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Biomedical subjects

C Murray

Publications and source records attributed to C Murray.

At least 73 records · Page 4Linked to original sources
PubMed1996

Expansion and manipulation of natural killer cells in patients with metastatic cancer by low-dose continuous infusion and intermittent bolus administration of interleukin 2.

Interleukin 2 (IL-2) administered at low doses for prolonged periods can markedly expand the number of CD56(+) natural killer (NK) cells in patients with metastatic cancer. The cytotoxic capacity of NK cells obtained from patients receiving IL-2 in vivo can be dramatically augmented by additional exposure to IL-2 in vitro. These observations formed the basis of a clinical trial in which patients with metastatic cancer were treated with low-dose continuous daily infusions of IL-2 to increase the number of their NK cells in conjunction with intermittent boluses of additional IL-2 to stimulate this expanded pool of cytotoxic cells. Twenty-three patients were registered to receive IL-2 at 4.5 x 10(5) units/m2/day for 8 weeks by continuous i.v. infusion. After 4 weeks of "priming" with low-dose continuous infusion IL-2, cohorts of three to five patients received 5 weekly 2-h boluses of IL-2 at doses ranging from 2.5 x 10(5) units/m2 to 1.0 x 10(6) units/m2. Low-dose continuous infusion IL-2 was usually well tolerated; 2-h bolus infusions of IL-2 were often associated with high fevers and constitutional symptoms that resolved after several hours. Low-dose continuous infusion IL-2 resulted in the progressive expansion of circulating CD56(+)CD3(-) NK cells. In contrast, each bolus infusion of IL-2 resulted in an immediate dramatic decrease in both the number of NK cells and activated T lymphocytes with recovery noted within 24 h. Bolus doses of IL-2 as low as 2.5 x 10(5) units/m2 were capable of producing these effects. Cytolytic activity against NK-sensitive and -resistant targets correlated with the presence of circulating activated NK cells. Our results demonstrate that NK cells expanded by low-dose continuous infusions of IL-2 can be further activated in vivo by exposure to very low doses of IL-2 as a 2-h i.v. bolus. This capacity to manipulate human NK cells in vivo through varying the dose and schedule of IL-2 administration may help in defining the therapeutic potential of these cytotoxic effectors in the treatment of both neoplastic and infectious diseases.

Adult↗
PubMed1995

Recombinant interleukin-2 infusions and decreased IgG2 subclass concentrations.

The administration of low doses of recombinant interleukin-2 (rIL-2) in vivo to patients with malignant neoplasms has been demonstrated to selectively increase the number of circulating natural killer (NK) cells in these patients. Recent evidence from SCID mouse models suggests that IgG subclass levels can be influenced by the presence and activity of NK cells. Therefore, we sought to examine the effect of rIL-2 infusions on human serum IgG subclass concentrations. We determined serum IgG subclass concentrations in 27 cancer patients receiving low-dose rIL-2 by daily continuous intravenous infusion. Eleven of these patients had active, metastatic, nonhematologic tumors; 16 patients had received IL-2 when they were in a minimal residual disease state after autologous or allogeneic bone marrow transplantation. Samples obtained before beginning IL-2 therapy and 8 to 10 weeks into therapy were tested. Treatment with IL-2 resulted in an increase in the percentage of CD56+ NK cells from 18% to 54% (P = .0001). A significant decrease in geometric mean IgG2 concentration from 2,017 micrograms/mL to 1,655 micrograms/mL was noted over this time interval (P = .03). Furthermore, the geometric mean IgG2 concentration after treatment was significantly lower than that of healthy controls (P = .026). In contrast, no significant changes in serum IgG1, IgG3, or IgG4 were noted during r-IL2 infusions. Our data suggest that rIL-2 treatment selectively decreases serum IgG2 concentrations. We speculate that increased NK cells mediate downregulation of human serum IgG2.

Adult↗
PubMed1995

Skeletal response to recombinant human growth hormone (rhGH) in children treated with long-term corticosteroids.

