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Biomedical subjects

M Murphy

Publications and source records attributed to M Murphy.

At least 109 records · Page 6Linked to original sources
PubMed2000

Dietary folate and the prevalence of neural tube defects in the British Isles: the past two decades.

OBJECTIVES: To measure the changes in folate consumption and the prevalence of neural tube defects in the British and Irish populations during the past two decades. DESIGN: Ecological study. MAIN OUTCOME MEASURES: Average daily dietary folate consumption for Britain for the period 1980-1996 was estimated from the National Food Survey. Annual neural tube defect prevalences for the same period were obtained from the Oxford Record Linkage Study Neural Tube Defect register, the Glasgow EUROCAT register, and the three Irish EUROCAT registers (Belfast, Dublin and Galway). RESULTS: Dietary folate consumption increased on average by 1.6% per annum in Scotland and 1.4% in England during the study period. The annual rate of decline of neural tube defect prevalence averaged 10.4% in the Irish population, 8.2% in Glasgow, and 5.2% in Oxfordshire and West Berkshire. CONCLUSIONS: The decline in neural tube defect prevalence observed in all British and Irish populations since the early 1970s continued with the introduction of folate fortification of cereals, which produced measurable increases in average daily folate consumption. Further declines in neural tube defect prevalence may be achieved by targeted folate supplementation during the periconceptual period.

Diet↗
PubMed2000

Functional heterogeneity and high frequencies of cytomegalovirus-specific CD8(+) T lymphocytes in healthy seropositive donors.

Human cytomegalovirus (HCMV) infection is largely asymptomatic in the immunocompetent host, but remains a major cause of morbidity in immunosuppressed individuals. Using the recently described technique of staining antigen-specific CD8(+) T cells with peptide-HLA tetrameric complexes, we have demonstrated high levels of antigen-specific cells specific for HCMV peptides and show that this may exceed 4% of CD8(+) T cells in immunocompetent donors. Moreover, by staining with tetramers in combination with antibodies to cell surface markers and intracellular cytokines, we demonstrate functional heterogeneity of HCMV-specific populations. A substantial proportion of these are effector cytotoxic T lymphocytes, as demonstrated by their ability to lyse peptide-pulsed targets in "fresh" killing assays. These data suggest that the immune response to HCMV is periodically boosted by a low level of HCMV replication and that sustained immunological surveillance contributes to the maintenance of host-pathogen homeostasis. These observations should improve our understanding of the immunobiology of persistent viral infection.

CD8-Positive T-Lymphocytes↗
PubMed2000

Peptic ulcer bleeding: accessory risk factors and interactions with non-steroidal anti-inflammatory drugs.

AIMS: To determine risk factors for peptic ulcer bleeding other than non-steroidal anti-inflammatory drugs (NSAIDs). Methods-Data on possible antecedent risk factors obtained in a large case control study of 1121 patients admitted to hospitals in Glasgow, Newcastle, Nottingham, Oxford, and Portsmouth with bleeding peptic ulcers were compared with the same information obtained in 989 population controls. Data were analysed by logistic regression with the calculation of odds ratios (OR) and 95% confidence intervals (CI). RESULTS: From a logistic regression model, oral anticoagulants (OR 7. 8; 95% CI 2.8-21.5), previous peptic ulcer (3.8; 2.6-4.9), treatment for heart failure (5.9; 2.3-13.1), oral corticosteroid use (2.7; 1. 3-4.5), treatment for diabetes (3.1; 1.2-4.3), and current smoking (1.6; 1.2-2.0) were all independent risk factors. No association was found with use of calcium channel antagonists. Odds ratios for concomitant NSAID usage were multiplicative with the exception of current smoking. CONCLUSIONS: Some 45% of admissions for peptic ulcer bleeding in England and Wales in those aged 60 or more are calculated to be attributable to, or associated with, these accessory risk factors, which, together with those associated with aspirin or other NSAID use will account for over 80% of predisposing factors to ulcer bleeding.

Aged↗
PubMed2000

Influence of lipoxin A(4) and other lipoxygenase-derived eicosanoids on tissue factor expression.

Lipoxins (LX) are eicosanoids generated via transcellular biosynthetic routes during inflammation, hypersensitivity reaction, and after angioplasty. LXs are modulators of leukocyte trafficking and vascular tone. Their influence on the coagulation cascade has not been determined. In this study, we evaluated the influence of LXs on the expression of tissue factor (TF), a key regulator of coagulation. TF activity was measured in lysates of monocytes, human umbilical vein endothelial cells, and ECV304 cells using a one-stage clotting assay. LXA(4) stimulated TF activity in each cell type. The influence of LXA(4) on TF activity by ECV304 cells was studied further to explore the mechanism of induction of TF expression. LXA(4)-induced TF activity was dose dependent, cycloheximide sensitive, and associated with increased TF mRNA levels. Induction of TF activity was specific for LXA(4) and was not observed with LXB(4), the other major lipoxin generated by mammalian cells. Furthermore, ECV304 cell TF expression was not influenced by 15(R/S)-methyl-LXA(4) or 16-phenoxy-LXA(4), synthetic analogs of LXA(4) that activate the myeloid LXA(4) receptor, and was not modulated by SKF-104353, which blocks LXA(4) bioactivities transduced through the putative shared LXA(4)/LTD(4) receptor. LXA(4)-stimulated TF expression was blunted by pertussis toxin and by GF-109203X, an inhibitor of protein kinase C, and was not associated with degradation of IkappaBalpha. Our results establish that LXA(4) induces TF activity via cell signaling pathways with different structural and receptor requirements from those described for inhibition of leukocyte-endothelial cell interactions. They suggest a role for LXA(4) as a modulator of TF-related vascular events during inflammation and thrombosis.

