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Biomedical subjects

M Rigby

Publications and source records attributed to M Rigby.

At least 19 recordsLinked to original sources
PubMed2000

CEP-1347 increases ChAT activity in culture and promotes cholinergic neurone survival following fimbria-fornix lesion.

Recent evidence suggests that the activation of the Jun N-terminal kinase (JNK) signal transduction pathway may be important in neuronal responses to stresses such as trophic factor deprivation. Preventing the activation of JNK and expression of c-Jun may, therefore, be neuroprotective. Here, we report that the small molecule CEP-1347, which has been shown to inhibit the JNK signalling pathway, promotes cholinergic activity in cultured embryonic septal neurones. In vivo, we have shown that CEP-1347, administered either by sub-cutaneous (s.c.) injection or by continuous infusion, is partially neuroprotective, for cholinergic neurones in the medial septum, following fimbria-fornix transection. These data suggest that small molecules such as CEP-1347 may have beneficial effects in treating neurodegenerative diseases.

Animals↗
PubMed2000

Right ventricular long axis function in adults and children with Ebstein's malformation.

OBJECTIVES: To assess right ventricular function in adults and children with Ebstein's anomaly. DESIGN: Prospective study. SETTING: Tertiary referral centre. SUBJECTS: Fifteen patients (8 adults and 7 children) with Ebstein's anomaly and 14 healthy controls. INTERVENTIONS: Transthoracic echocardiography was performed in all. Right ventricular function was assessed from long axis M-mode recordings of the right atrio-ventricular free wall. Total systolic excursion as well as peak shortening and lenghtening rates of the right ventricle were measured. RESULTS: Children and adult patients with Ebstein's anomaly differed in terms of age at diagnosis, the adult group having been diagnosed later 19.8+/-15.8 vs. 5.9+/-6.2 years, P<0.05. Measures of right ventricular long axis function in children with Ebstein's anomaly showed a significantly reduced systolic excursion 1.4+/-0.4 vs. 2.4+/-0.53 cm, P<0.05 and peak lenghtening rate; early 8.04+/-4.3 vs. 11.8+/-2.4 cm/s and late 6.14+/-3.6 vs. 10.6+/-4.3 cm/s, P=0.05 compared to controls. In contrast, measurements of right ventricular long axis function in adults with Ebstein's anomaly showed no significant difference when compared to the control group. Transtricuspid Doppler flow velocities were not different between patient's groups and corresponding controls. CONCLUSION: The right ventricle assessed by this simple, non-invasive technique reveals a significantly reduced systolic and diastolic function in children with Ebstein's malformation compared to controls but a 'normal' right ventricular function comparable to controls in adult patients. Significant right ventricular dysfunction in children with Ebstein's anomaly could account for their earlier presentation. Long term follow up of the right ventricular abnormalities is needed in such children to discover more about the natural history of the disease.

Adult↗
PubMed2000

EDG receptors as a therapeutic target in the nervous system.

EDG receptors are a family of closely related G-protein-coupled receptors, so-called since the first family member to be cloned is encoded by an endothelial differentiation gene. Of the six family members identified, five use lysophospholipids as their endogenous ligands. The sixth receptor, EDG-6, remains an orphan. These receptors activate multiple secondary-messenger pathways involving coupling to Gi, Gq/11, and G12/13 trimeric guanine nucleotide-binding proteins and are thought to play an important role in cell growth, development and maintenance, and cytoskeletal-dependent changes. EDG receptors are expressed in most mammalian cells and tissues, each subtype having a distinct distribution pattern, raising the possibility of tissue-specific biological roles that could be explored in drug-discovery programs. In this study the distribution of EDG-receptor mRNA within the nervous system has been investigated. As seen in peripheral tissues, these receptors appear to be discretely localized within specific brain regions and cell types. For example, EDG-1, -3, -4 receptors are confined to neuronal cells, EDG-2 receptors to white matter tracts, while EDG-5 receptors appear to be expressed in various cell types, including neuronal cells, white matter tracts, and ependymal cells. EDG-6-receptor mRNA was not detected in the nervous system. Speculation as to the role of these receptors in physiological/pathophysiological processes, particularly those involving cell development, proliferation, maintenance, migration, differentiation, plasticity, and apoptosis can be made from such distribution studies. EDG receptors located in brain neuronal cells might, for example, influence apoptosis and be involved in cell rescue following ischemic damage or during the early stages of progressive neurodegenerative diseases. Those restricted to oligodendrocytes might play a crucial role in myelination and offer a potential target in the treatment of demyelinating diseases, such as multiple sclerosis. In order to explore the role of these receptors, it is necessary to identify selective compounds. To this end we have developed an agonist-induced [35S]GTP gamma S binding assay using an HEK cell line expressing a pertussis-toxin-insensitive human-EDG-2-receptor-rat-Gi alpha 1-fusion protein. Such as assay system overcomes the problems associated with the almost ubiquitous responsiveness of mammalian cells to lysophospholipid. This assay lends itself to high throughput application, opening up the possibility of identifying compounds to further probe the therapeutic potential of EDG receptor manipulation.