Corticosteroid therapy causes osteopenia and growth retardation in children; such changes are associated with diminished rates of bone formation and turnover. Since growth hormone activates bone remodeling, the biochemical and skeletal responses to rhGH were evaluated in four pediatric patients, aged 12.8 +/- 3 years, with long-term corticosteroid use (5 +/- 2 years). Recombinant human growth hormone (rhGH), 0.125 mg/kg, was given 3 times/week by subcutaneous injection for 12 months. Iliac crest bone biopsies were obtained after double tetracycline labeling before and at the end of rhGH therapy; serum levels of calcium, phosphorus, alkaline phosphatase, parathyroid hormone (intact), 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D3, osteocalcin (BGP), and insulin-like growth factor-1 (IGF-1) were measured every 3 months during the treatment period. The average dose of prednisone was 0.24 +/- 0.05 mg/kg/day initially, and this did not change during the study. Serum calcium, phosphorus, alkaline phosphatase, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D3, and BGP were unchanged during the rhGH therapy, but the serum IGF-1 level increased by 71%, p < 0.01. Eroded bone perimeter and cancellous bone area did not change significantly during rhGH therapy. Bone formation rates rose from 423 +/- 475 to 781 +/- 407 microns2/mm2/day, p < 0.05, and the length of double tetracycline-labeled bone perimeter increased by 85%, p < 0.05. The bone formation rate in the growth hormone group exceeded the values of an age-matched reference group (14.3 +/- 3 years), 780 +/- 407 microns2/mm2/day versus 411 +/- 479 microns2/mm2/day, p < 0.05.(ABSTRACT TRUNCATED AT 250 WORDS)

25-Hydroxyvitamin D 2↗
PubMed1995

Disclosure of donor insemination: parental attitudes.

Disclosures by parents with a child conceived by donor insemination were compared to those of parents with adopted children and parents with children conceived by in vitro fertilization. None of the donor-insemination parents had told their child. The factors found to create the greatest difficulties for disclosure were the father's infertility, the timing and method of telling, and the lack of genetic information for the child.

Adoption↗
PubMed1995

Families created by the new reproductive technologies: quality of parenting and social and emotional development of the children.

The creation of families by means of the new reproductive technologies has raised important questions about the psychological consequences for children, particularly where gamete donation has been used in the child's conception. Findings are presented of a study of family relationships and the social and emotional development of children in families created as a result of the 2 most widely used reproductive technologies, in vitro fertilization (IVF) and donor insemination (DI), in comparison with control groups of families with a naturally conceived child and adoptive families. The quality of parenting was assessed using a standardized interview with the mother, and mothers and fathers completed questionnaire measures of stress associated with parenting, marital satisfaction, and emotional state. Data on children's psychiatric state were also obtained by standardized interview with the mother, and by questionnaires completed by the mothers and the children's teachers. The children were administered the Separation Anxiety Test, the Family Relations Test, and the Pictorial Scale of Perceived Competence and Social Acceptance. The results showed that the quality of parenting in families with a child conceived by assisted conception is superior to that shown by families with a naturally conceived child. No group differences were found for any of the measures of children's emotions, behavior, or relationships with parents. The findings are discussed in terms of their implications for understanding the role of genetic ties in family functioning and child development.

Adoption↗
PubMed1995

Further evidence that reading ability is not preserved in Alzheimer's disease.

BACKGROUND: Pre-morbid intelligence level is routinely assessed in Alzheimer's disease using the National Adult Reading Test (NART). This practice is based on the assumption that pronunciation of irregular words remains unaffected by the disease process. Recent reports have suggested that reading ability may become compromised in moderately demented subjects. METHOD: Sixty-eight probably Alzheimer patients were classified into stages of severity (minimal, mild and moderate) using the Mini-Mental State Examination (MMSE). NART and demographic equations were used to estimate pre-morbid ability. RESULTS: A significant correlation emerged between dementia severity and reading ability, NART v. MMSE scores, r = 0.46, P < 0.01. When the total sample was subdivided into moderate, mild and minimal subgroups, significant between-group differences emerged, despite the groups being well matched for age, sex, and years of full-time education. Pre-morbid IQ, as estimated by demographic regression equations, did not correlate with dementia severity. CONCLUSION: NART performance is compromised in moderate Alzheimer disease, and the measure provides a serious underestimate of pre-morbid IQ in patients with an MMSE of 13 or less.

Aged↗
PubMed1995

Distinct patterns of minimal residual disease associated with graft-versus-host disease after allogeneic bone marrow transplantation for chronic myelogenous leukemia.

