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Biomedical subjects

B Murphy

Publications and source records attributed to B Murphy.

At least 37 records · Page 2Linked to original sources
PubMed1999

Impaired wound contraction in stromelysin-1-deficient mice.

OBJECTIVE: To determine whether the deletion of stromelysin-1, a single metalloproteinase gene product, will alter the time course and quality of dermal wound repair in mice. SUMMARY BACKGROUND DATA: After dermal injury, a highly coordinated program of events is initiated by formation of a fibrin clot, followed by migration of keratinocytes, contraction of the dermis, recruitment of inflammatory macrophages, formation of granulation tissue with angiogenesis, and finally tissue remodeling. Matrix metalloproteinases are rapidly induced in the dermis and granulation tissue and at the leading edge of the epidermis in the healing wounds. METHODS: Incisional and circular full-thickness wounds 2 to 10 mm were made in the dermis of stromelysin-1-deficient and wild-type mice. The wounds were analyzed for rate of cellular migration and epithelialization. The wound contraction was examined by immunohistochemical staining for alpha-smooth muscle actin and fluorescent staining for fibrillar actin. RESULTS: Independent of the age of the animal, excisional wounds in stromelysin-1-deficient mice failed to contract and healed more slowly than those in wild-type mice. Cellular migration and epithelialization were unaffected in the stromelysin-1-deficient animals. The functional defect in these mice is failure of contraction during the first phase of healing because of inadequate organization of actin-rich stromal fibroblasts. CONCLUSIONS: Excisional dermal wound healing is impaired in mice with a targeted deletion in the stromelysin-1 gene. Incisional wound healing is not affected. These data implicate stromelysin-1 proteolysis during early wound contraction and indicate that stromelysin-1 is crucial for the organization of a multicellular actin network.

Animals↗
PubMed1999

Health and well-being of women family carers: a comparative study with a generic focus.

OBJECTIVE: To examine differences between women family carers of people with chronic illnesses or disabilities and a group of women 'non-carers' in self-reported physical health, psychological well-being, life satisfaction, social support and feelings of overload. METHOD: Using a computer-assisted telephone interviewing system, a random survey of more than 26,000 households was conducted in Victoria to identify and then interview a representative sample of family carers of people with disabilities or chronic illnesses. The women in the sample (n = 857) were then compared with a sample of women with 'usual family responsibilities' (n = 219) in terms of physical and emotional states. RESULTS: We found higher rates of self-reported ill-health and use of medication, more negative effect, and less life satisfaction and perceived social support, among carers than among women in the comparison group. Even though the latter were more likely to be caring for one or more children, compared with the carers they reported less overload. Irrespective of carers status, women without partners expressed less life satisfaction, and more social isolation and negative effect. CONCLUSIONS AND IMPLICATIONS: The poorer health status and emotional well-being of carers compared with non-carers among women, and associations between overload, social isolation, negative effect and health problems within carers, point to a number of practical interventions such as promoting an awareness in GPs and other health professionals of the impact of caregiving on the health of their patients; informing them about relevant community services; and encouraging appropriate referrals.

Adaptation, Psychological↗
PubMed1999

Geography of intestinal permeability and absorption.

