OBJECTIVE: To investigate responses to the clonidine challenge test in depression, and after electroconvulsive therapy (ECT) or desipramine treatment for depression, in order to determine the usefulness of noradrenergic responses to clonidine as a state or trait marker in depression. PATIENTS: Twenty-six patients with depression and 15 control subjects. SETTING: The psychiatric ward of St. Joseph's Hospital in Hamilton. INTERVENTIONS: In the patients with depression: clonidine challenge pre- and post-treatment with ECT or desipramine. In the controls: 2 clonidine challenge tests 4 to 8 weeks apart. OUTCOME MEASURES: The primary measure was the growth hormone response to the clonidine challenge. Plasma norepinephrine, 3-methoxy-4-hydroxyphenylglycol (MHPG), cortisol, blood pressure, pulse and sedation levels were examined in subgroups of participants as secondary measures. RESULTS: The pre-treatment growth hormone response to clonidine was significantly more blunted in patients than in controls (p = 0.02). This response improved in both treatment groups after therapy and, although it remained decreased, there was no longer a significant difference in response between the patients and the controls. In the patients, a decreased growth hormone response to clonidine at baseline was correlated with response to treatment. Of the secondary measures, patient baseline norepinephrine levels were significantly elevated pre- and post-treatment, although there were no significant group-by-time challenge effects. MHPG levels were not significantly different pre- and post-treatment between patients and controls. Baseline blood pressure and pulse were elevated in the patients pre- and post-treatment. These differences were not statistically significant and did not change after treatment. Sedation levels were not significantly different among the groups at baseline. Clonidine-induced sedation occurred significantly earlier in the patients pretreatment and improved to the range of the controls after treatment. Pretreatment cortisol response was significantly more blunted in the patients who received ECT than in the controls; however, the group-by-time effect post-treatment was no longer significant. DISCUSSION: Treatment with either desipramine or ECT modified noradrenergic functioning in patients with depression, as assessed by growth hormone response to the clonidine challenge. In the patients, a decreased growth hormone response at baseline was correlated with clinical response. Changes between pre- and post-treatment measures suggest that this challenge test may not be sensitive enough to serve as a trait marker but may correlate with the state of depression in a subpopulation of these patients.

Adrenergic alpha-Agonists↗
PubMed1997

Rate of decline of percentage CD4+ cells is faster in HIV-1 than in HIV-2 infection.

Increasing evidence suggests that the pathogenesis of HIV-1 is different from that of HIV-2. Thus, we have measured, longitudinally at various times over a median follow-up of 2.1 years, the percentage CD4+ cells of 94 patients infected with HIV-1 and 164 patients infected with HIV-2. The pattern of decline of CD4% over time was linear for patients with either infection. Multilevel statistical modeling techniques showed that after stratifying for HIV status, the rate of decline of CD4% was faster among patients who died than among those who survived (difference in rate of decline = 2.34% CD4+ cells/year; p = 0.0002). After stratifying for survival status, the rate of decline was faster and less variable among patients infected with HIV-1 than among patients infected with HIV-2 (difference in rate of decline = 1.12% CD4+ cells/year; p = 0.05). The proportion of patients who showed no fall in CD4+ cells was higher in HIV-2 than in HIV-1 infection (p = 0.026). These data suggest fundamental differences between the two infections, with HIV-1 being more pathogenic resulting in a faster and more homogeneous rate of decline than HIV-2. In HIV-2 infection, disease in many patients progresses slowly, but in some the advance is just as fast as that in HIV-1 infection. The reasons for this marked heterogeneity need elucidation to understand the disease and to target therapeutic interventions against HIV-2 in those most at risk.

Acquired Immunodeficiency Syndrome↗