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Biomedical subjects

J Munro

Publications and source records attributed to J Munro.

At least 37 records · Page 2Linked to original sources
PubMed2001

Polymorphisms in the genes for mGluR types 7 and 8: association studies with schizophrenia.

A dysfunctional glutamatergic system has been implicated in the pathophysiology of schizophrenia. The group III metabotropic glutamate receptor (mGluR) types 7 and 8 presynaptically inhibit glutamate release, thereby modulating glutamatergic transmission in the brain. We conducted association studies to investigate the novel Tyr433Phe (mGluR7) variant and the 2846-C/T (mGluR8) polymorphism in schizophrenia. Both variants, present at high frequencies, failed to demonstrate any significant association with schizophrenia (mGluR7 [Tyr433Phe] allele: P=0.33; genotype: P=0.63; mGluR8 [2846-C/T] allele: P=0.72; genotype: P=0.63).

Adult↗
PubMed2001

The reported use of dietary supplements (sip feeds) in hospitals in Wessex, UK.

AIMS: To assess the prevalence of the use of supplements (sip feeds) in district general, psychiatric and community hospitals in the former Wessex health region. METHOD: Cross sectional study of prevalence and determinants of supplement use in 10 district general hospitals (covering medical, surgical, orthopaedic, and elderly specialities), 4 psychiatric hospitals and 3 community hospitals. RESULTS: Overall 14% of patients were being supplemented although the variation across hospitals and specialities was wide (0%-35%); elderly care patients within district hospitals were most likely to be supplemented (20%; range 12-35%). In 34% of patients there was no documented reason as to why supplements were given. 60% of patients were not weighed on admission; 70% did not have a weight history recorded and 83% did not have a current weight recorded. Documentation regarding supplement use appeared to be recorded in an unsystematic manner. CONCLUSIONS: Many patients were not being weighed on admission and appeared to have no documentation as to why supplements were given. Given the importance of malnutrition in hospital patients a more evidence based, objective approach to assessing nutritional requirements, intake and support may be beneficial.

Age Factors↗
PubMed2001

Applications of pharmacogenetics in psychiatry: personalisation of treatment.

In spite of the lack of epidemiological information, pharmacogenetic research has produced evidence of the relationship between genes and treatment response. Genetic variants of metabolic enzymes are related to toxic reactions; polymorphisms in genes coding for drug-targeted neurotransmitter receptors influence therapeutic efficacy. Also, recent studies have shown that response to antipsychotic drugs can be predicted by looking at the individual's pharmacogenetic profile. In addition to providing the first evidence that treatment response can be predicted by looking at a core of key genes, these studies illustrate the feasibility of individualisation of psychiatric treatment.

Aryl Hydrocarbon Hydroxylases↗
PubMed2000

Systematic screening of the 14-3-3 eta (eta) chain gene for polymorphic variants and case-control analysis in schizophrenia.

The neuronal protein 14-3-3 eta is a candidate gene for schizophrenia because it maps chromosome 22q12, a region implicated in the disease by linkage analysis, and is involved in brain development. We systematically screened this gene for polymorphic variants by comparison of public EST sequence data (five cDNAs and 72 ESTs, 21,155 bp of sequence) in parallel with single-stranded conformational polymorphism analysis, and we compared these methods by using a simple power calculation. Twelve potential polymorphisms were identified from EST sequence comparison, and two of these (a 5'-VNTR and 753G/A) were confirmed by SSCP analysis and sequencing. Three additional infrequent polymorphisms (-408T/G; 177 C/G; and 989 A/G) were found by SSCP only. We next examined these variants for association with schizophrenia. One variant in untranslated region of exon 1 (-408 T/G) was found to occur more frequently in the schizophrenic subjects (8%) than the controls (3%; P = 0.01). After fivefold correction of the P value for multiple testing, marginal association was found. Haplotype analysis of pairs of polymorphisms provided no evidence for association of this gene with schizophrenia in the population studied. Am. J. Med. Genet. (Neuropsychiatr. Genet. ) 96:736-743, 2000.

