Biomedical subjects

R Murray

Publications and source records attributed to R Murray.

At least 19 recordsLinked to original sources

PubMed2001

No association between T102C polymorphism of serotonin-2A receptor gene and clinical phenotypes of Chinese schizophrenic patients.

Serotonin dysfunction has been implicated in the pathogenesis of schizophrenia. Previous studies have shown an association between the T102C polymorphism of the 5HT2a receptor gene and schizophrenia. However, negative findings have also been reported. One possible explanation for such discrepancy is disease heterogeneity due to the current limitations in the diagnosis of schizophrenia. We conducted a case-control study of the T102C polymorphism with detailed characterisation of the clinical phenotypes to investigate the possible association with schizophrenia not only at the diagnostic level, but also with reference to other clinical phenotypes potentially related to serotonin dysfunction. Four hundred and seventy-one biologically unrelated schizophrenic patients and 523 unrelated healthy controls of Han Chinese descent in Hong Kong were compared for genotypes and allele frequencies of the T102C polymorphism by PCR amplification and restriction analysis. No evidence of association was detected at the diagnostic level and various clinical phenotypes. However, we found a trend association with small effect size between genotype 102T/102C and patients with better verbal fluency and less motor co-ordination soft neurological signs. There is a need for future large-scale studies on the possible associations between genetic polymorphisms and neurocognitive function impairments in schizophrenia.

Adolescent↗

PubMed2001

Reducing violence in severe mental illness: randomised controlled trial of intensive case management compared with standard care.

OBJECTIVES: To establish whether intensive case management reduces violence in patients with psychosis in comparison with standard case management. DESIGN: Randomised controlled trial with two year follow up. SETTING: Four inner city community mental health services. PARTICIPANTS: 708 patients with established psychotic illness allocated at random to intervention (353) or control (355) group. INTERVENTION: Intensive case management (caseload 10-15 per case manager) for two years compared with standard case management (30-35 per case manager). MAIN OUTCOME MEASURE: Physical assault over two years measured by interviews with patients and case managers and examination of case notes. RESULTS: No significant reduction in violence was found in the intensive case management group compared with the control group (22.7% v 21.9%, P=0.86). CONCLUSIONS: Intensive case management does not reduce the prevalence of violence in psychotic patients in comparison with standard care.

Adult↗

PubMed2001

IL-7 is critical for homeostatic proliferation and survival of naive T cells.

In T cell-deficient conditions, naive T cells undergo spontaneous "homeostatic" proliferation in response to contact with self-MHC/peptide ligands. With the aid of an in vitro system, we show here that homeostatic proliferation is also cytokine-dependent. The cytokines IL-4, IL-7, and IL-15 enhanced homeostatic proliferation of naive T cells in vitro. Of these cytokines, only IL-7 was found to be critical; thus, naive T cells underwent homeostatic proliferation in IL-4(-) and IL-15(-) hosts but proliferated minimally in IL-7(-) hosts. In addition to homeostatic proliferation, the prolonged survival of naive T cells requires IL-7. Thus, naïve T cells disappeared gradually over a 1-month period upon adoptive transfer into IL-7(-) hosts. These findings indicate that naive T cells depend on IL-7 for survival and homeostatic proliferation.

Animals↗

PubMed2001

Structural magnetic imaging of the hippocampus in early onset schizophrenia.

BACKGROUND: Previous literature suggests that hippocampal volume reductions in schizophrenia may occur either during adolescence or at the point of transition to overt psychosis. The authors tested these hypotheses by examining the hippocampal formation in adolescents with recent onset schizophrenia. METHODS: We compared the volumes of the left and right hippocampus, obtained using stereologic methods from magnetic resonance brain images, from 40 adolescents with recent onset schizophrenia to those of an equal number of matched healthy control subjects. Symptoms were rated using the Positive and Negative Syndrome Scale. RESULTS: Compared with control subjects, adolescents with schizophrenia had reduced whole brain volume. After adjusting for brain volume, no group differences were observed in hippocampal volume. Duration of illness was negatively correlated with the volume of the left hippocampus. We found no effect of pregnancy and birth complications or family history of psychosis on hippocampal volumes. There was a negative correlation between severity of psychopathology and hippocampal volumes, which was significant for negative symptoms. CONCLUSIONS: Specific hippocampal volume reductions in early onset schizophrenia do not seem to predate the onset of or to occur at the point of transition to psychosis but may develop in adolescence during the early stages of the illness.

