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Biomedical subjects

B Murphy

Publications and source records attributed to B Murphy.

At least 55 records · Page 3Linked to original sources
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↗
PubMed1997

Synthetic MHC class I peptide prolongs cardiac survival and attenuates transplant arteriosclerosis in the Lewis-->Fischer 344 model of chronic allograft rejection.

BACKGROUND: A synthetic peptide corresponding to residues 75-84 of the alpha1 domain of HLA-B7 molecule (HLA-B7.75-84 [Allotrap]) inhibits cytotoxic T cell function in vitro and, when combined with subtherapeutic doses of cyclosporine (CsA), prolongs allogeneic cardiac survival. We now report the effects of HLA-B7.75-84 in the Lewis --> Fischer 344 rat model of chronic cardiac allograft rejection. METHODS: Animals were treated with CsA (5 mg/kg/day s.c.) alone or with CsA plus alternate-day HLA-B7.75-84 (20 mg/kg/day i.p.) for 30 days. Allografts harvested at day 100 were evaluated by histology and immunohistology. RESULTS: HLA-B7.75-84 plus CsA prolonged allograft survival (75% of allografts survived >90 days) compared with CsA alone (27% of allografts survived >90 days) (P<0.05). Histologic examination of control allografts showed dense cellular infiltrates and moderate transplant arteriosclerosis (>75% of arteries showed 10-20% occlusion). Infiltrating leukocytes consisted of macrophages (>75% cells), T cells (10-20%), and rare natural killer cells (<5%). Cell activation was shown by expression of major histocompatibility complex class II antigens (>75%), interleukin (IL) 2 receptor (5-10%), and staining for IL-2 (approximately 5% of intragraft mononuclear cells), interferon-gamma (5-10%) and tumor necrosis factor-alpha (approximately 20%). Leukocytes and vessels also showed labeling for the fibrogenic cytokine, transforming growth factor-beta, and all vessels showed dense deposition of IgG (IgG2a, IgG2b) and C3. The addition of HLA-B7.75-84 decreased overall cellularity (P<0.01) without affecting the composition of the infiltrate, but completely prevented transplant arteriosclerosis, diminished myocardial injury, and abrogated expression of IL-2R, IL-2, interferon-gamma, tumor necrosis factor-alpha, and transforming growth factor-beta. HLA-B7.75-84 also blunted the humoral response, which resulted in a predominance of vascular deposition of the non-complement-fixing IgG2c isotype and a concomitant decrease in C3. CONCLUSIONS: Therapy with synthetic class I major histocompatibility complex peptide (HLA-B7.75-84) attenuates key histologic features of graft arteriosclerosis, in association with inhibition of multiple cytokines and growth factors and modulation of host alloantibody responses in vivo, which is of interest since Allotrap is currently undergoing clinical trials.

Animals↗
PubMed1997

The role of abdominal adiposity and insulin resistance in dyslipidemia of chronic renal failure.

