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Biomedical subjects

D G Wilkinson

Publications and source records attributed to D G Wilkinson.

At least 37 records · Page 2Linked to original sources
PubMed1999

Did knowledge, opinions, background, and health authority advice influence early prescribing of the novel Alzheimer's disease drug donepezil in general practice?--national postal survey.

BACKGROUND: Donepezil was licensed in the UK in February 1997 for the treatment of Alzheimer's disease. AIMS: To determine the advice from health authorities about prescribing Alzheimer's disease drugs. To determine whether the first general practitioners who prescribed donepezil in England differed from non-prescribers in terms of knowledge, opinions, background, and the prescribing-advice issued by their health authority. METHODS: National postal survey of pharmaceutical advisors. Structured postal survey of all general practitioners in England who prescribed donepezil to two or more patients within the first 6 months of launch, compared with a random sample of non-prescribers. RESULTS: Pharmaceutical advisors' survey: 75/100 pharmaceutical advisors responded, of whom 83% indicated that general practitioners should not initiate prescribing of Alzheimer's disease drugs and 63% said that they should not prescribe, even under shared care arrangements. General practitioner survey: 311/473 (66%) prescribers and 484/947 (51%) non-prescribers responded after two mailings. Prescribers were similar to non-prescribers in terms of demographic and practice characteristics, knowledge about Alzheimer's disease, diagnostic and initial management strategies, and the prescribing advice from health authorities. Prescribers were significantly more likely than non-prescribers to strongly agree/agree that new drugs should be prescribed for mild (p=0.0008) and moderate (p=0.003) Alzheimer's disease, that they should normally be initiated (p=0.003) and monitored by a general practitioner (p<0.0001), and that financial constraints should not be a consideration (p=0.0001). CONCLUSION: Early prescribers differed from non-prescribers in their opinions about using Alzheimer's disease drugs. Future research should examine methods to promote nationally equitable and rational prescribing of new drugs.

Journal Article↗
PubMed1999

PHF2, a novel PHD finger gene located on human chromosome 9q22.

We have isolated and characterized a novel PHD finger gene, PHF2, which maps to human Chromosome (Chr) 9q22 close to D9S196. Its mouse homolog was also characterized and mapped to the syntenic region on mouse Chr 13. The predicted human and mouse proteins are 98% identical and contain a PHD finger domain, eight possible nuclear localization signals, two potential PEST sequences, and a novel conserved hydrophobic domain. Northern analysis shows widespread expression of PHF2 in adult tissues, while in situ hybridization on mouse embryos reveals staining in the neural tube and dorsal root ganglia significantly above a ubiquitous low level expression signal. From its expression pattern and its chromosomal localization, PHF2 is a candidate gene for hereditary sensory neuropathy type I, HSN1.

Adult↗
PubMed1999

Eph receptors and ephrins in neural development.

Ephrins, ligands for the Eph family of receptor tyrosine kinases, are pivotal players in many developmental phenomena in both the central and peripheral nervous systems. Ephrins appear to act typically, but not exclusively, as repellents throughout development to influence axon pathfinding and topographic mapping, as well as restricting cell migration and intermingling. Recent findings are beginning to characterize the function and signaling of ephrins, as well as major roles for them in other tissues.

Animals↗
PubMed1999

The pharmacology of donepezil: a new treatment of Alzheimer's disease.