Adolescent↗

PubMed2001

Familiality of symptom dimensions in schizophrenia.

The division of schizophrenic symptoms into three core dimensions - psychomotor poverty, reality distortion, and disorganisation - is well established. When factor analytic studies have included affective symptoms they have identified two additional dimensions - manic and depressive. Whether these five dimensions represent underlying psychopathology of a genetic or environmental aetiology remains unclear. The aims of this study were to perform factor analysis of symptoms in a group of familial schizophrenic patients and to investigate the familiality of the symptom dimensions identified, and their relationship to clinical characteristics. Symptoms were recorded, using the Operational Criteria Checklist for Psychotic Illness, for 155 Caucasian subjects with an RDC diagnosis of schizophrenia, schizoaffective disorder, or psychosis of unknown origin, from 61 families multiply affected with schizophrenia. Factor analysis indicated five symptom dimensions: depressive, manic, reality distortion, disorganisation, and psychomotor poverty. The psychomotor poverty, disorganisation, and manic dimensions were shown to be familial. Psychomotor poverty, disorganisation, and reality distortion were all associated with deterioration from premorbid functioning and chronic course of the disorder. In addition, psychomotor poverty was significantly related to poor premorbid functioning, as well as to single marital status and unemployment at onset. Disorganisation was significantly related to single marital status and unemployment at onset. The familiality of the psychomotor poverty, disorganisation, and manic dimensions supports their use in the delineation of homogeneous subsets for genetic studies.

Adult↗

PubMed2001

Cerebral mycobacterium avium infection in an HIV-infected patient following immune reconstitution and cessation of therapy for disseminated mycobacterium avium complex infection.

Reported here is a case of cerebral Mycobacterium avium complex infection that occurred in an HIV-infected patient, who had been treated for disseminated infection and had discontinued clarithromycin and ethambutol following a significant rise in his CD4+ T-cell count after starting highly active antiretroviral therapy. He responded well to excision of the lesion and reinstitution of multidrug therapy. Caution should be exercised when considering ceasing maintenance therapy for disseminated Mycobacterium avium complex infection in HIV-infected patients who demonstrate an apparently good immunologic response to highly active antiretroviral therapy, as this response may not necessarily restore protective immunity against all opportunistic pathogens.

AIDS-Related Opportunistic Infections↗

PubMed2001

Role of anti-aromatase agents in postmenopausal advanced breast cancer.

PURPOSE: Endocrine therapy is a well-recognized approach to the treatment of postmenopausal patients with advanced breast cancer, particularly those with estrogen receptor-positive tumors. The availability of anti-aromatase agents, both reversible (nonsteroidal) and irreversible (steroidal), provides clinicians with additional hormonal treatment options. METHODS: A MEDLINE search was conducted to identify studies that evaluated anti-aromatase therapy in the treatment of postmenopausal women with advanced breast cancer. In selecting studies, priority was given to randomized, controlled trials. RESULTS: Tamoxifen is the standard first-line therapy for advanced breast cancer. However, recent results have demonstrated the efficacy of newer anti-aromatase agents in this setting. Among patients who have progressed after tamoxifen therapy, anti-aromatase agents have emerged as first choice therapy based on their better tolerability and improved efficacy compared with megestrol acetate. Exemestane and anastrozole (irreversible and reversible anti-aromatase agents, respectively) have demonstrated survival benefits over megestrol acetate in second-line therapy. Anti-aromatase agents have also demonstrated efficacy in patients who have failed multiple hormonal therapies. Based on these data, an algorithm for the treatment of postmenopausal women with advanced breast cancer is proposed. CONCLUSIONS: The enhanced tolerability and superior efficacy of anti-aromatase inhibitors compared with megestrol acetate has resulted in these agents becoming the endocrine treatment of choice for women with advanced breast cancer who have progressed after tamoxifen treatment. The increased use of tamoxifen in the adjuvant setting and the demonstrated activity of aromatase inhibitors in first-line therapy will further increase the role of these agents.

