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Biomedical subjects

B Murphy

Publications and source records attributed to B Murphy.

At least 19 recordsLinked to original sources
PubMed1995

The indirect pathway of allorecognition. The occurrence of self-restricted T cell recognition of allo-MHC peptides early in acute renal allograft rejection and its inhibition by conventional immunosuppression.

There is evidence that T cells can "directly" recognize intact allo-MHC molecules on the surface of allogeneic stimulator or target cells, and/or "indirectly" recognize processed allo-MHC peptides presented by self antigen-presenting cells (APCs). We and others have recently demonstrated that in vivo-primed rat CD4+ T cells recognize and proliferate to specific polymorphic amino acid sequences when presented as MHC allopeptides by self APCs. Studies on the mechanisms of indirect T cell recognition of alloantigen are now reported. First, we studied the immunogenicity of 4 synthetic polymorphic class II MHC allopeptides representing full-length sequences of the hypervariable domains of RT1.Du beta (DR or I-E-like) in several responder strains: LEW (RT1(l)), ACI (RT1a), BUF (RT1b), BN (RT1n), and control syngeneic WF (RT1u) strains. Immunogenicity of the individual 25mer allopeptides varied in the different responder strains, indicating that self-restricted T cell recognition of allo-MHC peptides is determined not only by polymorphisms, but also by the responder MHC genotype. Self-restricted CD4+ T cell recognition of processed allo-MHC peptides has been shown to occur during acute skin and cardiac allograft rejection, and there is evidence that this pathway may play an important role in initiating and amplifying the immune response to allografts. T cells from LEW animals primed in vivo by WF (RT1u) vascularized renal allografts were capable of proliferating to the RT1.Du beta peptides as early as 3 days postengraftment, when presented by self APCs. We then tested the effects of various immunosuppressive drugs on self-restricted primed T cell proliferative response to an immunogenic MHC allopeptide in vitro. Methylprednisolone, cyclosporine, and FK506 inhibited the proliferative response of RT1.Du beta 2-primed LEW T cells in a dose-dependent fashion. In addition, a single injection of cyclosporine (25 mg/kg i.m.) to LEW recipients of WF renal allografts on the day of transplantation completely abolished the proliferative response of in vivo-primed T cells to RT1.Du beta 2, indicating the susceptibility of the indirect pathway of allorecognition to conventional immunosuppressive drugs.

Amino Acid Sequence↗
PubMed1995

A potential vulnerability locus for schizophrenia on chromosome 6p24-22: evidence for genetic heterogeneity.

In 265 Irish pedigrees, with linkage analysis we find evidence for a vulnerability locus for schizophrenia in region 6p24-22. The greatest lod score, assuming locus heterogeneity, is 3.51 (P = 0.0002) with D6S296. Another test, the C test, also supported linkage, the strongest results being obtained with D6S296 (P = 0.00001), D6S274 (P = 0.004) and D6S285 (P = 0.006). Non-parametric analysis yielded suggestive, but substantially weaker, findings. This locus appears to influence the vulnerability to schizophrenia in roughly 15 to 30% of our pedigrees. Evidence for linkage was maximal using an intermediate phenotypic definition and declined when this definition was narrowed or was broadened to include other psychiatric disorders.

Chromosomes, Human, Pair 6↗
PubMed1995

Culture methods for the detection of minimal tumor contamination of hematopoietic harvests: a review.

The evaluation of minimal residual disease in patients and hematopoietic cell grafts is of considerable importance for staging disease, determining the response to treatment, and monitoring the efficiency of ex vivo purging or positive selection procedures. The most widely used techniques are immunocytochemical staining and the polymerase chain reaction; however, these assays do not measure the viability or clonogenic capacity of the detected cells. For this purpose, a culture technique must be used. This paper reviews the status, advantages, and limitations of this approach and the detection of tumor cells in bone marrow and peripheral blood.

Bone Marrow Purging↗
PubMed1995

Information for family carers: does it help?

Family carers in Victoria were identified through a statewide telephone survey in 1993. A total of 976 carers was interviewed and a random sample of approximately one in 10 (n = 103) were offered the Carer Support Kit leaflet. The leaflet details the components of the Carer Support Kit (a Federal Government initiative developed in 1992-93) and informs carers how to apply for it through the Victorian Carers' Association. Approximately three-quarters of these carers accepted the offer, and around a third subsequently applied for the kit. Carers who applied for the kit reported significantly more overload and lower life satisfaction than those who did not apply. Only two-thirds of those mailed the kit (just 23 per cent of the eligible study sample) went on to use it. Those who had not used it reported significantly more negative emotions and health problems than those who used it, suggesting that stress and crises could preclude utilisation of the information. A brief evaluation of the components of the kit is presented; however, findings need to be treated with caution in view of the small sample size.