The atherogenic profile of high triglyceride, reduced high-density lipoprotein (HDL) cholesterol, and small low-density lipoprotein particle size found in patients on chronic hemodialysis is known to be associated with insulin resistance and abdominal obesity in the general population. To assess the influence of insulin resistance and abdominal adiposity on the lipid profile in subjects on hemodialysis, intravenous glucose tolerance test and dual-energy x-ray absorptiometry were performed in 26 nondiabetic subjects on hemodialysis and compared with 22 nondiabetic control subjects matched for age, sex, and body mass index. Subjects on hemodialysis were found to have higher triglyceride (133 mg/dL [95% confidence interval, 115 to 159 mg/dL] v 97 mg/dL [95% confidence interval, 80 to 124 mg/dL]; P < 0.05), lower HDL cholesterol (36 +/- 3 mg/dL v 51 +/- 4 mg/dL [mean +/- SEM]; P < 0.01), enhanced insulin response to glucose (2.72 +/- 0.28 mUL(-1) min per mg dL(-1) v 1.67 +/- 0.22 mUL(-1) min per mg dL(-1); P < 0.01), and reduced sensitivity to the action of insulin (2.24 min(-1) per mUL(-1) min [95% confidence interval, 1.86 to 2.75 min(-1) per mUL(-1) min] v 4.17 min(-1) mUL(-1) min [95% confidence interval, 2.95 to 5.9 min(-1) per mUL(-1) min]; P < 0.01) than the control subjects. Abdominal adiposity measured by dual-energy x-ray absorptiometry (2,004 +/- 210 g v 2,163 +/- 198 g [mean +/- SEM]; P = NS) and percentage of body fat distributed to the abdomen (10.5% +/- 0.3% v 9.7% +/- 0.5% [mean +/- SEM]; P = NS) did not differ between the two groups. Subjects on hemodialysis were insulin resistant, but unlike control subjects, their lipid profile was not predicted by their insulin sensitivity. Abdominal adiposity was associated with a deteriorating lipid profile and insulin resistance in subjects on hemodialysis, as it was in control subjects. The presence of renal failure resulted in additional insulin resistance and a higher triglyceride level in the leaner subjects on hemodialysis compared with control subjects with similar levels of abdominal fat. In the more obese subjects, insulin sensitivity and triglyceride level did not differ between the two groups of subjects, although HDL cholesterol level remained low in subjects on hemodialysis. In conclusion, insulin resistance in subjects on hemodialysis did not directly account for their abnormal lipid profile. The negative impact of abdominal adiposity on the metabolic profile was preserved in subjects on hemodialysis, but the presence of renal failure itself resulted in insulin resistance in the leaner subjects and dyslipidemia in all subjects on hemodialysis compared with control subjects of comparable abdominal adiposity.

Abdomen↗
PubMed1997

Family caregiving: measurement of emotional well-being and various aspects of the caregiving role.

BACKGROUND: Past research and instrument development in caregiving have focused on specific aspects of caregiving or specific disability groups. This paper reports the scale characteristics of a new generic instrument developed to assess the experience of caregiving, and the social and emotional well-being of caregivers and a comparison group of 'non-caregivers'. METHODS: Using computer-assisted telephone technology, a random survey of 26000 households was conducted in Victoria, Australia to identify and interview 976 caregivers of people who were aged or had a long-term illness or disability of any kind, and 219 non-caregivers. Both groups were re-interviewed after 15 months. Scales administered on each occasion to caregivers and non-caregivers included life satisfaction, positive and negative affect, social support and overload; and to caregivers, caring role satisfaction, resentment and anger, and, in relation to the care recipient, measures of help provided and needed, severity of disability and behaviour problems. RESULTS: On each occasion and with each sample all scales demonstrated a satisfactory reliability. With a subsample of caregiver-care-recipient dyads (N = 67), caregiver reports of severity of disability, level of helped needed and provided were validated externally by clinician assessments. CONCLUSIONS: A comprehensive instrument to assess the experience of caregiving was developed. It is relevant to a broad range of ages, levels and types of disability and care provided; and, in assessing health and well-being, to both caregivers and non-caregivers. Scales, including both positive and negative dimensions, have demonstrated good internal consistency on two occasions. The instrument is potentially useful in a range of research and practical settings.

Activities of Daily Living↗
PubMed1997

High density lipoprotein (HDL) particle composition in patients with end stage renal failure (ESRF) on chronic dialysis.