Animals↗
PubMed2000

Putting the 'tele' into health-care effectively.

Although the introduction of new technologies has been successful and become accepted practice in many areas of industry, traditional methods have tended to prevail in health-care. Telemedicine has been adopted by enthusiasts who recognize the potential benefits of a 'global health service'. However, the more widespread introduction of telemedicine requires considerable organizational change in the way health-care is delivered. More evaluation is required of clinical outcomes, organizational effects, benefits to health-care providers and users, and quality assurance.

Global Health↗
PubMed2000

The need to ensure that the globalization of information and telematics does not destabilize health-care worldwide.

Modern telecommunication transcends institutional, organizational and cultural boundaries. In the context of health-care, this means that information, enquiries, demands and service provision can be routed anywhere, free of institutional or natural control. The Internet makes information available to anyone regardless of its quality, source or intention. Organizationally initiated applications such as telemedicine are usually intended to reinforce local systems, but their very design and intention indicate a potential rapidly to transcend inherited but electronically ineffectual boundaries. The consequences of such uncontrolled globalization of health-care activities will range from beneficial empowerment and quality improvement, to detrimental effects such as overloading of experts, and undermining of stable health-care systems. The major unplanned societal re-engineering effects in a paper-based culture are likely to be significant and global institutions need to respond by creating positive global frameworks and policies.

Clinical Competence↗
PubMed2000

TEAC-Health--research-based recommendations for European certification of health telematics services.

Health Telematics services are now a major part of health care delivery, and of citizens' health behaviour, and will rapidly develop further in scope and significance. However, despite their pivotal position in care and treatment, they are unregulated--unlike all other aspects of health care services. This anomaly is potentially putting the citizen at risk, and also underpinning good clinical practice as clinicians are uncertain of the integrity of specific health telematics tools. The TEAC-Health project, funded by the European Commission, has studied the issues, and produced evidence-based recommendations.

Europe↗
PubMed2000

An ICT solution for community mental health--putting virtuality into the vision.

The digital age has brought about revolutionary changes in the capacity and methods of managing information. There has been an evolutionary pathway leading from information technology through informatics to communication technology. The 'nineties' has been a decade of patient empowerment fuelled by Internet access and legal rights to information. Clinicians as a whole have lagged in their adoption of the new technologies. Mental health has been seen as a particularly difficult domain because of its multi-professional and multi-locational patterns of service delivery and its traditional reliance upon narrative in the absence of bio-pathologic data. The Hospitaller Order of St John of God has been facing these challenges. The authors describe an integrated information/communication technology (ICT) which can be provided on the clinician's desktop and show that the new integrated ICT affords new opportunities for addressing the needs of community-based mental health services.

Community Mental Health Services↗
PubMed1999

A rapid method for semi-quantitative analysis of neurite outgrowth from chick DRG explants using image analysis.

Neurite outgrowth from dorsal root ganglion (DRG) explants is a method of evaluating neurotrophic activity of growth factors and neurotrophin mimetics. The drawbacks to this approach are the difficulties in quantifying the response. Neurite counts are time consuming and labour intensive, and the accuracy is often questionable due to branching and fasciculation of the neurites. We report here a method of semi-quantitative analysis of neurite outgrowth from chick DRG explants, using image analysis to quantify the area occupied by neurites emanating from the ganglion. This method is rapid, takes into account both the length and number of neurites, and is unaffected by neurite fasciculation or branching. Primary explants of chick DRGs were treated with the neurotrophins nerve growth factor (NGF) or neurotrophin-3 (NT-3) and with the compound K252a. K252b was tested for potentiation of the response to NT-3. The results show a dose dependent outgrowth of neurites from explants treated with NGF, NT-3 and K252a, and potentiation of the NT-3 response by K252b. These responses were quantified by neurite area quantification using image analysis. We conclude that neurite area measurement using image analysis provides a robust means of evaluating neurotrophic activity of growth factors and neurotrophin mimetics in vitro.

Animals↗
PubMed1999

Involvement of caspases in proteolytic cleavage of Alzheimer's amyloid-beta precursor protein and amyloidogenic A beta peptide formation.

The amyloid-beta precursor protein (APP) is directly and efficiently cleaved by caspases during apoptosis, resulting in elevated amyloid-beta (A beta) peptide formation. The predominant site of caspase-mediated proteolysis is within the cytoplasmic tail of APP, and cleavage at this site occurs in hippocampal neurons in vivo following acute excitotoxic or ischemic brain injury. Caspase-3 is the predominant caspase involved in APP cleavage, consistent with its marked elevation in dying neurons of Alzheimer's disease brains and colocalization of its APP cleavage product with A beta in senile plaques. Caspases thus appear to play a dual role in proteolytic processing of APP and the resulting propensity for A beta peptide formation, as well as in the ultimate apoptotic death of neurons in Alzheimer's disease.

