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R Murray

Publications and source records attributed to R Murray.

At least 91 records · Page 5Linked to original sources
PubMed1998

Negative regulation by interleukin-3 (IL-3) of mouse early B-cell progenitors and stem cells in culture: transduction of the negative signals by betac and betaIL-3 proteins of IL-3 receptor and absence of negative regulation by granulocyte-macrophage colony-stimulating factor.

The receptors for interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), and IL-5 share a common signaling subunit betac. However, in the mouse, there is an additional IL-3 signaling protein, betaIL-3, which is specific for IL-3. We have previously reported that IL-3 abrogates the lymphoid potentials of murine lymphohematopoietic progenitors and the reconstituting ability of hematopoietic stem cells. We used bone marrow cells from betac- and betaIL-3-knock-out mice to examine the relative contributions of the receptor proteins to the negative regulation by IL-3. First, we tested the effects of IL-3 on lymphohematopoietic progenitors by using lineage-negative (Lin-) marrow cells of 5-fluorouracil (5-FU)-treated mice in the two-step methylcellulose culture we reported previously. Addition of IL-3 to the combination of steel factor (SF, c-kit ligand) and IL-11 abrogated the B-lymphoid potential of the marrow cells of both types of knock-out mice as well as wild-type mice. Next, we investigated the effects of IL-3 on in vitro expansion of the hematopoietic stem cells. We cultured Lin-Sca-1-positive, c-kit-positive marrow cells from 5-FU-treated mice in suspension in the presence of SF and IL-11 with or without IL-3 for 7 days and tested the reconstituting ability of the cultured cells by transplanting the cells into lethally irradiated Ly-5 congenic mice together with "compromised" marrow cells. Presence of IL-3 in culture abrogated the reconstituting ability of the cells from both types of knock-out mice and the wild-type mice. In contrast, addition of GM-CSF to the suspension culture abrogated neither B-cell potential nor reconstituting abilities of the cultured cells of wild-type mice. These observations may have implications in the choice of cytokines for use in in vitro expansion of human hematopoietic stem cells and progenitors.

Animals↗
PubMed1998

Case-control, haplotype relative risk and transmission disequilibrium analysis of a dopamine D2 receptor functional promoter polymorphism in schizophrenia.

The dopamine system has long been suspected of aetiological involvement in schizophrenia because of a number of lines of evidence pointing to excess dopaminergic activity in the illness. Recently, negative allelic association was reported between a single base deletion in the promoter region of the DRD2 gene, -141 delta C, and schizophrenia, with an odds ratio of 0.60. This was of particular interest since the deletion, which occurs in about 22% of the Japanese population, is functional in that it results in reduced (20-40% of wild-type) basal levels of receptor expression. We have examined this polymorphism in 229 family trios from SW China, consisting of both parents and a single offspring affected by schizophrenia, and 151 Caucasian cases with schizophrenia and 145 Caucasian normal controls from the UK. Using the haplotype-based haplotype relative risk method (HHRR), the frequency of the -141 delta C allele was 6.9% in the affected Chinese subjects compared to an estimated frequency of 9.0% in this population (chi 2 = 1.21, 1 df, ns), with an odds ratio of 0.76 (95% CI 0.46-1.25). Using the transmission disequilibrium test, we likewise found no evidence for linkage or linkage disequilibrium with this polymorphism (chi 2 = 0.94, 1 df, ns). In the Caucasian cases, the frequency of the -141 delta C was 13% compared to 10% in controls (chi 2 = 1.57, p = 0.21) with an odds ratio of 1.39 (95% CI 0.81-2.40). We thus conclude that the DRD2 -141 delta C polymorphism is less frequent in Chinese and Caucasian populations (9%) than in Japan (22%) and is not a significant risk factor for schizophrenia in our populations. The -141 delta C allele remains a strong candidate for a variety of other traits and diseases, including reward-related behaviours such as drug abuse, which have been associated with the dopamine system.

Adolescent↗
PubMed1998

The role of IL-7 in thymic and extrathymic development of TCR gamma delta cells.