Adult↗
PubMed1995

The role of emotionality and regulation in children's social functioning: a longitudinal study.

Multiple measures of children's emotionality (emotional intensity and negative affectivity), regulation (including attentional and behavioral regulation and coping), and social functioning (teachers' reports of nonaggressive/socially appropriate behavior and prosocial/socially competent behavior; and parents' reports of problem behavior) were obtained for 6-8-year-olds. In addition, emotionality, attentional regulation, and coping were assessed 2 years previously. Social functioning was expected to be predicted by low negative emotionality and high levels of regulation. In general, the data supported the predictions, although the findings for parent reports of problem behavior were primarily for boys. Prediction of social functioning from measures of regulation and emotionality occurred primarily within a given context (school vs. home) rather than across contexts, even though there were relations across reporters within the school or home context. In addition, vagal tone, a marker of physiological regulation, was positively related to competent social functioning and emotionality/regulation for boys, but inversely related for girls.

Affective Symptoms↗
PubMed1995

Prosocial development in late adolescence: a longitudinal study.

Change in prosocial moral reasoning over 15 years, gender differences in prosocial reasoning, and the interrelations of moral reasoning, prosocial behavior, and empathy-related emotional responses were examined with longitudinal data from 17-18- and 19-20-year-olds and data from adolescents interviewed for the first time. Hedonistic reasoning declined in use until adolescence, and then increased somewhat in early adulthood. Needs-oriented and stereotypic reasoning increased until mid-childhood or early adolescence and then declined in use. Direct reciprocity and approval reasoning, which appeared to be on the decline in mid-adolescence in previous follow-ups, showed no decline into early adulthood. Several modes of higher-level reasoning increased in use across adolescence and early adulthood. Females' overall reasoning was higher than males'. Scores on interview and objective measures of prosocial moral reasoning were positively correlated. Consistent with expectations, there was some evidence of relations among prosocial reasoning, prosocial behavior, sympathy, and perspective taking.

Adolescent↗
PubMed1994

A phase I trial of intrahepatic verapamil and doxorubicin. Regional therapy to overcome multidrug resistance.

BACKGROUND: Verapamil can modulate multidrug resistance in vitro, but only at levels that are not tolerable when administered systemically. Regional strategies of drug administration may permit the delivery of high concentrations of a drug to specific areas with lower systemic levels. Colorectal cancers typically express the multidrug resistance phenotype. METHODS: A Phase I trial was performed to determine the maximum tolerable dose (MTD) and dose limiting toxicities of verapamil by hepatic artery infusion, together with doxorubicin, to patients with hepatic metastases of colorectal cancer. Fourteen patients with metastatic colorectal cancer received a 14-hour intrahepatic infusion of verapamil. Six hours after the start of the infusion, a fixed dose of doxorubicin (50 mg/m2) was given, also via the hepatic artery, over a 30-minute period. Patients were followed by cardiac telemetry but were not in an intensive care setting, and no invasive monitoring was used. All patients had received prior intrahepatic chemotherapy. RESULTS: The MTD of intrahepatic verapamil on this schedule in this patient population was 1.2 mg/kg/hour. Hypotension was the dose limiting toxicity. No major objective responses were noted in this heavily pretreated patient population. A dose of 1.0 mg/kg/hour is recommended for Phase II trials. CONCLUSIONS: Based on estimations of normal hepatic artery blood flow, the estimated concentration of verapamil delivered to the hepatic tumors at 1.0 mg/kg/hour is 3.6 micrograms/ml (7.3 microM), which is comparable to concentrations at which an in vitro reversal of MDR is seen. This study demonstrates that the systemic toxicities of an MDR reversal agent can be overcome by regional drug delivery, establishing this approach as an important model system for further study of MDR modulation.

Adenocarcinoma↗
PubMed1993

Immunohistological detection of C5b-9 complement complexes in normal and pathological human livers.

The immunohistological localization of components and neoantigens of the C5b-9 human terminal complement complex was studied in 30 human liver biopsies. C5b-9, apparently in the soluble SC5b-9 form, was invariably detected in normal liver capsule and normal portal tract connective tissue. In livers with fibrosis and or cirrhosis, the pathological connective tissue contained variable amounts of SC5b-9 which was distributed in a similar way to that seen in normal livers. There was no significant C5b-9 deposition outside of the portal tract and capsule in any of the liver biopsies. In particular, in pathological livers, there was no deposition in relation to cellular infiltrates or areas of hepatic necrosis. These data support the concept that C5b-9 is a common component of connective tissue but do not indicate that C5b-9 mediated pathways are involved in the pathogenesis of hepatic injury.