Acute Disease↗
PubMed1999

Cloning of a novel G-protein-coupled receptor GPR 51 resembling GABAB receptors expressed predominantly in nervous tissues and mapped proximal to the hereditary sensory neuropathy type 1 locus on chromosome 9.

Query of the expressed sequence tag database with the rat metabotropic GABABR1A receptor amino acid sequence using the TFASTA algorithm revealed two partial cDNA fragments whose sequence information was then used to isolate by PCR a novel full-length human cDNA encoding a putative G-protein-coupled receptor (GPCR), termed GPR 51. Sequence analysis revealed that it encoded a protein of 941 amino acids, similar in size and homology to GABAB receptors followed by metabotropic glutamate receptors but not other GPCRs. GPR 51 expressed in COS-1 cells showed no specific binding for [3H](+)baclofen and when expressed in Xenopus oocyte and Xenopus melanophore functional assays showed no activity to GABA, (-)baclofen, and glutamic acid. Northern blot analysis and in situ hybridization revealed that GPR 51 transcripts were predominantly expressed in the central nervous system with highest abundance in the cortex, thalamus, hippocampus, amygdala, cerebellum, and spinal cord. In contrast, GPR 51 receptor transcripts were almost not detected in the peripheral tissues. Gene GPR 51 was localized by radiation hybrid mapping to chromosome 9, 4.81 cR from the WI-8684 marker, and proximal to the hereditary sensory neuropathy type 1 locus.

Amino Acid Sequence↗
PubMed1999

Selective NMDA NR2B antagonists induce antinociception without motor dysfunction: correlation with restricted localisation of NR2B subunit in dorsal horn.

The present study investigated the regional distribution of the N-methyl-D-aspartate (NMDA) receptor containing the NR2B subunit protein in rat lumbar spinal cord and examined whether selective NR2B antagonists would exhibit antinociception with reduced side-effect liability than subtype non-selective NMDA antagonists and anticonvulsants. Immunocytochemical studies showed the NR2B subunit had a restricted distribution, with moderate labelling of fibres in laminas I and II of the dorsal horn suggesting a presynaptic location on primary afferent fibers and possible involvement in pain transmission. In the in vivo studies, the NMDA/glycine antagonists (MK-801, 0.02-1 mg/kg i.p., L-687,414 10-300 mg/kg i.p., and L-701,324 1-10 mg/kg i.p.) and the anticonvulsant, gabapentin (10-500 mg/kg p.o.), induced rotarod deficits at antinociceptive doses. In contrast, the selective NR2B antagonists, (+/-)-CP-101,606 (1-100 mg/kg p.o.) and (+/-)-Ro 25-6981 (3-100 mg/kg i.p.) showed a significant dose window. (+/-)-CP-101,606 caused no motor impairment or stimulation in rats at doses up to 100 mg/kg p.o., which is far in excess of those inhibiting allodynia in neuropathic rats (ID50 4.1 mg/kg, p.o.). (+/-)-Ro 25-6981 also showed a significant separation (ID50 allodynia 3.8 mg/kg, i.p.), however, some disruption of rotarod performance was observed at 100 mg/kg. The anticonvulsant lamotrigine (3-500 mg/kg p.o.) also showed a good dose window. These findings demonstrate that NR2B antagonists may have clinical utility for the treatment of neuropathic and other pain conditions in man with a reduced side-effect profile than existing NMDA antagonists.

Acetates↗
PubMed1999

The management and policy challenges of the globalisation effect of informatics and telemedicine.

Managers and policy makers face new and as yet unrecognised challenges--particularly loss of control--through the application of new information technologies in healthcare. Whilst informatics and telemedicine are important developments, the potential for adverse organisational and societal effects should be recognised and anticipated. Health organisations are frequently seen as circumscribed networks, and these in turn form local alliances with related organisations. Information technologies are frequently construed as relating to operational systems within organisations, not least electronic patient record systems and diagnostic systems. These can then be linked to new generation health business systems, to provide accurate management information at low additional cost. However, this pair of assumptions is now seriously flawed, due to the effects of the latest developments in health informatics and telemedicine. In particular, telecommunications and Internet technologies render ineffectual previous external barriers of distance and national boundaries, whilst within the organisation the combination of knowledge bases with information technologies creates tendencies towards internal autonomy. Organisational and national policy control of health care face direct and radical challenges through perverse effects of otherwise beneficial developments, and early action is needed.

Database Management Systems↗
PubMed1999

Analysis of the neurotrophic effects of GPI-1046 on neuron survival and regeneration in culture and in vivo.