Donepezil (donepezil hydrochloride, E-2020, Aricept, Eisai), launched in March 1997, was the first drug to be marketed for the symptomatic treatment of Alzheimer's disease (AD) in the UK. It had been launched a year earlier in the US where clinicians had already had experience of tacrine (THA). Donepezil is a piperidine based, potent, specific, non-competitive and reversible inhibitor of acetylcholinesterase (AChE). It is structurally dissimilar from other established cholinesterase inhibitors, namely THA (an acridine compound) and the carbamates, physostigmine and rivastigmine and has a pharmacokinetic and tolerability profile distinct from these agents. Experimentally, donepezil inhibits AChE activity in human erythrocytes and increases extracellular acetylcholine levels in the cerebral cortex and the hippocampus of the rat. Pharmacologically, donepezil has a half-life of approximately 70 h lending itself to once daily administration. The most common adverse events reported in clinical trials have been gastrointestinal, typically nausea, vomiting, diarrhoea and constipation. Headache, dizziness and sleep disturbance have also been reported; there has been no evidence of hepatotoxicity. Clinically a number of placebo-controlled trials have shown that donepezil 5 or 10 mg daily was associated with significant improvements in cognitive function, as assessed by the Alzheimer's disease Assessment Scale-cognitive subscale (ADAS cog) after 12 or 24 weeks treatment. Significant improvements in global function and activities of daily living have also been demonstrated after 24 weeks treatment compared with placebo in patients with mild to moderate AD. Donepezil was the first rational treatment available in the UK for this disabling condition and as such received considerable attention. Much of the original attention was negative, ostensibly based on the scientific view that there was not enough published evidence to justify widespread use, but this was driven by concerns about the potentially high drug costs if all patients with AD were eligible to receive it. Considerable data have now been produced from Phase II, III and post-marketing surveillance. This drug evaluation will review the basic pharmacology of donepezil and place it in context with the trial data and the author's clinical experience with the drug.

Alzheimer Disease↗
PubMed1999

Mobility and dementia: is physiotherapy treatment during respite care effective?

BACKGROUND: Mobility problems experienced by elderly people with a dementia are associated with falls, fractures and admission to long-term care. A hospital respite care admission is therefore often seen as an opportunity to provide physiotherapy treatment. AIM: To find whether elderly people with a dementia and a mobility problem show a greater improvement in mobility skills if given physiotherapy treatment than if given non-physical activities intervention during a hospital respite admission. METHOD: A controlled randomized multicentre trial with independent blinded assessment. The Southampton Mobility Assessment (mobility score) and Two Minute Walking Test (distance walked) were undertaken at the beginning and end of the study admission and beginning of the next respite admission. Following the first assessment, participants were randomized to either physiotherapy or activities. RESULTS: Eighty-one participants, from 12 clinical centres, with a mean age of 81.9 years and CAPE I/O score of 2. During the study admission there was a non-significant trend for a lower reduction in mobility score of the physiotherapy group (Mann-Whitney; p = 0.614) and a non-significant trend for greater decrease in distance walked in the activities group (t-test; p = 0.325). DISCUSSION: The results of this trial do not support the positive changes demonstrated elsewhere. However, changes in respite care during the early stages of this trial may have produced differences between the sample for this trial and that for the pilot study. This trial was therefore underpowered. CONCLUSION: This trial suggests that future research needs to change the focus from clinical settings to presentations.

Aged↗
PubMed1998

Segmental expression of the EphA4 (Sek-1) receptor tyrosine kinase in the hindbrain is under direct transcriptional control of Krox-20.

Segmentation of the vertebrate hindbrain leads to the formation of a series of rhombomeres (r) with distinct identities. Recent studies have uncovered regulatory links between transcription factors governing this process, but little is known of how these relate to molecules mediating cell-cell signalling. The Eph receptor tyrosine kinase gene EphA4 (Sek-1) is expressed in r3 and r5, and function-blocking experiments suggest that it is involved in restricting intermingling of cells between odd- and even-numbered rhombomeres. We have analysed the cis-acting regulatory sequences of the EphA4 gene in transgenic mice and identified a 470 bp enhancer element that drives specific expression in r3 and r5. Within this element, we have identified eight binding sites for the Krox-20 transcription factor that is also expressed in r3 and r5. Mutation of these binding sites abolishes r3/r5 enhancer activity and ectopic expression of Krox-20 leads to ectopic activation of the enhancer. These data indicate that Krox-20 is a direct transcriptional activator of EphA4. Together with evidence that Krox-20 regulates Hox gene expression, our findings reveal a mechanism by which the identity and movement of cells are coupled such that sharply restricted segmental domains are generated.