BACKGROUND: Hypertriglyceridaemia, low high density lipoprotein (HDL) cholesterol level and reduced LDL particle size are the major features of uraemic dyslipidaemia. They are also found in the Insulin Resistance Syndrome. AIM: To examine alterations in HDL composition in patients on chronic dialysis and their relationship with insulin resistance. METHODS: HDL particle size was determined in 33 patients on chronic haemodialysis (HD), 27 on chronic ambulatory peritoneal dialysis (CAPD) and 32 control non-diabetic subjects (C) without renal disease by non-denaturing 3-30% polyacrylamide gradient gel electrophoresis. A weighted HDL particle size score was calculated taking into account both HDL particle size and percentage total HDL protein concentration of each HDL band of the individual. Lipid and apolipoliprotein concentrations were determined in HDL2 and HDL3 particles obtained by sequential ultracentrifugation. In a subset of 24 control subjects and 22 subjects on HD, insulin sensitivity was also determined by an intravenous glucose tolerance test (IVGTT). RESULTS: HDL particles were found to be more triglyceride enriched and apoAI depleted in subjects on HD even though plasma triglyceride level was highest in patients on CAPD. Five subpopulations of HDL particles were identified by gradient gel electrophoresis in all subjects combined. In the subgroup of subjects who underwent IVGTT, the weighted HDL particle size score correlated positively with HDL cholesterol level (r = 0.6, p < 0.0005), LDL particle size (r = 0.47, p < 0.001), and insulin sensitivity (r = 0.48, p < 0.001), and negatively with plasma triglyceride level (r = 0.37, p < 0.01). CONCLUSIONS: We conclude that even though HDL cholesterol is reduced to a similar level in subjects on both forms of dialysis for end stage renal failure, abnormalities of HDL composition are more marked in subjects on HD. Reduction in HDL particle size is linked with insulin resistance and accompanies reduction in LDL particle size and hypertriglyceridaemia.

Cholesterol, HDL↗
PubMed1997

The role of general practitioners and pharmacists in information exchange with family carers.

As a trial of the provision of community-service information to family carers, general practitioners and pharmacists from the Western region of Melbourne were supplied with tear-off pads listing suburb-specific community services, and were encouraged to discuss service needs with carers of people with disabilities and distribute the lists to carers accordingly. One hundred and nine general practitioners and 58 pharmacists participated in pretrial and post-trial interviews assessing their knowledge of community services and frequency of discussion with carers. Before the trial, general practitioners had significantly higher self-rated knowledge of community services and reportedly discussed these with carers more often than did pharmacists. After the five-month trial period, pharmacists showed a significant increase in self-rated knowledge and frequency of discussion. General practitioners' knowledge and discussion showed a nonsignificant increase. After the trial, the two did not differ in knowledge of services; however, general practitioners maintained a higher reported frequency of discussion about services with carers. General practitioners and pharmacists appear to be well placed to act as a service link for family carers. However, additional high-intensity strategies are needed to assist them in this role.

Caregivers↗
PubMed1997

Hormonal therapy of breast cancer: state of the art.

Hormonal therapy has an established role in the treatment of women with metastatic breast cancer and also is now a major component of adjuvant systemic therapy for those with early-stage disease. Moreover, recent data suggest that hormonal agents may have a potential use in the prevention of breast cancer in high-risk groups. This article will provide a general overview of the current roles of hormonal therapy and describe future directions that show particular promise.

Antineoplastic Agents, Hormonal↗
PubMed1996

Acquired systemic tolerance to rat cardiac allografts induced by intrathymic inoculation of synthetic polymorphic MHC class I allopeptides.