The putative neurotrophic effects of the immunophilin ligand GPI-1046 were evaluated in established experimental systems of neuron survival and axon growth in vitro and in vivo. GPI-1046 marginally increased neurite outgrowth of chick dorsal root ganglia in culture under conditions where a very robust effect of nerve growth factor was seen. GPI-1046 failed to protect dopaminergic neurons from 1-methyl-4-phenylpyridinium in culture or to protect cultured cortical neurons from experimentally induced apoptosis in vitro. In adult rats in vivo, daily administration of GPI-1046 (10 mg/kg, s.c.) for three days enhanced the maximal regeneration distance of both motor and large myelinated sensory axons measured using an electrophysiological assay. However, detailed morphometric analysis of these animals failed to provide evidence for an increase in axon numbers in GPI-1046-treated animals. The ability of GPI-1046 to promote the recovery of dopaminergic function following unilateral 6-hydroxydopamine lesions of the substantia nigra was also tested in rats. In the first study, the duration of amphetamine (3 mg/kg, s.c.)-induced circling, but not the maximal number of rotations, was significantly reduced in animals treated with GPI-1046 for five days (10 mg/kg/day). In a second study, testing the effects of delayed GPI-1046 administration, chronic treatment with GPI-1046 (10 mg/kg/day) for two weeks, beginning one month after surgery, did not alter circling responses. Morphometric analysis failed to reveal any changes in either the density of tyrosine hyroxylase-positive fibres in dopaminergic target areas or in cell numbers in the substantia nigra in both experiments. Thus, while GPI-1046 produced marginal effects on neurite outgrowth in dorsal root ganglia cultures and on functional paramaters of nerve regeneration in vivo, we failed to obtain evidence in support of the notion of a general neuroprotective effect of the compound or for an effect on morphologic nerve regeneration in vivo.

1-Methyl-4-phenylpyridinium↗
PubMed1999

Health informatics as a tool to improve quality in non-acute care--new opportunities and a matching need for a new evaluation paradigm.

Whilst most health care is delivered to people living at home, the focus of innovation in health informatics concepts has been largely on acute hospitals. However, delivery of services in community settings, and often related to long-term conditions, is complex, and involves multiple professions and agencies, delivery of care in several locations including home settings, and individually tailored care for episodes lasting over long periods of time. This challenge is poorly supported by current information systems. However, computer-based record systems have a major potential to improve quality of care by enabling integrated care delivery through multi-professional electronic patient records, whilst also providing quality assurance processes. In turn, though, this requires a new evaluation paradigm. Firstly, the multi-disciplinary and holistic ideal of integrated care requires an as yet inadequately developed framework to give structure to assessment of the value and utility of the data recorded and the way in which they are processed and presented, mapped to clinical processes and to the views of consumers as prime stakeholders. Secondly, a deeper and longer-term evaluation philosophy is needed which does not stop after the initial confirmation of system functioning, but continues on with a deepening into the effects on the individual clinical services, and then on the host user organisation. This paper maps out the new paradigm, and suggests specific issues which merit practical research to reset evaluation and assessment tools to this new setting and viewpoints.

Ambulatory Care↗
PubMed1999

Considerations on the quality of medical software and information services.

Fast developments in information and communication technology have made it possible to develop new services for citizens. One of the most interesting areas is health care. Medical knowledge is usually valid all over the world that makes the market global. Information services and decision support software are becoming important tools for medical professionals but also ordinary citizens are interested in health related information. It has been estimated that by the year 2010 the turnover of health care telematics industry may be close to that of the drug industry today. The nature of this global information industry is very different from any industry in history. Since there are no frontiers, no clear products and no shops in the information market, it is difficult to develop any effective legislation. However, the history of medicine has shown that health care sector cannot be free from regulation without risking citizens' health. The huge commercial potential of the Internet has already been used to promote products and services that have no proven effect on health and that may sometimes be even dangerous. In this paper we discuss the needs and possibilities to assess the quality of medical decision support software and information services. For brevity the terms medical software and medical knowledge are used, but the issues also relate to informatics systems used by any health professional, and to computerised systems used to schedule care or to organise record systems.

Decision Support Systems, Clinical↗
PubMed1999

Finding ethical principles and practical guidelines for the controlled flow of patient data.

The application of computing to health care, and particularly to electronic patient records, offers major benefits but raises issues of confidentiality and of potential misuse. Sound access control mechanisms are therefore important, but most models focus upon informed consent by the data subject. This raises challenges in mental health care, and for other vulnerable patients including those comatose, and the severely ill and temporarily distressed. Published algorithms which are used to control record access within a controlled environment therefore have value, as a means of ensuring an open and informed, yet ethically sound, solution. The paper describes the background and issues, and gives an example of such an algorithm.

Computer Security↗