Aged↗

PubMed2001

Does socioeconomic status predict course and outcome in patients with psychosis?

BACKGROUND: We examined the relationship between socioeconomic status (SES) and course and outcome of patients with psychosis. Two hypotheses were examined: a) patients with higher best-ever SES will have better course and outcome than those with lower best-ever SES, and b) patients with greater downward drift in SES will have poorer course and outcome than those with less downward drift. METHOD: Data were drawn from the baseline and 2-year follow-up assessments of the UK700 Case Management Trial of 708 patients with severe psychosis. The indicators of SES used were occupational status and educational achievement. Drift in SES was defined as change from best-ever occupation to occupation at baseline. RESULTS: For the baseline data highly significant differences were found between best-ever groups and negative symptoms (non-manual vs. unemployed--coef -10.5, p=0.000, 95% CIs 5.1-15.8), functioning (non-manual vs. unemployed--coef -0.6, p=0.000, 95% CIs 0.3 to -0.8) and unmet needs (manual vs. unemployed - coef 0.5, p=0.004, 95% CIs 0.2-0.9). No significant differences between best-ever groups were found for days in hospital, symptoms, perceived quality of life and dissatisfaction with services. Significant differences for clinical and social variables were found between drift and non-drift SES groups. There were no significant findings between educational groups and clinical and social variables. CONCLUSIONS: Best-ever occupation, but not educational qualifications, appeared to predict prognosis in patients with severe psychosis. Downward drift in occupational status did not result in poorer illness course and outcome.

Adult↗

PubMed2001

Testing hypotheses on specific environmental causal effects on behavior.

There have been strong critiques of the notion that environmental influences can have an important effect on psychological functioning. The substance of these criticisms is considered in order to infer the methodological challenges that have to be met. Concepts of cause and of the testing of causal effects are discussed with a particular focus on the need to consider sample selection and the value (and limitations) of longitudinal data. The designs that may be used to test hypotheses on specific environmental risk mechanisms for psychopathology are discussed in relation to a range of adoption strategies, twin designs, various types of "natural experiments," migration designs, the study of secular change, and intervention designs. In each case, consideration is given to the need for samples that "pull-apart" variables that ordinarily go together, specific hypotheses on possible causal processes, and the specification and testing of key assumptions. It is concluded that environmental risk hypotheses can be (and have been) put to the test but that it is usually necessary to use a combination of research strategies.

Adult↗

PubMed2001

Executive summary: developing objectives, content, and competencies for the training of emergency medical technicians, emergency physicians, and emergency nurses to care for casualties resulting from nuclear, biological, or chemical incidents.

STUDY OBJECTIVE: The task force assessed the needs, demands, feasibility, and content of training for US civilian emergency medical responders (paramedics, nurses, and physicians) for nuclear/biological/chemical (NBC) terrorism. METHODS: A task force representing key professional organizations, stakeholders, and disciplines involved in emergency medical response conducted an iterated instructional-design analysis on the feasibility and content of such training with input from educational professionals. We then analyzed 6 previously developed training courses for their congruence with our recommendations. RESULTS: The task force produced descriptions of learning groups, content and learning objectives, and barriers and challenges to NBC education. Access to training and sustainment of learning (retention of knowledge) represent the significant barriers. The courses analyzed by the task force did not meet all objectives and challenges addressed. CONCLUSION: The task force recommends training programs and materials need to be developed to overcome the identified barriers and challenges to learning for these audiences. Furthermore, the task force recommends incorporating NBC training into standard training programs for emergency medical professionals.