PURPOSE: Allogeneic bone marrow transplantation (BMT) has been shown to provide effective therapy for chronic myelogenous leukemia (CML), but previous reports have also demonstrated the persistence of bcr-abl-positive cells for months to years after BMT in the majority of patients. To evaluate the biologic significance of persistent bcr-abl-positive cells, we examined the relationship between clinical parameters known to affect the risk of relapse and the ability to detect bcr-abl-positive cells post-BMT. PATIENTS AND METHODS: We analyzed 480 samples from 92 patients at two transplant centers for the presence of bcr-abl-positive cells by polymerase chain reaction (PCR). Two different BMT preparative regimens and protocols for prevention of graft-versus-host disease (GVHD) were used. One center used cyclophosphamide plus total-body irradiation (CY/TBI) and T-cell-depleted marrow; the second center used busulfan plus cyclophosphamide (Bu/CY) and untreated marrow with cyclosporine and methotrexate (Csp/MTX) as GVHD prophylaxis. RESULTS: We first determined the percent of patients at each center with > or = one PCR-positive (PCR+) result at defined intervals post-BMT. Between 0 and 6 months post-BMT, the majority of patients (80% to 83%) in both populations had PCR-detectable bcr-abl-positive cells. Between 6 and 24 months post-BMT, 80% to 88% of patients who received T-cell-depleted marrow remained PCR+, as compared with 26% to 30% of patients who received unmodified marrow. After 24 months post-BMT, the percentage of PCR+ patients was not significantly different in the two populations. This pattern of detection of bcr-abl-positive cells post-BMT followed the development of chronic GVHD in patients who received unmodified marrow. All patients were also divided into three groups based on post-BMT PCR results as follows: (1) persistent PCR+ (n = 29), (2) intermittent PCR-negative ([PCR-] n = 40), and (3) persistent PCR- (n = 23). These three groups were found to have a low, intermediate, and high probability of maintaining remission and disease-free survival, respectively (P = .0001). Intermittent or persistent PCR- results, which reflect levels of minimal residual disease < or = the limit of detection by PCR, were clearly associated with both acute (P = .004) and chronic (P = .000005) GVHD. Nevertheless, 44% of patients without GVHD also had intermittent or persistent PCR- assays. CONCLUSION: The persistence of PCR-detectable bcr-abl-positive cells early post-BMT in more than 80% of patients suggests that neither BMT preparative regimen effectively eradicates CML cells in most patients. Subsequently, acute and/or chronic GVHD are associated with a decreased ability to detect residual bcr-abl-positive cells, which suggests that immunologic mechanisms mediated by donor cells are important for inducing long-term remissions after BMT. The demonstration that 44% of patients without GVHD had either low or undetectable levels of residual leukemia suggests the presence of mechanisms capable of suppression or eradication of CML independent of GVHD.

Acute Disease↗
PubMed1995

Purification of a trypsin inhibitor (PFTI) from pumpkin fruit phloem exudate and isolation of putative trypsin and chymotrypsin inhibitor cDNA clones.

The major trypsin inhibitor from pumpkin (Cucurbita maxima cv Supermarket Hybrid) fruit phloem exudate was purified by affinity and reverse phase chromatography. The protein has a molecular weight of approximately 8100 by SDS-PAGE and is blocked at the N-terminal serine. Following sequencing of a CNBr fragment, 3'- and 5'-RACE were used to isolate full length cDNAs corresponding to a trypsin inhibitor and to two chymotrypsin inhibitors. The three genes are similar, both in their translated and non-translated regions. Comparison of the full length translated proteins show that they are members of the proteinase inhibitor I family and almost identical apart from the P1 site in the proteinase binding loop. The genes encode proteins of 67 amino acids and appear to lack not only both pre- and prepro-peptide sequences but also the single disulphide present in most proteinase inhibitor I family members.

Amino Acid Sequence↗
PubMed1995

Osteoporosis workup: evaluating bone loss and risk of fractures.

Osteoporosis afflicts millions of Americans, causing an age-related increase in the incidence of fractures of the hip, wrist, spine, and other bones. Older patients require assessment of their fracture risk, including evaluation of skeletal fragility and risk of falls. Secondary causes of bone loss should be sought in individuals with bone density lower than expected for age. Preventive measures, such as supplementary calcium and vitamin D, and environmental changes to decrease the risk of falls in the home are recommended. Physical therapy may decrease the risk of falls and help maintain bone mass. Antiresorptive therapy should be considered for any individual at high risk for fracture, regardless of age.

Age Factors↗
PubMed1994

Effect of low-dose interleukin-2 on disease relapse after T-cell-depleted allogeneic bone marrow transplantation.