IL-7-deficient (IL-7(-/-)) mice have reduced numbers of B and TCR alpha beta cells, but lack mature TCR gamma delta cells. Although most T cell development occurs in the thymus, some intestinal intraepithelial lymphocytes (IEL), including TCR gamma delta cells, can develop extrathymically. Epithelial cells in both thymus and intestine synthesize IL-7, suggesting that TCR gamma delta cell development could occur in either site. To evaluate the role of thymic IL-7 in development of TCR gamma delta cells, newborn TCR beta-deficient (TCR beta(-/-)) thymi were grafted to IL-7(-/-) mice. Donor- and host-derived TCR gamma delta cells were recovered from thymus grafts, spleen, and IEL. However, when IL-7(-/-) thymi were grafted to TCR beta(-/-) mice, no development of graft-derived TCR gamma delta cells occurred, indicating that extrathymic IL-7 did not support TCR gamma delta IEL generation from newborn thymic precursors. In contrast, TCR gamma delta IEL development occurred efficiently in adult, thymectomized, irradiated C57BL/6J mice reconstituted with IL-7(-/-) bone marrow. This demonstrated that extrathymic development of TCR gamma delta IEL required extrathymic IL-7 production. Thus, intrathymic IL-7 was required for development of thymic TCR gamma delta cells, while peripheral IL-7 was sufficient for development of extrathymic TCR gamma delta IEL.

Animals↗
PubMed1998

Testosterone and IL-6 requirements for human C-reactive protein gene expression in transgenic mice.

In vitro, IL-6 is the main inducer of the human C-reactive protein (CRP) gene, and IL-1 and steroids can enhance this effect. However, in mice, IL-6 is necessary but not sufficient for induction of the human CRP transgene, and testosterone is required for its constitutive expression by males. To examine the relative contributions of testosterone and IL-6 in the regulation of CRP gene expression, we produced CRP-transgenic (CRPtg), IL-6-deficient (IL-6-/-) mice. Male CRPtg/IL-6-/- mice expressed CRP constitutively, but CRP levels were not increased after injection of LPS. However, acute-phase CRP levels were attained after injection of IL-6. In contrast, female CRPtg/IL-6-/- mice did not express CRP constitutively or after administration of LPS, IL-6, IL-1, or IL-6 plus IL-1. Like males, testosterone-treated CRPtg/IL-6-/- females expressed CRP constitutively, and their transgene responded to injection of IL-6. The endogenous acute-phase protein serum amyloid P (SAP) was expressed constitutively equally by male and female IL-6-/- mice, responded minimally to LPS, and did not respond to either IL-6 or IL-1 alone. Acute-phase levels of SAP were induced in IL-6-/- mice by injection of IL-6 together with IL-1 or LPS. We conclude that in vivo, both constitutive and IL-6-dependent acute-phase expression of the CRP transgene require testosterone. In contrast, testosterone is not required for expression of the SAP gene, which requires IL-1 plus IL-6 for acute-phase induction.

Age Factors↗
PubMed1998

Obstetric complications and familial morbid risk of psychiatric disorders.

Obstetric complications (OCs) have been found to occur in higher frequency in patients with schizophrenia. One explanation for this finding is that the genes that contribute to the schizophrenia phenotype also influence the likelihood to experience OCs. If this were true, morbid risk of psychiatric illness should be higher in the first-degree relatives of both schizophrenic and control probands exposed to OCs, compared to probands not exposed to OCs. We set out to test this hypothesis. Information on OCs, blind to family history of psychiatric disorder, was collected retrospectively through maternal interview in 151 psychotic patients and 100 controls. Family history (FH) in relatives of cases (n = 600) and controls (n = 461) was assessed with the FH-RDC and through personal interviews. Tests for associations between family history and OCs were conducted using Cox proportional hazard regression. In the cases, familial morbid risk of affective disorder was greater in those with a history of OCs (hazard ratio (HR) = 1.9, P = 0.007). Analyses examining individual complications revealed associations between FH of affective disorder and pre-eclampsia (HR = 2.9, P = 0.003) and FH of affective disorder and breech presentation (HR = 2.8, P = 0.02), especially when family history in the relatives was confined to affective illness in the mother (HR pre-eclampsia = 4.4, P = 0.009; HR breech-presentation = 4.2, P = 0.008). In controls, affective illness in the mother was not only associated with breech presentation (HR = 7.0, P = 0.01) and pre-eclampsia (HR = 4.4, P = 0.03) but also with other complications. Familial morbid risk of schizophrenia and related psychoses was not associated with OCs. The positive associations between OCs and familial morbid risk of affective disorder suggest that the factors that contribute to familial aggregation of affective symptoms in psychotic patients also influence the likelihood to experience OCs. Although the proportion of OCs that could be attributed to these factors was very small, part of the relationship between family history of affective disorder and psychosis may be mediated by OCs.