BACKGROUND: Intestinal morphology and function vary geographically. AIMS: These functions were assessed in asymptomatic volunteers in European, North American, Middle Eastern, Asian, African, and Caribbean countries. METHODS: Five hour urine collections were obtained from each subject following ingestion of a 100 ml iso-osmolar test solution containing 3-0-methyl-D-glucose, D-xylose, L-rhamnose, and lactulose after an overnight fast, to assess active (3-0-methyl-D-glucose) and passive (D-xylose) carrier mediated, and non-mediated (L-rhamnose) absorption capacity, as well as intestinal permeability (lactulose:rhamnose ratio). RESULTS: A comparison of results for subjects from tropical countries (n=218) with those resident in the combined temperate and subtropical region (Europe, United States, Qatar) (n=224) showed significant differences. Residents in tropical areas had a higher mean lactulose:rhamnose ratio and lower mean five hour recoveries of 3-0-methyl-D-glucose, D-xylose, and L-rhamnose, indicating higher intestinal permeability and lower absorptive capacity. Investigation of visiting residents suggested that differences in intestinal permeability and absorptive capacity were related to the area of residence. Subjects from Texas and Qatar, although comprised of several ethnic groups and resident in a subtropical area, showed no significant difference from European subjects. CONCLUSIONS: There are clearly demarcated variations in intestinal permeability and absorptive capacity affecting asymptomatic residents of different geographical areas which correspond with the condition described as tropical enteropathy. Results suggest the importance of environmental factors. The parameters investigated may be relevant to the predisposition of the indigenous population and travellers to diarrhoeal illness and malnutrition. Intestinal function in patients from the tropics may be difficult to interpret, but should take into account the range of values found in the asymptomatic normal population.

Adult↗
PubMed1999

Inhibition of allorecognition by a human class II MHC-derived peptide through the induction of apoptosis.

The interaction of the T-cell receptor with the major histocomatibility complex (MHC)-peptide complex is central to T-cell activation. Variation in the nature of the peptide bound within the groove of the MHC molecule may result in an altered T-cell response. Because some naturally processed peptides bound within the groove of the class II MHC molecule are derived from the MHC molecules themselves, we studied the inhibitory effects of synthetic class II MHC peptides on alloimmune responses in vitro. Three peptides derived from a highly conserved region of the class II MHC alpha chains inhibited the rat mixed lymphocyte response (MLR) in a dose-dependent manner, with the human HLA-DQA1 peptide also inhibiting the human and mouse MLR. No effect was seen on mitogen-induced T-cell proliferation. HLA-DQA1 inhibited cytolytic T lymphocyte (CTL) generation in a dose-response fashion, with no reduction in preformed CTL killing, suggesting that the inhibitory effect is targeted at CD4(+) T-cell function. Cell-cycle analysis by flow cytometry showed that restimulation of primed T cells in the presence of HLA-DQA1 resulted in increased apoptosis, whereas unstimulated cells were not affected. These data demonstrate that synthetic peptides derived from highly conserved regions of the class II MHC alpha chain can alter CD4(+) T-lymphocyte alloimmune responses in vitro, and this effect is mediated by the induction of apoptosis in activated T cells.

Adjuvants, Immunologic↗
PubMed1999

Immunomodulatory functions of low-molecular weight hyaluronate in an acute rat renal allograft rejection model.

Low molecular weight hyaluronate (LMW-HA) blocks interactions between T lymphocyte CD44 and hyaluronate (HA), a heteropolysaccharide that is expressed on the surface of endothelial cells and ubiquitously in the extracellular matrix. This study was undertaken to assess the ability of LMW-HA to modify the course of experimental acute renal allograft rejection. Lewis (LEW) rats were bilaterally nephrectomized and received an orthotopic, fully MHC-mismatched, Wistar-Furth (WF) kidney transplant. Animals received either no treatment, low doses of cyclosporin A (CsA) on days 0 to 5, LMW-HA on days 0 to 5, or CsA plus LMW-HA on days 0 to 5 after transplantation. With no treatment, CsA monotherapy, or HA monotherapy, animals rejected their allografts at a median of 15, 13, and 7.5 d, respectively (P = NS). In contrast, combined CsA plus LMW-HA therapy prevented acute rejection and significantly prolonged graft survival (P = 0.008) to a median of 49.0 d. CsA/LMW-HA-treated grafts also demonstrated better preservation of renal function at day 30 (serum creatinine level, 1.38+/-0.8 mg/dl), compared with surviving animals treated with CsA alone (2.9+/-0.55 mg/dl, P<0.05). Histologic graft analysis of CsA/LMW-HA-treated animals at day 7 after transplantation showed minimal rejection and leukocyte infiltration, compared with all other groups. Intragraft gene expression analysis, using semiquantitative reverse transcription-PCR, at the same time point showed reductions of CD4, CD8, and interferon-gamma transcript levels in the combined-treatment group. This is the first study demonstrating the immunomodulatory functions of LMW-HA in vivo in the setting of organ transplantation. Defining the exact mechanisms that underlie this immunomodulation may provide the rationale to develop novel strategies for use in clinical transplantation.