14-3-3 Proteins↗
PubMed2000

Impact of NHS direct on demand for immediate care: observational study.

OBJECTIVES: To quantify the impact of NHS Direct on the use of accident and emergency, ambulance, and general practitioner cooperative services. DESIGN: Observational study of trends in use of NHS Direct and other immediate care services over 24 months spanning introduction of NHS Direct. SETTING: Three areas in England in first wave of introduction of NHS Direct, and six nearby general practitioner cooperatives as controls. SUBJECTS: All contacts with these immediate care services. MAIN OUTCOME MEASURES: Changes in trends in use after introduction of NHS Direct. RESULTS: NHS Direct received about 68 500 calls from a population of 1.3 million in its first year of operation, of which 72% were out of hours and 22% about a child aged under 5 years. Changes in trends in use of accident and emergency departments and ambulance services after introduction of NHS Direct were small and non-significant. Changes in trends in use of general practitioner cooperatives were also small but significant, from an increase of 2.0% a month before introduction of NHS Direct to -0.8% afterwards (relative change -2. 9% (95% confidence interval -4.2% to -1.5%)). This reduction in trend was significant both for calls handled by telephone advice alone and for those resulting in direct contact with a doctor. In contrast, the six control cooperatives showed no evidence of change in trend; an increase of 0.8% a month before NHS Direct and 0.9% after (relative change 0.1% (-0.9% to 1.1%)). CONCLUSION: In its first year NHS Direct did not reduce the pressure on NHS immediate care services, although it may have restrained increasing demand on one important part-general practitioners' out of hours services.

Emergency Service, Hospital↗
PubMed2000

Association analysis of the 5-HT5A gene in depression, psychosis and antipsychotic response.

The serotonergic system is targeted by both antidepressants and atypical antipsychotic drugs such as clozapine. Genetic variation in the 5-HT5A gene might be involved in susceptibility to depression, the major psychoses or in influencing clinical response to treatment. To examine this hypothesis we genotyped two polymorphisms (-19G/C; 12A/T) in the human 5-HT5A receptor gene in a sample of 269 unrelated schizophrenic patients treated with clozapine, 112 bipolar patients, 75 unipolar patients and 187 controls. After five-fold correction for multiple testing, allelic association was found with the -19G/C polymorphism and bipolar affective disorder, (p = 0.025; OR 0.56), unipolar depression (p = 0.004; OR 0.52) and schizophrenia (p = 0.036; OR 0.67) indicating a potential protective effect of the G19 allele. For the 12A/T polymorphism allelic association was observed with unipolar depression only (p = 0.004). We conclude that allelic variation in the human 5-HT5A receptor gene may be involved in susceptibility to schizophrenia and affective disorders but not in determining response to clozapine.

Alleles↗
PubMed2000

Pharmacogenetic prediction of clozapine response.

We did association studies in multiple candidate genes to find the combination of polymorphisms that give the best predictive value of response to clozapine in schizophrenic patients. A combination of six polymorphisms in neurotransmitter-receptor-related genes resulted in 76.7% success in the prediction of clozapine response (p=0.0001) and a sensitivity of 95% (+/- 0.04) for satisfactory response. These results will form the basis for a simple test to enhance the usefulness of clozapine in psychiatric treatment.

Alleles↗
PubMed2000

No influence of adrenergic receptor polymorphisms on schizophrenia and antipsychotic response.

The adrenergic system plays an important role in psychiatric disorders such as depression and schizophrenia. Antagonism of the adrenergic receptor subtypes alpha1A and alpha2A has been found to have an antipsychotic effect. Genetic mutations in these receptors could be related to the alterations in the adrenergic system observed in psychiatric patients and to failure to respond to drug antagonism. We have studied one polymorphism in the alpha1A-adrenergic receptor (Arg492Cys) and two polymorphisms in the promoter region of the alpha2A-adrenergic receptor (-1291-C/G and -261-G/A) in a sample of clozapine-treated schizophrenic patients and controls. No clear differences were observed between the different groups suggesting that these polymorphisms did not play an important role in the aetiology of the disorder or in determining antipsychotic response.