Age of Onset↗
PubMed1998

Liarozole--a novel treatment approach for advanced prostate cancer: results of a large randomized trial versus cyproterone acetate. Liarozole Study Group.

OBJECTIVES: To compare the efficacy of oral liarozole, the first retinoic acid metabolism-blocking agent (RAMBA) to be developed as differentiation therapy for human solid tumors, with that of cyproterone acetate (CPA), an antiandrogen for the treatment of metastatic prostate cancer. Liarozole promotes differentiation of cancer cells by increasing the intratumoral levels of retinoic acid. METHODS: A total of 321 patients with metastatic prostate cancer in relapse after first-line endocrine therapy entered a Phase III international multicenter study (recruitment from February 1992 to August 1994) comparing liarozole (300 mg two times daily) with CPA (100 mg two times daily). RESULTS: Accounting for differences in baseline prognostic factors, the adjusted hazard ratio for survival was 0.74 in favor of liarozole (P = 0.039), indicating a 26% lower risk of death than in patients treated with CPA. Median crude (unadjusted) survival time was the same in the liarozole group as in the CPA group (10.3 months). More patients showed a PSA response (at least 50% reduction in PSA from baseline) when treated with liarozole (20%) than with CPA (4%) (P < 0.001). Prostate-specific antigen (PSA) responders had a median survival benefit of 10 months over nonresponders, irrespective of treatment (hazard ratio 0.43; P = 0.0018). PSA response was apparent within 3 months in approximately 90% of patients who responded. Pain improved more in the liarozole group than in the CPA group (P = 0.03). PSA responders had lower median pain scores than nonresponders (1.7 versus 2.5) and better quality of life (median Functional Living Index-Cancer score 108 versus 98) at end point, ie, treatment discontinuation, as well as throughout the treatment period. Among the most frequently occurring adverse events in the liarozole group were dry skin (51% of patients), pruritus (25%), rash (16%), nail disorders (16%), and hair loss (15%). These adverse events were generally mild to moderate in severity and did not affect the overall quality of life score. There were no detectable effects of either treatment on vital signs such as blood pressure, heart rate, electrocardiogram, and body weight. CONCLUSIONS: Liarozole is superior to CPA in terms of PSA response, PSA progression, and survival, and is capable of maintaining patients' quality of life. The observed adverse events were mild to moderate in nature. These results show that liarozole is a possible treatment option after first-line endocrine therapy has failed.

Aged↗
PubMed1998

Does the method of data collection affect the reporting of depression in the relatives of depressed probands?

BACKGROUND: Data is usually collected from different sources in family studies in depression. We sought to determine what effect different methods of data collection had on the reporting of the lifetime prevalence of depression in the relatives of depressed probands. METHOD: We examined the psychiatric histories of 519 first-degree relatives of a consecutive series of 89 hospitalised depressed probands to ascertain their lifetime prevalence of RDC Major Depression. These data on relatives were obtained either directly with the SADS-L (n = 116), indirectly with the Family History RDC (FH-RDC) (n = 283) or by examining the casenotes of the probands (n = 120). RESULTS: The method of data collection had a marked effect on the reported prevalence of depression, with direct interview being much more sensitive in detecting the less severe forms of the illness. The lifetime prevalence of hospitalised depression in relatives, however, was unaffected by the method of the data collection. Variation in lifetime prevalence of depression between the SADS-L and FH-RDC appeared to be due mainly to differences in the sensitivity of the instrumentation rather than to biases in sampling. CONCLUSION: We confirm that indirect sources of family information have reduced sensitivity for the detection of depression in relatives compared with direct interview. LIMITATIONS: The numbers of relatives directly interviewed were small and the probands represented a severely affected sample which limits the generalisability of the findings. CLINICAL RELEVANCE: Combining data from different methods of collection in family studies is therefore problematic unless a narrow definition of caseness is used (e.g. depression requiring hospitalisation).