Animals↗
PubMed1997

The EphA4 and EphB1 receptor tyrosine kinases and ephrin-B2 ligand regulate targeted migration of branchial neural crest cells.

BACKGROUND: During vertebrate head development, neural crest cells migrate from hindbrain segments to specific branchial arches, where they differentiate into distinct patterns of skeletal structures. The rostrocaudal identity of branchial neural crest cells appears to be specified prior to migration, so it is important that they are targeted to the correct destination. In Xenopus embryos, branchial neural crest cells segregate into four streams that are adjacent during early stages of migration. It is not known what restricts the intermingling of these migrating cell populations and targets them to specific branchial arches. Here, we investigated the role of Eph receptors and ephrins-mediators of cell-contact-dependent interactions that have been implicated in neuronal pathfinding-in this targeted migration. RESULTS: Xenopus EphA4 and EphB1 are expressed in migrating neural crest cells and mesoderm of the third arch, and third plus fourth arches, respectively. The ephrin-B2 ligand, which interacts with these receptors, is expressed in the adjacent second arch neural crest and mesoderm. Using truncated receptors, we show that the inhibition of EphA4/EphB1 function leads to abnormal migration of third arch neural crest cells into second and fourth arch territories. Furthermore, ectopic activation of these receptors by overexpression of ephrin-B2 leads to scattering of third arch neural crest cells into adjacent regions. Similar disruptions occur when the expression of ephrin-B2 or truncated receptors is targeted to the neural crest. CONCLUSIONS: These data indicate that the complementary expression of EphA4/EphB1 receptors and ephrin-B2 is involved in restricting the intermingling of third and second arch neural crest and in targeting third arch neural crest to the correct destination. Together with previous work showing that Eph receptors and ligands mediate neuronal growth cone repulsion, our findings suggest that similar mechanisms are used for neural crest and axon pathfinding.

Animals↗
PubMed1997

Hox9 genes and vertebrate limb specification.

Development of paired appendages at appropriate levels along the primary body axis is a hallmark of the body plan of jawed vertebrates. Hox genes are good candidates for encoding position in lateral plate mesoderm along the body axis and thus for determining where limbs are formed. Local application of fibroblast growth factors (FGFs) to the anterior prospective flank of a chick embryo induces development of an ectopic wing, and FGF applied to posterior flank induces an ectopic leg. If particular combinations of Hox gene expression determine where wings and legs develop, then formation of additional limbs from flank should involve changes in Hox gene expression that reflect the type of limb induced. Here we show that the same population of flank cells can be induced to form either a wing or a leg, and that induction of these ectopic limbs is accompanied by specific changes in expression of three Hox genes in lateral plate mesoderm. This then reproduces, in the flank, expression patterns found at normal limb levels. Hox gene expression is reprogrammed in lateral plate mesoderm, but is unaffected in paraxial mesoderm. Independent regulation of Hox gene expression in lateral plate mesoderm may have been a key step in the evolution of paired appendages.

Animals↗
PubMed1997

Eph-related receptors and their ligands: mediators of contact dependent cell interactions.

Recent studies of the large families of Eph-related receptor tyrosine kinases and their ligands suggest that they have key roles in embryonic development. These receptors mediate cell contact dependent signalling by binding to membrane-bound ligands, and certain ligands may themselves transduce signals. Functional studies indicate that in a number of tissues the receptors and ligands are expressed in complementary domains and mediate repulsive interactions that restrict cell and axon migration. In addition, they can also stimulate cell migration. Eph-related receptors and their ligands are therefore mediators of cell interactions required for tissue patterning and neuronal pathfinding during development. The potential clinical implications of these findings are discussed.

Animals↗
PubMed1997

Roles of Eph receptors and ephrins in neural crest pathfinding.