Adjuvants, Immunologic↗
PubMed1999

HLA-derived peptides as novel immunomodulatory therapeutics.

A growing body of experimental evidence demonstrates that synthetic peptides corresponding to linear sequences of MHC (HLA in humans) proteins have immunomodulatory effects in vitro and in vivo in animal models and in humans. Although the original concept was that these peptides inhibited antigen recognition at the MHC-T cell receptor interface via physical blockade, it is now clear that the mechanisms responsible for the myriad of functional effects are more complex. Recent findings show that some peptides affect signal transduction and cell cycle progression. Fragments of MHC molecules can dampen or downregulate immune responses via a variety of mechanisms. Some soluble MHC molecules or synthetic peptides are capable of inducing and maintaining immunologic tolerance in animals. This information suggests that synthetic peptides themselves or drugs mimicking their effects may represent a new class of immunotherapeutics.

Animals↗
PubMed1999

Multimodality therapy of patients with locally advanced squamous cell cancer of the head and neck: preliminary results of two pilot trials using paclitaxel and cisplatin.

Chemotherapy has been integrated into the initial treatment of patients with locally advanced squamous cell cancer of the head and neck to improve locoregional control and survival. Two strategies for improving these outcomes are the use of new, potentially more effective drugs either with concurrent radiotherapy or as induction regimens. Because of its inherent activity against squamous cell cancer of the head and neck and its radiation-sensitizing properties, paclitaxel may be a valuable agent in the treatment of this patient population. We describe the preliminary results of two trials that evaluated the combination of paclitaxel and cisplatin in patients with locally advanced disease: a phase I trial of weekly paclitaxel and cisplatin with concurrent postoperative radiation therapy in patients with high-risk disease and a phase I/II trial of paclitaxel as a 96-hour infusion in combination with cisplatin as induction therapy. These studies identified tolerable doses of paclitaxel and cisplatin administered in these settings, with apparent clinical activity. These trials formed the basis for subsequent evaluation of induction paclitaxel and cisplatin followed by definitive radiotherapy and concurrent weekly paclitaxel and cisplatin plus radiotherapy.

Adult↗
PubMed1998

Molecular cloning and characterization of a transcription regulator with homology to GC-binding factor.

GC-binding factor (GCF) represses transcription of certain genes and is encoded by a 3.0-kilobase mRNA (Kageyama, R., and Pastan, I. (1989) Cell 59, 815-825). The GCF cDNA hybridizes to two additional mRNA species, 4.2 and 1.2 kilobases. We have used differential hybridization to identify a cDNA clone (termed GCF2) for the 4. 2-kilobase mRNA and find that it is highly expressed in HUT-102 cells. The open reading frame consists of 2256 nucleotides and encodes a protein of 752 amino acids with a calculated molecular mass of 83 kilodaltons. GCF2 expressed in vitro using reticulocyte lysates and Escherichia coli migrates as a 160-kilodalton protein in SDS-polyacrylamide gel electrophoresis but has a molecular mass of 83 kilodaltons as determined by mass spectrum analysis. GCF2 binds to epidermal growth factor receptor promoter fragments, and the major binding site is located between nucleotides -249 and -233. Cotransfection assays show that GCF2 acts to repress transcription from the epidermal growth factor receptor promoter in constructs containing the major GCF2 binding site and not when the site had been mutated. Thus, GCF2 is a newly identified transcriptional repressor with aberrant electrophoretic mobility.

Amino Acid Sequence↗
PubMed1998

Interferon regulatory factor-1 is a major regulator of epidermal growth factor receptor gene expression.