This study extends the finding that intrathymic (IT) injection of 3M KC1 extracts of T cells induces transplant tolerance to the use of well defined polymorphic MHC class I allopeptides derived from the hypervariable domain of RT1.Au (WF MHC class I). While three of the six synthetic RT1.Au peptides were immunogenic, three others were nonimmunogenic when tested in ACI responders. In our initial studies, we examined the effects of IT injection of a mixture of equal concentrations of the three nonimmunogenic RT1.Au peptides on WF cardiac allograft survival in ACI recipients. The results showed that a single IT injection of 100 and 300 microg class I MHC allopeptides on day -7 relative to cardiac transplant did not significantly prolong graft survival in naive ACI recipients (MST of 9.8, and 12.3 days vs. 10.5 days in controls). In contrast, 600 microg allopeptides injected IT resulted in modest prolongation of graft to an MST of 19.5 days. However, IT injection of 600 microg allopeptides combined with 0.5 ml ALS on day -7 led to permanent acceptance (>200 days) of cardiac allografts in 7/9 ACI recipients compared with survival of 24.2 days in ALS alone treated controls. In contrast, similar treatment led to acute rejection of third party (Lewis) cardiac allografts. Intravenous injection of 600 microg allopeptides combined with ALS did not result in prolonged graft survival (26.8 days). The long-term unresponsive ACI recipients (>100 days) challenged with second-set cardiac grafts accepted permanently donor-type (WF) grafts while rejecting the third party (Lewis) grafts, a finding that confirms acquired systemic tolerance. These findings confirm the role of IT injection of synthetic polymorphic allopeptides in the induction of acquired thymic tolerance and provide the rationale for testing this strategy in large animals and eventually in man.

Amino Acid Sequence↗
PubMed1996

Mechanisms of indirect allorecognition in graft rejection: class II MHC allopeptide-specific T cell clones transfer delayed-type hypersensitivity responses in vivo.

Recent animal studies suggest that indirect T-cell recognition of alloantigen plays an important role in allograft rejection and tolerance. In this study, we generated T cell clones from Lewis (LEW, RT1(l)) rat lymph node cells that had been primed in vivo by immunization with immunogenic class II MHC allopeptide RT1.D(u)beta2, representing residues 20-44 of the polymorphic beta chain of RT1.Dbeta(u) (Wistar Furth [WF]). Using reverse transcriptase polymerase chain reaction transcript analysis with specific rat T cell receptor Vbeta primers, we show that six out of nine T cell clones specifically proliferated to RT1.D(u)beta2 and expressed Vbeta 9. One of these clones, clone 2F4, which specifically proliferated to RT1.D(u)beta2 in a dose-response fashion and produced interferon-gamma in response to restimulation by RT1.D(u)beta2, was selected for further studies. The beta-chains of RT1.D(l) and RT1.D(u) residues 20-44 differ by two amino acids at positions 30 and 38. We synthesized two peptides, each containing a single polymorphic site: RT1.D(u)beta 20-33 and RT1.D(u)beta 31-44. Both these peptides were immunogenic by LEW responders, since lymph node cells primed by immunization proliferated equally to the peptides in vitro. Interestingly, in vitro dose-response studies with clone 2F4 showed better proliferative response to peptide RT1.D(u)beta 20-33 than to peptide RT1.D(u)beta 31-44, indicating that this T cell clone preferentially recognizes a single amino acid difference on residue 30. Finally, it has been suggested that indirect allorecognition by CD4+ T cells mediate graft rejection by delayed-type hypersensitivity responses, although definitive studies are lacking. Systemic injection of the 2F4 clone to naive LEW rats elicited an antigen-specific delayed-type hypersensitivity response against RT1.D(u)beta2 peptide and WF splenocytes, confirming indirect presentation in vivo. These data demonstrate that Th1 cell clones generated by in vivo priming via the indirect pathway utilize specific T cell receptor Vbeta and recognize single amino acid differences in the allopeptide. More importantly,these Th1 clones are capable of mediating a specific immune response in vivo. These studies with MHC allopeptide-specific T cell clones further delineate the cellular mechanisms of indirect allorecognition and provide a potential strategy to study its role in acute and chronic rejection, and tolerance.

Adoptive Transfer↗
PubMed1996

T cell recognition of xeno-MHC peptides during concordant xenograft rejection.