Amino Acid Substitution↗
PubMed2000

Replicative senescence as a barrier to human cancer.

There is evidence that one critically short telomere may be recognized as DNA damage and, as a consequence, induce a p53/p21WAF- and p16INK4A-dependent G1 cell cycle checkpoint to cause senescence. Additionally, senescence via a p53- and p16(INK4A)-dependent mechanism can be induced by the over- or under-stimulation of certain signalling pathways that are involved in cancer. Central to this alternative senescence mechanism is the p14ARF protein, which connects oncogene activation, but not DNA damage, to p53 activation and senescence. We find that immortal keratinocytes almost invariably have dysfunctional p53 and p16 and have high levels of telomerase, but very often express a wild-type p14(ARF). Furthermore, when normal keratinocytes senesce they show a striking elevation of p16 protein, but not of p14(ARF) or its downstream targets p53 and p21(WAF). These results suggest that p16, rather than p14(ARF), is the more important gene in human keratinocyte senescence, but do not exclude a co-operative role for p14(ARF), perhaps in the induction of senescence by activated oncogenes in neoplasia. Regardless of mechanism, these results suggest that replicative senescence acts as a barrier to human cancer development.

Carrier Proteins↗
PubMed2000

Identification of novel polymorphisms in the 5' flanking region of CYP1A2, characterization of interethnic variability, and investigation of their functional significance.

CYP1A2 activity has been demonstrated to be bimodally or trimodally distributed in several populations, consistent with a codominant or recessive functional genetic polymorphism. However, studies aimed at identifying polymorphisms in CYPIA2 have not yet adequately accounted for this distribution pattern. To search for functional polymorphisms, we performed genome-walking, polymerase chain reaction (PCR) sequencing, and cloning, and identified three novel polymorphisms in the 5' flanking region of CYP1A2: a T-3591G substitution, a G-3595T substitution, and a T-3605 insertion. The frequency of the T-3591G substitution was determined by a PCR-restriction fragment length polymorphism assay, and found to be significantly higher (P < 0.0001) in Taiwanese (allele frequency 0.128, n = 125) compared to Caucasians (0.017, n = 87) or African Americans (0.024, n = 104). The functional consequence of the T-3591G and the G-3595T substitutions was determined by site-directed mutagenesis followed by transient transfection experiments. The T-3591G mutation was shown to be nonfunctional, while although the G-3595T mutation appeared to result in an increase in promoter activity, this was only to a small degree and therefore unlikely to be important in vivo. In addition, we report 532 bases of 5' flanking sequence further upstream than that reported to date, and four sequence discrepancies compared to the original published sequence (G-3649C, deltaT-3650, deltaA-4072, and C-4093 ins).

Black or African American↗
PubMed2000

The National Adult Reading Test as a measure of premorbid IQ in schizophrenia.

OBJECTIVES: To investigate the validity of the NART as an estimate of premorbid IQ in schizophrenia. DESIGN: A within-in participants, follow-back design was adopted. METHODS: A sample of adults with schizophrenia who had presented to psychiatric services and had a measure of IQ routinely taken during childhood were traced and subject to follow-up WAIS-R and NART IQ assessment (N = 24). Measures of current IQ and NART estimated premorbid IQ were compared with the measure of IQ taken 'premorbidly', i.e. in childhood. RESULTS: There were no significant differences between childhood and adult measures of IQ. However there were significant differences between these two indices and NART estimated IQ, particularly where IQ deviated from general population means. The Vocabulary subtest of the WAIS-R performed better as an estimate of both premorbid and current IQ in the sample. CONCLUSION: Use of a word-reading test such as the NART to predict past levels of intellectual function should proceed with caution, particularly where IQ does not fall in the 'average' category. Use of more than one index of prior level of function is recommended.

Adolescent↗
PubMed2000

New labour and Britain's National Health Service: an overview of current reforms.

Britain's National Health Service (NHS) has been the subject of unprecedented market reforms, which have failed to solve its problems. The New Labour government elected in 1997 has halted the drive toward the marketization of health care and replaced cost with quality as the central concern of NHS administration and policy. Major changes are occurring in the regulation of professional activity, with profound implications for the medical profession and the health service. The authors discuss these changes and possible future problems for the NHS.