Overexpression of the epidermal growth factor receptor (EGFR) occurs in many tumors and in breast cancer correlates with poor prognosis for treatment. Here, we report that interferon regulatory factor-1 (IRF-1) induces EGFR promoter activity up to 200-fold compared to 3-10-fold induction by other regulators. The region of the promoter that is required for this induction was defined using deletion mutants. In addition, we found that IRF-1 and tricostatin A, a deacetylase inhibitor, have a synergistic effect on EGFR promoter activity. This indicates that the increase in EGFR promoter activity by IRF-1 may also involve changes in chromatin structure. These results identify IRF-1 as a major regulator of EGFR gene expression.

Base Sequence↗
PubMed1998

Depletion of omega-3 fatty acid levels in red blood cell membranes of depressive patients.

BACKGROUND: It has been hypothesized that depletion of cell membrane n3 polyunsaturated fatty acids (PUFA), particularly docosahexanoic acid (DHA), may be of etiological importance in depression. METHODS: We measured the fatty acid composition of phospholipid in cell membranes from red blood cells (RBC) of 15 depressive patients and 15 healthy control subjects. RESULTS: Depressive patients showed significant depletions of total n3 PUFA and particularly DHA. Incubation of RBC from control subjects with hydrogen peroxide abolished all significant differences between patients and controls. CONCLUSIONS: These findings suggest that RBC membranes in depressive patients show evidence of oxidative damage. Possible interpretations, and implications for the etiology and treatment of depression, are discussed.

Adolescent↗
PubMed1998

Melanocortin mediated inhibition of feeding behavior in rats.

Melanocortinergic neurons are believed to play a role in the control of food intake. Melanocortin receptor agonists and antagonists modulate feeding in several mouse models of chemically and genetically induced hyperphagia. To date, little information is available describing the role of this neurological system in the control of the natural feeding cycle in genetically intact rats. To evaluate the involvement of melanocortins in spontaneous nocturnal feeding, the synthetic melanocortin receptor agonist, MTII and the antagonist, SHU9119 were administered ICV (third ventricle) alone and in combination. Dose-dependent inhibition or stimulation of food intake was observed with MTII or SHU9119, respectively. Co-injections containing equal concentrations of MTII and SHU9119 resulted in food intake that was indistinguishable from controls. Food intake patterns observed in studies in which various dose combinations of MTII and SHU9119 were co-injected are consistent with the concept that both affect feeding by acting on similar melanocortin receptors. The hypothesis that effects of melanocortins on feeding may be mediated via an NPY related pathway was tested by co-injecting MTII and NPY in a 2-h satiated food intake paradigm. MTII inhibited food intake induced by 5.0 microg hNPY in a dose dependent manner with the highest dose tested abolishing the NPY feeding response. The studies suggest that melanocortins act via specific receptors to control food intake in rats, possibly via an NPY related pathway. If similar neurochemical processes operate in humans, selectively modulating specific melanocortin receptor signaling may be an approach to the treatment of human obesity.

Animals↗
PubMed1998

Cytokine analysis of human renal allograft aspiration biopsy cultures supernatants predicts acute rejection.

BACKGROUND: A Th1 response is said to be associated with transplant rejection and Th2 with tolerance, although this is not agreed by all. Cytokines evaluation in peripheral blood and urine in kidney transplants produces variable results. We hypothesized that measurement of major cytokines involved in Th1/Th2 paradigm on transplant renal-infiltrating cells could bring valuable scientific and clinical information. METHODS: Fifty-six adult cadaver kidney transplants were subdivided into 21 stable patients (group A), 22 suffering acute rejection (group B), 10 with chronic rejection (group C) and three with CMV disease (group D). Fine-needle aspiration biopsies were cultured and their supernatants analysed for IL-2, IL-4, IL-10 and IFN-gamma. RESULTS: Group A produced small amounts of both IL-2 and IL-10 while group B synthetized significantly higher IL-2 and significantly lower IL-10 amounts than group A. Group B produced significantly more IL-2 than A on day 7 post-transplantation, several days before rejection supervened. Group C produced IL-10 and very low amount of IL-2. Group D produced both IL-2 and IL-10. We did not find any IL-4, and IFN-gamma was present in a few samples. For IL-2, sensitivity, specificity, negative and positive predictive values for acute rejection were 100, 87.2, 94.7 and 83.3%, respectively. CONCLUSIONS: Cytokine analysis in fine-needle aspiration biopsy cultures supernatants is a very useful immunological screening method for kidney transplants. IL-2 synthesis on day 7 post-transplantation reliably predicted the risk of impending acute rejection during the first weeks. The cytokine pattern suggests that acute rejection is associated with Th1, stable patients with Th0/Th2, and chronic rejection with Th2 patterns.