Bias↗
PubMed1998

Primary sensory neurons migrate in response to the chemokine RANTES.

We examined the potential for the C-C chemokine RANTES to stimulate dorsal root ganglia (DRG) cell migration. Embryonic day 12 (E12.5) mouse DRG cells migrated in response to RANTES, in vitro, differentiating to the nociceptive phenotype within 18 h. In addition, RANTES stimulated intracellular calcium mobilization in DRG cells. RANTES expression was demonstrated by polymerase chain reaction analysis to be present in E10.5 limb bud, E12.5 DRG, Schwann cells, spinal cord and skin. RANTES protein was detected immunohistochemically in E12.5 DRG and the cutaneous layers of the developing hind limb. Thus, RANTES expression is spatially and temporally consistent with an effector molecule in sensory neuropoiesis, potentially expanding the role of this chemokine to include neurotropism.

Animals↗
PubMed1998

The general approach to the difficult patient.

Difficult patients are familiar to emergency physicians. This article explores characteristics of the difficult patient, recognized emergency department processes, and physician characteristics that can contribute to difficulties. These difficulties can be minimized by caregivers who are skilled in managing the therapeutic relationship. This relationship is characterized by firm boundaries, good communication, patient trust, wisdom, and an effective system that supports both patients and caregivers.

Attitude of Health Personnel↗
PubMed1998

Impaired development of Th2 cells in IL-13-deficient mice.

We report that Th2 cell cultures generated using T cells or splenocytes from IL-13-deficient mice produce significantly reduced levels of IL-4, IL-5, and IL-10 compared with wild-type. In contrast, IL-4 and IL-5 production by mast cells stimulated in vitro with PMA, ionomycin, or IgE cross-linking are unaffected. In vitro Th2 cell differentiation cannot be rescued by the addition of exogenous factors, but in vivo antigen challenge and administration of IL-13 can increase Th2-like cytokine responses as can infection with the parasitic nematode Nippostrongylus brasiliensis. IL-13-deficient mice also have lower basal levels of serum IgE and biased antigen-specific immunoglobulin responses. Thus, IL-13 is an important regulator of Th2 commitment and may therefore play a central role in atopy and infectious diseases.

Animals↗
PubMed1998

Quality of parenting and vulnerability to depression: results from a family study.

BACKGROUND: We examined a group of subjects at familial risk of depression and explored the relationship between the perceptions of parents and a history of depression. We also investigated: (a) whether any difference in perceived parenting found between those with and without a past history of depression was an artefact of the depression; and (b) whether the relationship between parenting and depression was explained by neuroticism. METHOD: We took a sample of first-degree relatives selected from a family study in depression and subdivided them by their history of mental illness on the SADS-L, into those: (a) without a history of mental illness (N = 43); and (b) those who had fully recovered from an episode of RDC major depression (N = 34). We compared the perceptions of parenting, as measured by the Parental Bonding Instrument (PBI), in these two groups having adjusted for the effect of neuroticism and subsyndromal depressive symptoms. We also had informants report on parenting of their siblings, the latter being subdivided into those with and without a past history of depression. RESULTS: Relatives with a past history of depression showed lower care scores for both mother and father combined compared with the never ill relatives. The presence of a history of depression was associated with a non-significant reduction in the self-report care scores compared to the siblings report. Vulnerable personality (as measured by high neuroticism) and low perceived care were both found to exert independent effects in discriminating between the scores of relatives with and without a history of depression and there was no interaction between them. CONCLUSION: This study confirmed that low perceived parental care was associated with a past history of depression, that it was not entirely an artefact of having been depressed, and suggested that this association was partially independent of neuroticism.