Bioterrorism↗

PubMed2001

Does cisapride influence cardiac rhythm? Results of a United States multicenter, double-blind, placebo-controlled pediatric study.

BACKGROUND: Major concerns about serious cardiac side effects underlie the recent decision by the FDA and Janssen Pharmaceutica (Titusville, NJ) to make cisapride available only through a limited access program. Concerns have grown despite the fact that most instances of prolonged QTc and other ventricular arrhythmias occurred while the drug was used concomitantly with contraindicated drugs. This study sought to analyze electrocardiograms (ECGs) from a multicenter pediatric study and to identify abnormalities in QTc interval associated with cisapride use. METHODS: Children between 6 months and 4 years of age were enrolled if they manifested symptoms of gastroesophageal reflux not responding to medical therapy for at least 6 weeks. In 49 subjects, ECGs obtained before and after randomization to receive 0.2 mg/kg dose three times daily or placebo were reviewed independently and blindly by two pediatric cardiologists. Placebo and active drug groups were compared for QTc and for change in QTc from baseline values after 3 to 8 weeks of treatment. RESULTS: Mean QTc among patients taking the drug was 408+/-18 ms. None was higher than 450 ms. Change between baseline and subsequent QTc at 3 to 8 weeks of treatment was 2+/-20 ms. CONCLUSIONS: In our study group of children without underlying cardiac disease or electrolyte imbalance, cisapride was found to have no significant effect on cardiac electrical function compared with placebo. These results are consistent with the drug's record of exceedingly infrequent cardiac events. Because the availability of this prokinetic is threatened, its safety and the safety and efficacy of alternative treatment options (including surgery) should be studied further.

Arrhythmias, Cardiac↗

PubMed2001

Superior temporal gyrus abnormalities in early-onset schizophrenia: similarities and differences with adult-onset schizophrenia.

OBJECTIVE: The superior temporal gyrus is associated with developmental mechanisms of brain lateralization and the pathogenesis of language-related schizophrenic symptoms. It therefore lends itself to investigation of developmental deviance in the early onset of schizophrenia. METHOD: Using stereological methods, the authors obtained bilateral measurements of the superior temporal gyrus (total, gray matter, and white matter volumes) from 40 adolescents with recent-onset schizophrenia and an equal number of matched healthy volunteers. Symptoms were rated by using the Positive and Negative Syndrome Scale. RESULTS: The total and gray matter volume of the right superior temporal gyrus was significantly lower in patients with early-onset schizophrenia than in the healthy volunteers, even after differences in whole brain volume were controlled. Bilateral superior temporal gyrus volumes were positively correlated with the age at onset of psychosis, while severity of thought disorder and hallucinations were inversely related to right superior temporal gyrus volume. CONCLUSIONS: In patients with early-onset schizophrenia, the predominantly right-sided volumetric abnormalities found in the superior temporal gyrus may reflect a particularly early neurodevelopmental disruption. The relationship between language-related symptoms and superior temporal gyrus volume is similar to that seen in adult-onset cases but not as lateralized.

Adolescent↗

PubMed2001

Comparison of the outcome and treatment of psychosis in people of Caribbean origin living in the UK and British Whites. Report from the UK700 trial.

BACKGROUND: The comparative outcome of psychosis in British Whites and UK African-Caribbeans is unclear. Some report that African-Caribbeans have worse outcome, whereas others claim better symptomatic outcome and a more benign course. AIMS: To compare the course, outcome and treatment of psychosis in African-Caribbeans and British Whites in a large multi-centre sample. METHOD: A secondary analysis of 708 patients with research diagnostic criteria-defined psychosis from a 2-year, randomised controlled trial of case management. Outcome measures (hospitalisation, illness course, self-harm, social disability and treatment received) were adjusted for socio-economic and clinical differences between groups at baseline using regression analysis. RESULTS: African-Caribbeans were less likely to have a continuous illness and to receive treatment with antidepressant or psychotherapy. CONCLUSIONS: The outcome of psychosis is complex but differs between UK African-Caribbeans and British Whites. This may reflect risk factors that increase the rate of psychosis in UK African-Caribbeans. Treatment differences require further investigation.