Arachidonic Acid↗
PubMed2000

Effects of 7 years of growth hormone replacement therapy in hypopituitary adults.

Short-term studies of GH replacement in adult hypopituitarism have usually demonstrated beneficial effects on body composition and circulating lipids, with neutral or occasionally adverse effects on glucose tolerance. Fasting hyperinsulinemia has been reported. GH effects on cardiac function have been variable. The effects of long-term GH therapy, taking into account the consequences of increasing age, are not fully known. Thirty-three hypopituitary, initially middle-aged adults were studied over a 7-yr period; 12 patients took GH therapy (mean, 0.7 mg daily) continuously (group A); 11 took GH for only 6-18 months, a minimum of 5 yr previously (group B); and 10 patients never received GH therapy (group C). Other pituitary replacement was maintained. Effects on anthropometry, body composition (by bioimpedance analysis, total body potassium, and dual energy x-ray absorptiometry), circulating lipids, glucose and insulin concentrations, cardiac 2-dimensional and Doppler echocardiography, and exercise tolerance were assessed before and after the treatment period. Continuous GH therapy had no significant effect on body weight, but it prevented the increase in waist circumference and waist to hip ratio that occurred in the patients without GH substitution (waist to hip ratio, group A, 0.87+/-0.08 at baseline, 0.85+/-0.09 at 7 yr; group B, 0.89+/-0.11 at baseline, 0.94+/-0.11 at 7 yr; P < 0.005 for GH effect; group C, 0.87+/-0.10 at baseline, 0.92+/-0.10 at 7 yr; P < 0.005 for GH effect). A GH-induced decrease in subscapular skinfold thickness was also observed. By bioimpedance analysis, GH therapy caused an increase in total body water and fat-free mass, and a decrease in the percent body fat. Although changes occurred with time in all groups, no significant additional GH therapy effects were observed on glucose tolerance, insulin concentrations, lipid levels, cardiac dimensions, echocardiographic diastolic function, or exercise tolerance. In conclusion, prolonged GH substitution in middle-aged hypopituitary adults causes a sustained improvement in body composition. Other benefits, e.g. on lipid levels and exercise tolerance, were not apparent at 7 yr when comparisons were made with GH-untreated hypopituitary controls. Potentially adverse effects on glucose tolerance and insulinemia did not develop with prolonged GH therapy.

Absorptiometry, Photon↗
PubMed2000

Extensive soft tissue uptake of 99Tcm methylene diphosphonate in a patient with multiple myeloma.

Bone scintigraphy is not usually performed in multiple myeloma (MM), as marrow deposits characteristically show no tracer uptake. However, metastatic bone disease often mimics MM both clinically and biochemically, resulting in a substantial number of MM patients undergoing bone scintigraphy. Variable appearances in these cases have been reported, ranging from normal to a superscan, the latter a result of massive tracer uptake within bone. Soft tissue uptake has been documented, often when MM is complicated by secondary amyloidosis. This usually results in mainly solid organ uptake of tracer. We report a case of MM where massive soft tissue uptake occurred, primarily within muscles, with very little isotope elsewhere.

Aged↗
PubMed2000

Rumen fermentation in lactating cows selected for milk fat content fed two forage to concentrate ratios with hay or silage.

Sixteen multiparous cows, including eight rumen fistulated cows, were used in a 4x4 Latin square experiment designed to study dietary effects on rumen and blood parameters and milk production in cows differing in genetic capacity for milk fat content. Diets contained forage to concentrate ratios of 50:50 or 30:70 with either grass hay or silage as the forage. Ruminal fermentation was characterized by a high molar percentage of butyrate, 14 to 17%. Forage to concentrate ratio affected most rumen parameters, with the exception of the molar percentage of propionate (18 to 19%). The silage had a higher fiber degradation rate compared with hay. Compared to hay diets, silage diets had higher ruminal outflow rates, lower acetate:propionate ratios, and greater milk production with no differences in milk composition. Cows selected for low milk fat had higher molar percentages of propionate in the rumen. The low milk fat cows had higher milk production than cows selected for high milk fat but did not differ in milk fat yield. Cows fed the 30:70 diets had higher plasma insulin concentrations in response to a glucose challenge. The low milk fat cows had lower basal concentrations of insulin and lower insulin responses to a glucose challenge. Small changes in nutrient metabolism and supply were sufficient to influence milk production.