Neural crest cells migrate along specific pathways to their destinations and, like neuronal growth cones, must be guided by extracellular cues. One example of neural crest pathfinding is the segmental migration of branchial and trunk neural crest; this is associated with the patterning of the skeletal components of the branchial arches and of the peripheral nervous system. In this review, we discuss recent work that has implicated Eph receptors and their ephrin ligands in mediating repulsive interactions that restrict neural crest cell migration. We relate these findings to the roles of these receptors and ligands in growth cone guidance and the segmental restriction of cell movement in the hindbrain.

Animals↗
PubMed1997

Krox-20 is a key regulator of rhombomere-specific gene expression in the developing hindbrain.

The morphogenesis of the vertebrate hindbrain involves a transient segmentation process leading to the formation of reiterated organisation units called rhombomeres (r). A number of regulatory genes expressed with a rhombomere-specific pattern have been identified, including the gene encoding the transcription factor Krox-20, which is restricted to r3 and r5. We have previously demonstrated that in r3 and r5 Krox-20 directly controls the transcription of Hoxa-2 and Hoxb-2. In the present study, we provide evidence that Krox-20 is required for the expression of another Hox gene, Hoxb-3, in r5 specifically. Furthermore, the regulatory role of Krox-20 is not restricted to the control of Hox gene expression, since it is also involved in the activation of a receptor tyrosine kinase gene, Sek-1, in r3 and r5 and in the repression of the follistatin gene in r3 but not in r5. In conclusion, at least five regulatory genes belonging to different families are under the direct or indirect control of Krox-20 in r3 and/or r5 and this transcription factor therefore appears as a key regulator of gene expression in the developing hindbrain.

Animals↗
PubMed1997

Cell movements, neuronal organisation and gene expression in hindbrains lacking morphological boundaries.

Rhombomeres are segmental units of the hindbrain that are separated from each other by a specialised zone of boundary cells. Retinoic acid application to a recently segmented hindbrain leads to disappearance of posterior rhombomere boundaries. Boundary loss is preceded by changes in segmental expression of Krox-20 and Cek-8 and followed by alterations in Hox gene expression. The characteristic morphology of boundary cells, their expression of follistatin and the periodic accumulation of axons normally associated with boundaries are all lost. In the absence of boundaries, we detect no change in anteroposterior dispersal of precursor cells and, in most cases, no substantial cell mixing between former rhombomeric units. This is consistent with the idea that lineage restriction can be maintained by processes other than a mechanical barrier composed of boundary cells. Much of the early organisation of the motor nuclei appears normal despite the loss of boundaries and altered Hox expression.

Animals↗
PubMed1996

Distinct and overlapping expression patterns of ligands for Eph-related receptor tyrosine kinases during mouse embryogenesis.

Recent studies have implicated Eph-related receptor tyrosine kinases and their membrane-bound ligands in restricting or stimulating the movement of cells and axons. Members of these large families of receptors and ligands fall into two major binding specificity classes, in which the GPI-anchored subgroup of ligands can each bind to all members of a subgroup of receptors, whereas the transmembrane ligands interact with a distinct subgroup of receptors. Analysis of expression patterns is therefore important in order to understand which receptor-ligand interactions occur in vivo. We have cloned mouse orthologues of five members of the ligand family and analysed in detail their developmental expression, in comparison with each other, and with the receptor specificity class they can interact with. We find that B61, AL-1/RAGS, LERK4, and ELF-1, members of the GPI-anchored subgroup of ligands, have both distinct and overlapping aspects to their expression in early mesoderm, somites, and branchial arches; in complex, dynamic patterns in the limb; and in spatial domains and specific neurons in the CNS. Similarly, Elk-L is expressed in hindbrain segments, the roof plate, and floor plate, which overlaps with that of other transmembrane ligands, but has distinct expression in somites. The expression domains of ligands are complementary to those of the corresponding receptors in a number of tissues, including the midbrain, hindbrain, and differentiating limbs, consistent with potential roles in restricting cell movement. In addition, we find that there are some overlaps in expression of receptors and ligands, for example in somites and the early limb. Taken together with previous studies showing that Eph-related receptors also have distinct but overlapping expression patterns, these data indicate that each ligand may have stage- and tissue-specific interactions with an individual member or multiple members of the receptor family.