Economic Competition↗
PubMed1999

Role of the alternative INK4A proteins in human keratinocyte senescence: evidence for the specific inactivation of p16INK4A upon immortalization.

The INK4A locus on human chromosome 9p21 encodes two genes that have been implicated in replicative senescence and tumor suppression, p16INK4A and p14ARF. In contrast to p16INK4A, which is up-regulated to high levels, we were unable to detect p14ARF protein in senescent human keratinocytes. Also, p53, an established target of p14ARF, did not increase, suggesting that p14ARF is not instrumental in human keratinocyte senescence. In neoplastic keratinocyte cultures, p16INK4A inactivation was invariably associated with the immortal phenotype, and there was evidence for the inactivation of p16INK4A, independent of p14ARF, in 6 of 10 lines that lacked large homozygous deletions. In contrast, we failed to detect exon 1beta mutations or p16INK4A-independent deletions. These results emphasize the previously proposed role for p16INK4A in human keratinocyte senescence but do not rule out a supporting role for p14ARF inactivation.

3T3 Cells↗
PubMed1999

Failure to respond to treatment with typical antipsychotics is not associated with CYP2D6 ultrarapid hydroxylation.

AIMS: To investigate whether or not there is a correlation between failure to respond to typical antipsychotics and CYP2D6 ultrarapid metaboliser status. METHODS: CYP2D6 phenotype (metaboliser status) was assigned following genotyping for gene duplication, as well as for the CYP2D6*3, CYP2D6*4, and CYP2D6*5 null alleles in 235 treatment-refractory patients and 73 nonrefractory patients. RESULTS: Four (1.7%) of the 235 treatment-refractory subjects were positive on the duplication assay, but, of these, two were found to represent duplications of a null allele (CYP2D6*4 ), therefore leaving only two (0.85%) positive for duplication of a wild type allele (ultrarapid metabolisers). Three (4.1%) of the nonrefractory subjects had a genotype consistent with ultrarapid metaboliser status. Fisher's exact test gave a two-tailed P value of 0.091, i.e. a trend towards an excess of ultrarapid metabolisers in the nonrefractory group, which was in the opposite direction to that predicted by our hypothesis. CONCLUSIONS: Although the results show a trend towards an excess of ultrarapid metabolisers in the nonrefractory group, the percentages in the two groups of patients are both within the range for ultrarapid metabolisers in Caucasian populations. Our data are not consistent with ultrarapid metaboliser status being a major cause of failure to respond to typical antipsychotics.

Alleles↗
PubMed1999

Generic and condition-specific outcome measures for people with osteoarthritis of the knee.

OBJECTIVES: The aims of this study were to evaluate two condition-specific and two generic health status questionnaires for measuring health-related quality of life in patients with osteoarthritis (OA) of the knee, and to offer guidance to clinicians and researchers in choosing between them. METHODS: Patients were recruited from two settings: 118 from knee surgery waiting lists and 112 from rheumatology clinics. Four self-completion questionnaires [Western Ontario and McMaster University Osteoarthritis Index (WOMAC), Health Assessment Questionnaire (HAQ), Short Form-36 (SF-36) and Euroqol] were sent to subjects on two occasions 6 months apart. Construct validity, convergent validity, internal consistency and responsiveness were examined using primarily non-parametric methods. RESULTS: All instruments proved satisfactory in terms of ease of use, acceptability to patients, internal consistency and reliability. In the surgical group, the OA-specific WOMAC performed better than the HAQ and the generic measures in terms of validity and responsiveness to change, whereas in the rheumatology group the SF-36 was more responsive. CONCLUSION: WOMAC is the instrument of choice for evaluating the outcome of knee replacement surgery in OA. The SF-36 provides a more general insight into patients' health and may be more responsive to change than the WOMAC in a heterogeneous rheumatology clinic population. Researchers wishing to undertake an economic evaluation might consider the EQ-5D for a surgical, but not a rheumatology clinic group.

Aged↗