Acute Disease↗
PubMed1998

Surgical management of giant nonmelanoma skin neoplasia.

BACKGROUND: Management of advanced integumentary malignancy has been controversial. We have evaluated and treated 10 patients with giant nonmelanoma skin neoplasias more than 8 cm in diameter. METHODS: Aggressive surgical ablation was prospectively recommended to treat giant basal cell or mixed basosquamous tumors and two purely squamous cell tumors. Radiation therapy was given in three surgical patients. Our data are analyzed retrospectively. RESULTS: Survival of the two patients who refused surgery was measured in weeks. One patient who refused adequate surgery survived 9 months before dying. All of the adequately treated surgical patients are alive as of this writing, including one who had subsequent resection of pulmonary metastases. Three patients required free tissue transfer. The average survival of surgically treated patients was 2.7 years. CONCLUSION: An aggressive surgical approach to the management of advanced/giant skin neoplasia is justifiable and the only treatment that may produce long-term survivability.

Aged↗
PubMed1998

Conservative management of splenic rupture in a haemophiliac adult.

The recognition of the grave risk of overwhelming sepsis in splenectomized individuals has led to the search for alternatives to splenectomy. Conservative management, first tried successfully in children and later extended to adult patients, has become the accepted form of treatment and has also been tried with success in haemophiliac children. The case presented here is important because this is the first report of a successful outcome of non-operative treatment of a ruptured spleen in a haemophiliac adult.

Adult↗
PubMed1997

Indirect allorecognition of major histocompatibility complex allopeptides in human renal transplant recipients with chronic graft dysfunction.

BACKGROUND: It has been suggested that T cells primed by processed donor major histocompatibility complex antigen (the "indirect" pathway of allorecognition) may be responsible for mediating chronic allograft rejection. The purpose of this study was to develop a clinically useful assay to study the occurrence of indirect allorecognition during chronic rejection in humans. METHODS: A panel of 20 mer peptides corresponding to the hypervariable regions of HLA-DRB1*0101, DRB1*1501, and DRB1*0301 were synthesized. Lymphocytes obtained from renal allograft recipients were cocultured with these peptides. Proliferation was assayed by DNA incorporation of [3H]thymidine, and positive proliferation was defined by a statistically significant increase in counts per minute over background with a minimum stimulation index of 2. The precursor frequency of allopeptide reactive T cells was determined by limiting dilution analysis. RESULTS: Lymphocytes from 82% of patients who were mismatched for at least one of the three DR molecules and had chronic allograft dysfunction specifically proliferated to the mismatched allopeptides (n=11). Proliferation was seen in only 6% of control subjects (2/33, P<0.0001). The proliferative response was low grade and was best detected on day 7-8 of culture in vitro. The precursor frequency of peptide-specific T cells was more than 10-fold higher compared with controls (P<0.001). CONCLUSIONS: These data demonstrate for the first time that T cells of patients with chronic graft dysfunction are primed to recognize and respond to specific donor-derived major histocompatibility complex allopeptides. Our results support the hypothesis that T cells primed via the indirect pathway of allorecognition may be important mediators of chronic rejection and provide the rationale to develop specific therapeutic strategies to prevent or interrupt this process.

Adult↗