T cell recognition of xenoantigens is likely to play a key role in rejection of xenografts surviving hyperacute and delayed xenograft rejection, but the mechanisms of how this might occur are unknown. We used synthetic rat class II MHC peptides to study the role of the indirect pathway, where processed xenogeneic MHC antigens are presented in the context of self MHC, in a concordant xenograft rejection model in vivo. Mice of four different strains, BALB/c, B1O.A, CBA/ca, and C57BL/6j, were immunized with a mixture of rat class II MHC 25-mer xenopeptides representing the full-length sequence of the beta chain hypervariable domain of either RT1.Du (DR and I-E like) or RT1.Bu (DQ and I-A like) of the Wistar-Furth (WF) (RT1u) rat. Draining lymph node cells were capable of recognizing and proliferating to specific class II xeno-MHC peptides. The immunogenicity of the different peptides varied with the responder mouse strain. Responder T cells were CD4+, and were inhibited by anti-I-A and anti-I-E antibodies. We then examined the proliferative response of T cells from B1O.A primed by WF skin or vascularized cardiac xenografts to the class II MHC xenopeptides, when presented by naive B1O.A splenic antigen-presenting cells. These T cells were capable of proliferating to the same xeno-MHC peptides shown to be immunogenic by immunization. These data confirm the occurrence of self-restricted T cell recognition of xeno-MHC peptides in xenograft rejection, and provide the rationale for further investigating the role of the indirect pathway of recognition in xenotransplantation.

Animals↗
PubMed1996

Irish study on high-density schizophrenia families: field methods and power to detect linkage.

Large samples of multiplex pedigrees will probably be needed to detect susceptibility loci for schizophrenia by linkage analysis. Standardized ascertainment of such pedigrees from culturally and ethnically homogeneous populations may improve the probability of detection and replication of linkage. The Irish Study of High-Density Schizophrenia Families (ISHDSF) was formed from standardized ascertainment of multiplex schizophrenia families in 39 psychiatric facilities covering over 90% of the population in Ireland and Northern Ireland. We here describe a phenotypic sample and a subset thereof, the linkage sample. Individuals were included in the phenotypic sample if adequate diagnostic information, based on personal interview and/or hospital record, was available. Only individuals with available DNA were included in the linkage sample. Inclusion of a pedigree into the phenotypic sample required at least two first, second, or third degree relatives with non-affective psychosis (NAP), one whom had schizophrenia (S) or poor-outcome schizo-affective disorder (PO-SAD). Entry into the linkage sample required DNA samples on at least two individuals with NAP, of whom at least one had S or PO-SAD. Affection was defined by narrow, intermediate, and broad criteria. The phenotypic sample contained 277 pedigrees and 1,770 individuals and the linkage sample 265 pedigrees and 1,408 individuals. Using the intermediate definition of affection, the phenotypic sample contained 837 affected individuals and 526 affected sibling pairs. Parallel figures for the linkage sample were 700 and 420. Individuals with schizophrenia from these multiplex pedigrees resembled epidemiologically sampled cases with respect to age at onset, gender distribution, and most clinical symptoms, although they were more thought-disordered and had a poorer outcome. Power analyses based on the model of linkage heterogeneity indicated that the ISHDSF should be able to detect a major locus that influences susceptibility to schizophrenia in as few as 20% of families. Compared to first-degree relatives of epidemiologically sampled schizophrenic probands, first-degree relatives of schizophrenic members from the ISHDSF had a similar risk for schizotypal personality disorder, affective illness, alcoholism, and anxiety disorder. With sufficient resources, large-scale ascertainment of multiplex schizophrenia pedigrees is feasible, especially in countries with catchmented psychiatric care and stable populations. Although somewhat more severely ill, schizophrenic members of such pedigrees appear to clinically resemble typical schizophrenic patients. Our ascertainment process for multiplex schizophrenia families did not select for excess familial risk for affective illness or alcoholism. With its large sample ascertained in a standardized manner from a relatively homogeneous population, the ISHDSF provides considerable power to detect susceptibility loci for schizophrenia.

Adult↗