Clusterin↗
PubMed1992

Normal bone density in Irish women: is American normative data suitable for use in Ireland?

The objective of the study was to determine whether or not U.S. normal data for female Vertebral Bone Mineral Density is suitable for use in an Irish population. One hundred and fifty-six healthy Caucasian women of permanent Irish domicile had bone densitometry performed using single energy quantitative computed tomography of L2, L3 and L4 vertebrae. We found that comparison of our results to normal American data shows a slight and progressive increase in bone mineral content of postmenopausal American women with age relative to the Irish population. This difference is small and not sufficient to justify development of separate normal values for Irish women. We conclude that this discrepancy may be due to a combination of environmental and racial factors or to the more rigorous exclusion criteria applied in our study.

Adult↗
PubMed1992

Differential expression of clusterin in inducible models of apoptosis.

Apoptosis (programmed cell death) and necrosis can be readily distinguished morphologically and biochemically. The most striking biochemical change observed in apoptotic cells is the cleavage of the genomic DNA into discrete nucleosome sized fragments, producing a laddering pattern when the DNA is examined electrophoretically. It has recently been shown that RNA and protein products of the testosterone-repressed prostate message-2 gene are induced, coordinate with the onset of cell death. This gene has been isolated from a variety of species and tissues, it is highly conserved, and collectively referred to as clusterin. We have examined a number of inducible leucocyte models of apoptosis, including glucocorticoid and calcium ionophore induced thymocyte death, 'aged' neutrophils and cytotoxic T cells, and found that in these situations that cell death is not associated with up-regulation of clusterin gene expression. The finding that clusterin is not expressed in all cells undergoing apoptosis would suggest that this molecule is not critical to the mechanism of cell death. It does, however, provide the first example of a readily detectable marker which is differentially expressed in cells undergoing apoptosis and adds further weight to the argument that apoptosis is not a uniform phenomena, but is dependent on the nature of the cells involved and the means of induction.

Animals↗
PubMed1992

Antibodies against cortisol block suppressive effects of corticosteroids on lymphocytes in vitro.

Lymphocyte transformation assays were used to test the ability of antibodies against cortisol to reduce bioactivity of corticosteroids in vitro. Mononuclear cells were separated from whole bovine blood and cultured in the presence of PHA alone, PHA + steroid, PHA + steroid + anticortisol, or PHA + steroid + anti-bovine serum albumin. Tritiated thymidine uptake was determined for all groups during the last 24 hr of a 72-hr culture period by scintillation counting. Polyclonal anticortisol against cortisol-bovine serum albumin conjugated in the 21 position was more effective in blocking cortisol activity than monoclonal anticortisol built against conjugates in the 3 position. The steroids that suppressed PHA-induced lymphocyte proliferation in a concentration-dependent manner were: cortisol, corticosterone, dexamethasone, prednisolone, 11-deoxycortisol, and 11-deoxycorticosterone. Aldosterone, cortisone, cholesterol, estradiol, and progesterone did not exhibit concentration-dependent effects and, thus, were not considered suppressive. These concentration-independent steroids were also the least suppressive (with the exception of aldosterone). Anticortisol was able to reduce bioactivity of suppressive corticosteroids that had an 11-hydroxy group, suggesting the antibody was primarily made against this site. Anti-BSA was not effective in blocking corticosteroid activity, but it did enhance proliferation of lymphocytes if added in combination with weakly suppressive steroids. Anticortisol also had an enhancing effect when added with some weakly suppressive steroids. We conclude that antibodies against cortisol are capable of reducing bioactivity of steroids that strongly suppress lymphocyte proliferation. Additionally, the 11-hydroxy group may be an important antigenic determinant of steroid molecules.

Adrenal Cortex Hormones↗
PubMed1991

The apolipoprotein A-I binding protein of placenta and the SP-40,40 protein of human blood are different proteins which both bind to apolipoprotein A-I.

A complement-associated protein SP-40,40, which is a normal constituent of human blood, binds to the main apoprotein, apoA-I, of high density lipoprotein (HDL). This protein, which is identical to apolipoprotein J, was compared to another apoA-I binding protein purified from human placenta. Immunologically the two apoA-I binding proteins are different.

Amino Acid Sequence↗