T-cell depletion of donor bone marrow has been associated with an increased risk of disease relapse after allogeneic bone marrow transplantation (BMT). Recombinant interleukin-2 (IL-2), which is capable of increasing the antileukemic activity of peripheral blood lymphocytes obtained from patients who have undergone BMT, has been proposed as a potentially useful agent to reduce the risk of relapse post-BMT. We have previously shown that IL-2 administered to patients at very low doses after BMT is both clinically tolerable and immunologically active. We now report on the clinical outcome of 29 patients treated with low-dose IL-2 after CD6-depleted allogenic BMT for hematologic malignancy. IL-2 was administered by continuous infusion for up to 3 months beginning at a median of 67 days post-BMT. Eligibility requirements for IL-2 therapy included demonstration of stable engraftment and absence of acute grade 2-4 graft-versus-host disease (GVHD). Low-dose IL-2 was well tolerated by the majority of patients, with only 4 of 29 subjects withdrawn early. Acute GVHD developed in only one individual. After 12 weeks of treatment, the mean number of circulating natural killer cells in patients increased 10-fold without any significant change in T-cell number. Of the 25 patients who received > or = 1 month of IL-2, only 6 have relapsed. Relapse rate and disease-free survival (DFS) were determined in the 25 patients who completed at least 4 weeks of IL-2 treatment and compared with historical controls transplanted at our institution for the same conditions and treated with an identical ablative regimen and method of T-cell depletion. Only control patients who had survived disease free for 100 days post-BMT were included in this analysis. Cox's proportional hazards regression model suggested that, compared with control patients without a history of GVHD, patients treated with IL-2 had a lower risk of disease relapse (hazard ratio 0.34; range, 0.14 to 0.82) and superior DFS (hazard ratio 0.39; range 0.18 to 0.87). A randomized controlled trial of IL-2 immunotherapy after T-cell-depleted BMT should now be undertaken.

Adult↗
PubMed1994

The phenotype and reconstitution of immunoregulatory T cell subsets after T cell-depleted allogeneic and autologous bone marrow transplantation.

In the present study, we examined changes in the expression of CD45RA, CD31, and CD29 on total CD4 and CD8 lymphocytes in patients who had received CD6 T cell-depleted allogeneic marrow and received no immune suppressive drugs after engraftment in order to identify defects in reconstitution of immunoregulatory T cells after allogeneic BMT. Results following allo-BMT were compared with normal controls and patients following autologous BMT. We showed that CD4+CD45RA+, CD4+CD29+ (CD29high), and CD4+CD31+ cells were markedly decreased during the first 24 months after allo- and auto-BMT. CD8+CD45RA+ cells recovered to normal levels within the first month after auto-BMT, while after allo-BMT, the CD8+CD45RA+ cells were at slightly low levels during the first month, but gradually increased to normal levels by 12 months post-BMT. CD8+CD29+ cells were increased during the first 12 months both after allo- and auto-BMT although during the first month, a decreased percentage of CD8+CD29+ cells was observed in allo-BMT patients. More important, CD4+CD29+, CD8+CD29+, and CD8+S6F1+ cells were significantly increased in patients with moderate-to-severe acute GVHD (grades II-IV) compared with those with or without mild acute GVHD (grade I), suggesting that CD4 helper-inducer (CD4+CD29high) and CD8 killer-effector (CD8+CD29highS6F1+) cells play an important role in the pathophysiology of acute GVHD.

Adult↗
PubMed1994

The development of a diploma/degree course for accident and emergency nurses.

The educational provision for nurses working in the field of Accident and Emergency nursing has not always been appropriate and effective. This paper provides a historical perspective of this provision. It also explores factors which are currently affecting the planning of A & E nursing courses and highlights how Bolton and Salford College of Midwifery and Nursing has in the past responded to challenges, and how it is currently delivering an A & E pathway to degree level through the ENB Framework and Higher Award.

Curriculum↗
PubMed1994

Clonidine infusion increases uptake of 99mTc-Exametazime in anterior cingulate cortex in Korsakoff's psychosis.