Amino Acid Sequence↗
PubMed1996

Elk-L3, a novel transmembrane ligand for the Eph family of receptor tyrosine kinases, expressed in embryonic floor plate, roof plate and hindbrain segments.

The Eph family of receptor tyrosine kinases has 13 distinct members and seven ligands for these receptors have been described to date. These receptors and their ligands have been implicated in regulating neuronal axon guidance and in patterning of the developing nervous system and may also serve a patterning and compartmentalization role outside of the nervous system as well. The ligands are all membrane-attached, and this attachment appears to be crucial for their normal function; five of the known ligands are linked to the membrane via a glycosyl phosphotidylinositol (GPI) linkage, while two of the ligands are transmembrane proteins. Despite the large number of Eph family receptors and ligands, they can be divided into just two major subclasses based on their binding specificities. All the GPI-anchored ligands bind and activate one subclass of the Eph receptors (that represented by Eck) while the two transmembrane ligands bind and activate the other major subclass of receptors (represented by Elk). Here we report the identification and characterization of the third, and most divergent, member of the transmembrane group of Eph ligands, which we term Elk-L3 (Elk-related receptor ligand number 3). Elk-L3 is notable for its remarkably restricted and prominent expression in the floor plate and roof plate of the developing neural tube and its rhombomere-specific expression in the developing hindbrain. The Elk-L3 gene has been localized to mouse chromosome 11 and human chromosome 17.

Amino Acid Sequence↗
PubMed1996

The expression and regulation of follistatin and a follistatin-like gene during avian somite compartmentalization and myogenesis.

We report on the normal and experimentally altered expression of two structurally related genes, Follistatin and Follistatin-like (Flik), in the somites of avian embryos. In normal chick embryos, Follistatin expression can first be seen in the cells of the dorsolateral somite quarter. During somite maturation, the cells of the dorsomedial quarter also express this gene. Within the dermomyotome it seems that only the muscle precursors are Follistatin-positive. The migrating precursors of limb and tongue muscle as well as the myotome cells show Follistatin expression. The manipulation experiments reveal that the expression of Follistatin in the somites can be inhibited by notochord signals. This effect can be mimicked by sonic hedgehog protein. Flik is expressed in the dorsomedial compartment of the somite and later on in the myotome. Unlike Follistatin, Flik expression requires signals emanating from the neural tube. Notochordal influences do not alter Flik expression. The expression of both genes does not depend on signals of intermediate or lateral mesoderm. Since the products of both genes are proposed to antagonize TGF-beta superfamily proteins during gastrulation and neuralization, we postulate that during myogenesis follistatin and flik counteract inhibiting effects of related molecules on muscle differentiation.

Animals↗
PubMed1996

Function of the Eph-related kinase rtk1 in patterning of the zebrafish forebrain.

Early during its development, the vertebrate brain is subdivided into regions that have distinct fates and correlate with the expression domains of regulatory genes, but little is known about the cell-cell interactions that establish this spatial pattern. Candidates for regulating such interactions are the Eph-related receptor tyrosine kinases (RTKs) which have spatially restricted expression in the developing brain. These RTKs may mediate cell-contact-dependent signalling by interacting with membrane-bound ligands, and have been implicated in axon repulsion and the segmental restriction of gene expression in the hindbrain, but nothing is known regarding their function in the rostral neural epithelium. Here we use a dominant-negative approach in the zebrafish embryo to interfere with the function of Rtk1, an Eph-related RTK expressed in the developing diencephalon. We find that expression of a truncated receptor leads to expansion of the eye field into diencephalic territory and loss of diencephalic structures, indicating a role for Rtk1 in patterning the developing forebrain.

Animals↗