Adolescent↗

PubMed2000

Transcriptional analysis of multiple sclerosis brain lesions reveals a complex pattern of cytokine expression.

Multiple sclerosis (MS) is a common and severe neurological disorder associated with an autoimmune response directed against myelin components within the CNS. Lymphocyte activation, extravasation, and recruitment, as well as effector function, involves the turning on and off of a number of genes, thus triggering specific transcriptional pathways. The characterization of the transcriptome in MS lesions should provide a better understanding of the mechanisms that generate and sustain the pathogenic immune response in this disease. Here we performed transcriptional profiling of 56 relevant genes in brain specimens from eight MS patients and eight normal controls by kinetic RT-PCR. Results showed a high transcriptional activity for the gene coding for myelin basic protein (MBP); however, it was not differentially expressed in MS samples, suggesting that remyelination is an active process also in the noninflammatory brain. CD4 and HLA-DRalpha transcripts were dramatically increased in MS as compared with controls. This reveals a robust MHC class II up-regulation and suggests that Ag is being presented locally to activated T cells. Although analysis of cytokine and cytokine receptor genes expression showed predominantly increased levels of several Th1 molecules (TGF-ss, RANTES, and macrophage-inflammatory protein (MIP)-1alpha) in MS samples, some Th2 genes (IL-3, IL-5, and IL-6/IL-6R) were found to be up-regulated as well. Similarly, both proinflammatory type (CCR1, CCR5) and immunomodulatory type (CCR4, CCR8) chemokine receptors were differentially expressed in the MS brain. Overall, our data suggest a complex regulation of the inflammatory response in human autoimmune demyelination.

Algorithms↗

PubMed2000

(-)-Spiro[1-azabicyclo[2.2.2]octane-3,5'-oxazolidin-2'-one], a conformationally restricted analogue of acetylcholine, is a highly selective full agonist at the alpha 7 nicotinic acetylcholine receptor.

Neuronal nicotinic acetylcholine receptors are members of the ligand-gated ion channel receptor superfamily and may play important roles in modulating neurotransmission, cognition, sensory gating, and anxiety. Because of its distribution and abundance in the CNS, the alpha 7 nicotinic receptor is a strong candidate to be involved in some of these functions. In this paper we describe the synthesis and in vitro profile of AR-R17779, (-)-spiro[1-azabicyclo[2.2. 2]octane-3,5'-oxazolidin-2'-one] (4a), a potent full agonist at the rat alpha 7 nicotinic receptor, which is highly selective for the rat alpha 7 nicotinic receptor over the alpha 4 beta 2 subtype. Preliminary SAR of AR-R17779 presented here indicate that there is little scope for modification of this rigid molecule as even minor changes result in significant loss of the alpha 7 nicotinic receptor affinity.

Acetylcholine↗

PubMed2000

Regulation of elastinolytic cysteine proteinase activity in normal and cathepsin K-deficient human macrophages.

Human macrophages mediate the dissolution of elastic lamina by mobilizing tissue-destructive cysteine proteinases. While macrophage-mediated elastin degradation has been linked to the expression of cathepsins L and S, these cells also express cathepsin K, a new member of the cysteine proteinase family whose elastinolytic potential exceeds that of all known elastases. To determine the relative role of cathepsin K in elastinolysis, monocytes were differentiated under conditions in which they recapitulated a gene expression profile similar to that observed at sites of tissue damage in vivo. After a 12-d culture period, monocyte-derived macrophages (MDMs) expressed cathepsin K in tandem with cathepsins L and S. Though cysteine proteinases are acidophilic and normally confined to the lysosomal network, MDMs secreted cathepsin K extracellularly in concert with cathepsins L and S. Simultaneously, MDMs increased the expression of vacuolar-type H(+)-ATPase components, acidified the pericellular milieu, and maintained extracellular cathepsin K in an active form. MDMs from a cathepsin K-deficient individual, however, retained the ability to express, process, and secrete cathepsins L and S, and displayed normal elastin-degrading activity. Thus, matrix-destructive MDMs exteriorize a complex mix of proteolytic cysteine proteinases, but maintain full elastinolytic potential in the absence of cathepsin K by mobilizing cathepsins L and S.