Adult↗
PubMed1998

Urbanization and psychosis: a study of 1942-1978 birth cohorts in The Netherlands.

BACKGROUND: Urban birth is associated with later schizophrenia. This study examined whether this finding is diagnosis-specific and which individuals are most at risk. METHODS: All live births recorded between 1942 and 1978 in any of the 646 Dutch municipalities were followed-up through the National Psychiatric Case Register for first psychiatric admission for psychosis between 1970 and 1992 (N = 42115). RESULTS: Urban birth was linearly associated with later schizophrenia (incidence rate ratio linear trend (IRR), 1.39; 95% confidence interval (95% CI), 1.36-1.42), affective psychosis (IRR, 1.18; 95% CI, 1.15-1.21) and other psychosis (IRR, 1.27; 95% CI, 1.24-1.30). Individuals born in the highest category of the three-level urban exposure were around twice as likely to develop schizophrenia. Associations were stronger for men and for individuals with early age of onset. The effect of urban birth was also stronger in the more recent birth cohorts. CONCLUSIONS: There are quantitative differences between diagnostic categories in the strength of the association between urban birth and later psychiatric disorder. High rates of psychosis in urban areas may be the result of environmental factors associated with urbanization, the effect of which appears to be increasing over successive generations.

Adult↗
PubMed1998

Rehydration strategies--balancing substrate, fluid, and electrolyte provision.

The combination of heat stress, dehydration, and exercise imposes perhaps the most-severe physiological challenge for the human body short of disease or serious bleeding. Exercise in the heat requires the body to attempt to cope simultaneously with competing demands for cardiovascular homeostasis, thermoregulatory control, and maintenance of muscle energetics. When dehydration is superimposed upon this scenario (as is often the case during most forms of exercise), the results can be catastrophic for both health and performance. Fluid replacement reduces the risk of heat illness and improves exercise performance by preventing or reducing dehydration and by providing a convenient means of ingesting carbohydrate. The fact that even low levels of dehydration (e.g., equivalent to a 2% loss of body weight) impair cardiovascular and thermoregulatory response, and reduces the capacity for exercise, is beyond scientific dispute. For these reasons, optimal performance is possible only when dehydration is minimized by ingesting ample volumes of fluid during exercise. Recent research has demonstrated that consuming fluid in direct proportion to sweat loss (or close to it) maintains important physiological functions and significantly improves exercise performance, even during exercise lasting only one hour. Preventing dehydration enables the cardiovascular system to maintain blood pressure and cardiac output, thereby sustaining the increase in skin blood flow and sweating that are essential for optimal temperature regulation. Remaining well hydrated during exercise also preserves muscle function, reducing the reliance on muscle glycogen as a fuel source. Carbohydrate ingestion also improves exercise performance, an effect that is independent of and additive to preventing dehydration. The practical application of this knowledge requires that athletes follow a more-aggressive fluid-replacement regimen than is now usually the case. Successful implementation of this regimen requires that coaches, athletes, and support personnel are made aware of the practical benefits of adequate fluid replacement, that appropriate fluid-replacement strategies are developed and implemented, and that athletes have the opportunity to train themselves to ingest larger volumes of fluid more frequently. Success during competition in warm weather is more likely for those athletes who are highly fit and well acclimatized to training and competing in the heat, and who diligently avoid even low levels of dehydration. The competitive advantage will definitely shift in favor of those athletes whose coaches and trainers recognize the fundamental value of fitness, acclimation, and hydration, coupled with other strategies for keeping athletes cooled and fueled.

Acclimatization↗
PubMed1998

Co-administration of citalopram and clozapine: effect on plasma clozapine levels.

Antidepressants are frequently used in the treatment of depressive symptoms associated with schizophrenia. In patients taking clozapine, choice of antidepressant is complicated by additive pharmacodynamic effects and by pharmacokinetic interactions. We predicted that citalopram would not elevate plasma clozapine levels when the two drugs were co-administered because it does not inhibit the relevant enzyme systems. In this preliminary study of five patients given citalopram and clozapine there was no overall change in mean clozapine levels. Based on this limited evidence, citalopram might be the antidepressant of choice in patients taking clozapine.