The effects upon regional brain function of infusing either saline or clonidine (1.5 microgram/kg) has been examined in 18 patients with alcoholic Korsakoff's psychosis using 99mTc-hexamethylpropyleneamineoxime (99mTc-HMPAO or 99mTc-Exametazime) and Single Photon Emission Tomography (SPET or SPECT). The hypothesis tested was that frontal lobe function would be increased by adrenoceptor stimulation. This was confirmed by an increase in the uptake of 99mTc-Exametazime into anterior cingulate regions of the frontal lobes. Patients were scanned before and after saline or clonidine infusion during performance of a verbal fluency task. There was a significantly increased performance of verbal fluency in patients given clonidine. This effect was variable and could not be unequivocably distinguished from increases in performance in the saline treated group. Nevertheless, the increase in neuropsychological performance was also correlated with increased function in left dorsolateral frontal cortex within the clonidine treated group. An exploratory examination of other brain areas suggested that relative increases in posterior cingulate cortex and changes in the symmetry of function within the thalamus may also be produced by acute infusion of clonidine in Korsakoff patients. The findings support the idea that adrenergic mechanisms may modulate cognitive performance by actions on attentional systems within the brain. These appear to be located primarily within limbic cortex. It is, of course, notable that this can occur in patients with profound and disabling amnesia.

Adult↗
PubMed1994

The differentiation of major depression from dementia of the Alzheimer type using within-subject neuropsychological discrepancy analysis.

The method of comparing premorbid versus current intellectual ability has become established clinical practice in the differential diagnosis of dementia versus depression. Recently, Schlosser & Ivison (1989) suggested that the comparison of premorbid ability versus current memory function may offer a more sensitive method of assessing early dementia. In the present study, a variety of within-subject discrepancy analyses comparing premorbid estimates with current measures of memory and intellectual functioning were compared across three groups: patients with dementia of the Alzheimer type, patients with major depression and healthy controls. The results revealed that, while mean group differences were easily demonstrated, the overlap between Alzheimer and depressed patients was large. It is concluded that none of the simple neuropsychological discrepancy analyses examined in the present study can be recommended for use in clinical practice for the differential diagnosis of dementia from major depression.

Aged↗
PubMed1994

Prolonged impairment of very late activating antigen-mediated T cell proliferation via the CD3 pathway after T cell-depleted allogeneic bone marrow transplantation.

One of the major obstacles in allogeneic bone marrow transplantation (allo-BMT) is prolonged T cell dysfunction resulting in a variety of infectious complications in the months to years after hematologic engraftment. We previously showed that immobilized extracellular matrix (ECM) proteins such as fibronectin (FN), the CS-1 domain of FN, or collagen (CO) acted synergistically with immobilized anti-CD3 to induce T cell proliferation. In addition, the comitogenic effect of ECMs could be mimicked by immobilized mAb reactive with a common beta 1 chain (CD29) of very late activating (VLA) antigens which include ECM receptors. Since the interaction of T cells with ECMs appears to play an important role in the process of T cell reconstitution following allo-BMT, we examined the expression of VLA antigens (alpha 1-alpha 6, beta 1) and their functional roles in CD3-mediated T cell proliferation at various times after T cell depleted allo-BMT. VLA beta 1 as well as VLA alpha 4, alpha 5, and alpha 6 expression was lower than normal controls during the first 3 mo after allo-BMT and auto-BMT, whereas these expressions returned to normal levels by 4 mo after allo-BMT and auto-BMT. Although alpha 1 and alpha 2 were not expressed on lymphocytes from normal controls, these antigens were expressed on lymphocytes at the detectable levels (5-15%) from patients after allo-BMT and auto-BMT. Both CD29 and CD3 were expressed at normal levels on lymphocytes from patients > 3 mo after allo-BMT, whereas T cell interaction with ECM through VLA proteins or crosslinking of VLA beta 1 expressed by T cells with anti-CD29 mAb results in poor induction of CD3-mediated T cell proliferation for a prolonged period (> 1 yr) after allo-BMT. In contrast, T cell proliferation induced by crosslinking of anti-CD2 or anti-CD26 with anti-CD3 was almost fully recovered by 1 yr post-allo-BMT. After autologous BMT, impaired VLA-mediated T cell proliferation via the CD3 pathway after auto-BMT returned to normal levels within 1 yr despite no significant difference in CD3 and CD29 expression following either allo- or auto-BMT. The adhesion of T cells from post-allo-BMT patients to FN-coated plate was normal or increased compared to that of normal controls. Moreover, the induction of the tyrosine phosphorylation of pp105 protein by the ligation of VLA molecules was not impaired in allo-BMT patients. These results suggest that there are some other defects in the process of VLA-mediated signal transduction in such patients. Our results imply that disturbance of VLA function could explain, at least in part, the persistent immunoincompetent state after allo-BMT and may be involved in susceptibility to opportunistic infections after allo-BMT.

Antigens, CD↗