Cathepsin B↗

PubMed2000

Haplotype transmission disequilibrium and evidence for linkage of the CHRNA7 gene region to schizophrenia in Southern African Bantu families.

Recent reports have strongly linked markers near the alpha-7 nicotinic cholinergic receptor subunit gene on human chromosome 15q13-q14 to a sensory gating deficit common in schizophrenics, and have shown positive though non-significant results linking this region to the primary phenotype of schizophrenia in a sample of North American families. We therefore tested for linkage between markers in this region of chromosome 15q and schizophrenia in a sample of 15 multiply affected and 5 single case families with schizophrenia drawn from the Bantu-speaking black population of South Africa. An initial replication using markers from the original study gave an affected-only LOD score maximum of 1.08 under a recessive model at Theta=0.00 for D15S1360, a dinucleotide polymorphism found on the same YAC as the alpha-7 receptor gene. Nonparametric affected-only multipoint analysis gave a Z-score of 1. 29, P=0.098, for D15S1360, and Z=1.45, p=0.075 for D15S118. We then increased the resolution of the map with an extended set of 20 markers. Again, two peaks were observed, with NPL scores of 1.81, p=0.037, at D15S1043 and 1.79 at D15S1360 and 1.80 at D15S1010, both p=0.037. Transmission disequilibrium testing of data from D15S1360 gave an allele-wise and genotype-wise chi(2) of 6.59, 2 df, p=0.037. Haplotype transmission disequilibrium testing using a restricted allele and haplotype set from D15S1043 and D15S1360 gave a global chi(2) of 10.647, 4 df, P=0.007, and a maximum chi(2) of 6.567, 1 df, P=0.004 for excess transmission of the 1.2 haplotype into affected offspring. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:196-201, 2000.

Bungarotoxins↗

PubMed2000

Peripheral nerve regeneration in interleukin 6-deficient mice.

BACKGROUND: Interleukin 6 (IL-6) is a multifunctional cytokine with effects on central and peripheral neurons. OBJECTIVE: To investigate the role of IL-6 in peripheral nerve regeneration by comparing IL-6 knockout and wild-type mice in a sciatic nerve model of injury and repair. DESIGN/SUBJECTS: Forty C57/BL6 (wild-type) and 40 IL-6 knockout mice were randomly assigned to 1 of 4 groups: sham surgery, sciatic nerve crush injury, sciatic nerve transection without repair, and sciatic nerve transection with epineurial suture repair. Walking tracks were assessed preoperatively and postoperatively at 10-day intervals for 50 days by means of a previously described mouse sciatic functional index. Distal segments of the sciatic nerves were harvested at the completion of the study for histomorphometric evaluation. RESULTS: The wild-type and knockout mice that underwent sham surgery showed similarly unimpaired function (P =.64 on day 50). The IL-6 knockout mice with the crush injury demonstrated decreased function on day 10 compared with the wild-type mice (P<.01) but completely recovered by day 40 (P =.55). Both IL-6 knockout and wild-type mice that underwent nerve transection without repair failed to recover function (P =.06 on day 50). There was no statistical difference in recovery between wild-type and IL-6 knockout mice that underwent nerve transection with epineurial suture repair (P =.30 on day 50). The morphometric data showed no significant differences in distal axon count between the wild-type and knockout mice after suture repair or crush injury (P>.32). CONCLUSIONS: The absence of IL-6 does not appear to impair peripheral nerve recovery after sciatic nerve injury. Although in vitro and in vivo studies suggest a role for IL-6 in peripheral nerve physiology, this cytokine does not appear to have a substantial effect on functional recovery in a mouse sciatic nerve injury and repair model.

Animals↗