Adolescent↗
PubMed1998

Lack of association between a polymorphism in the promoter region of the dopamine-2 receptor gene and clozapine response.

Dopamine receptors are strong candidates for involvement in schizophrenia and are targeted by a wide variety of antipsychotics. We hypothesized that genetic variation in these neurotransmitter receptors may influence clinical response to clozapine, an antipsychotic which displays high affinity for dopamine D2 receptors in the limbic system. To test this hypothesis, we studied a functional polymorphism in the promoter region of the D2 receptor gene (-141C Ins/Del) in a sample of 151 clozapine treated patients of British origin. In addition, the influence of this polymorphism on antipsychotic response in general was investigated on a sample of 146 Han Chinese schizophrenic patients treated with a variety of antipsychotics. No association was found between this polymorphism and clinical response in either of the two samples suggesting that genetic variation in D2 receptors does not play a major role in determining clinical response to antipsychotic treatment.

Antipsychotic Agents↗
PubMed1998

Failure to exclude a possible schizophrenia susceptibility locus on chromosome 13q14.1-q32 in southern African Bantu-speaking families.

Several recent reports have provided evidence suggesting linkage of markers on chromosome 13q14.1-q32 to schizophrenia in families from England, Wales, Japan and the USA, but not in Chinese families. We tested for linkage between markers in this region and schizophrenia in a sample of 16 families multiply affected with schizophrenia drawn from the Bantu-speaking black population of South Africa. Twelve markers spanning 76 cM of chromosome 13q were examined in these analyses, including 10 markers covering the most positive region in the studies of the English, Welsh and Chinese families, and two additional markers yielding the largest positive LOD scores in the American study. The map of markers used was D13S126-14.6cM-D13S119-12.2cM-D13S144-10.+ ++2cM-D13S160-7.9cM-D13S121-6.3cM -D13S71-1.6cM-D13S122- 4.9cM-D13S128-8.9cM-D13S770-1.4cM-D13S7 79-2.2cM-D13S64-7.4cM-D13S173. Parametric two-point analysis yields strongly negative LOD scores across the region D13S71-D13S64 under all models, and D13S71-D13S173 under a recessive model, when analysing either the whole sample or affected individuals only. ALOD maxima are 0.0 when allowing for heterogeneity for all markers in this subset. Under recessive modelling, the ALOD maximum is 0.717, theta = 0.0, alpha = 0.45, for D13S126 when analysing all samples. Affected-only analysis of this marker yields a maximum LOD score of 0.645, theta = 0.1, and an ALOD maximum of 0.697, theta = 0.0, alpha = 0.55. Non-parametric multipoint analysis of these markers provides no support for excess sharing of alleles identical by descent, although D13S119 and D13S770 show some evidence for excess sharing of alleles identical by state.

Black People↗
PubMed1998

The physiologic role of interleukin-3, interleukin-5, granulocyte-macrophage colony-stimulating factor, and the beta c receptor system.

Gene knockout techniques in the mouse have provided a unique opportunity to examine physiologic gene function. The phenotypes of mutant mice have resulted in a number of predicted as well as totally unexpected results, the latter perhaps providing the most valuable insight into otherwise unexplored biology. An excellent example to illustrate these points are gene knockout studies of interleukin (IL)-3, IL-5, granulocyte-macrophage colony-stimulating factor (GM-CSF), and the receptor system that cells use to bind these ligands. The role of IL-5 appears to be largely restricted to eosinophil biology, fulfilling expectations. However, the vivo function of GM-CSF, IL-3, and their receptor interaction has been more surprising. Neither cytokine nor their combination play an essential or even detectable role in primary bone marrow hematopoiesis, Instead, both IL-3 and GM-CSF play more specialized roles on certain cell subsets, basophil and mast cells, and alveolar macrophages, respectively. This review discusses recent findings with these mice, and based on these results, suggests a more appropriate view of the role of these cytokines and receptors in the hierarchy of molecular events leading to hematopoiesis.

Animals↗