Animal Feed↗
PubMed2000

Coronary heart disease in Filipino and Filipino-American patients: prevalence of risk factors and outcomes of treatment.

BACKGROUND: Very little has been published on Filipino (F) or Filipino-American (FA) health. Nothing has been written about coronary risk factors and their relationship to outcomes of percutaneous coronary intervention or cardiac surgical treatment in this group. The purpose of this study was to analyze prospectively collected data at a center treating coronary artery disease in a large series of Filipino patients. METHODS: From January 1, 1992 to December 1, 1996, 527 consecutive FA patients and 3,176 Caucasians (C) were identified from an ongoing cardiac database. In-hospital and late outcomes post discharge were evaluated and results between the FA and C groups were compared. RESULTS: The FA population had a higher incidence of hypertension (79% vs. 61%, p < 0.0001) and diabetes (34.7% vs. 24.1%, p < 0.001) compared to C patients. Hypercholesterolemia was similar in both groups. Obesity (FA 12.2% vs. C 18.3%, p < 0.0001) and current smoking (FA 15.8% vs. C 21.5%, p < 0.001) were more common in the C patients. Age at presentation did not differ between groups. Morbidity and mortality were higher in the FA patients following intervention in the catheterization lab (4.2% vs. 1.3%, p < 0.01). Logistic regression showed that FA ethnicity was an independent predictor of death after catheterization laboratory intervention (p < 0.01), along with emergency procedure, depressed ejection fraction, history of myocardial infarction (MI) and age greater than 65. For coronary bypass surgery, mortality and rate of MI was similar in both groups. Late follow-up post discharge (mean 17 months, range 12Eth 68) was obtained on 90% and 89% of eligible FA and C patients, respectively. Occurrence of late death and MI did not differ between the groups. However, need for any reintervention (catheterization laboratory or surgical) was significantly higher in the FA patients (21.2% vs. 14. 9%, p < 0.001). Cox proportional hazard regression modeling showed that FA ethnicity was an independent predictor of need for late reintervention (p < 0.01), along with type of initial treatment, history of diabetes, presence of triple vessel disease, initial presentation with acute MI and age greater than 65. CONCLUSION: Filipino-Americans have a higher prevalence of hypertension and diabetes, and a lower prevalence of smoking and obesity compared to Caucasians. FA ethnicity is an independent predictor of higher mortality after catheterization laboratory intervention and increased need for late reintervention. However, the rate of late MI and death in FA was similar to C patients. These results suggest that FA patients, especially those presenting with diabetes for CAD treatment, need to be followed closely after percutaneous intervention or cardiac surgery procedures.

Aged↗
PubMed2000

Intravenous ifosfamide/mesna is associated with depletion of plasma thiols without depletion of leukocyte glutathione.

Depletion of cellular glutathione (GSH) enhances the efficacy of many anticancer agents in preclinical systems. Limited published data showing depletion of GSH in vitro and in patients by ifosfamide and/or mesna provided the rationale for a Phase I trial. Ifosfamide and mesna were infused over 24 and 36 h, respectively, at equal daily doses; carboplatin was given after ifosfamide to a target plasma area under the curve of 4 mg x min x ml(-1). Plasma and peripheral WBC thiols were quantitated by high-performance liquid chromatography. The dose of ifosfamide was escalated from 2 to 8 g/m2; the maximum tolerated dose was 6 g/m2. Significant depletion in plasma cysteine and homocysteine, precursors for GSH synthesis, was observed (maximum, 95% to >99% at 8 g/m2). Plasma mesna and cysteine/ homocysteine levels were inversely correlated; nadir levels of cysteine/homocysteine were maintained for several hours after ifosfamide infusion had stopped and while mesna infusion was continuing. In vitro coincubation experiments confirmed that mesna reduces these thiols from disulfides to sulfhydryls, which are readily cleared, as evidenced by the significantly increased rate of excretion of cysteine in urine. In contrast, ifosfamide/mesna treatment caused a moderate depletion of plasma GSH in only 60% of the patients, with a nadir at 24 h and recovery immediately after the end of ifosfamide infusion. The GSH depletion in these patients was not dose related. The profile of GSH recovery in plasma after ifosfamide and the fact that mesna could not reduce GSH disulfides in vitro suggest that the observed GSH depletion in plasma in 60% of the patients may be related to direct reactions of GSH with ifosfamide metabolites and/or mesna. Our results indicate that mesna is a modulator of GSH precursors and that a prolonged infusion of mesna may be required to achieve GSH precursor starvation and the consequent GSH depletion in cells.

Acetaldehyde↗
PubMed2000

Development and implementation of a geriatric care/case management program in a military community-based family medicine residency.

This article discusses how the development of a longitudinal geriatric assessment form facilitated a case management program in identifying high-risk frail elders within a military family practice clinic. A careful review of geriatric assessment tools was performed. From this review, a model geriatric assessment form was developed. A "SWOT" (strengths, weaknesses, opportunities, and threats) analysis of the family medicine department was completed to determine if the environment was ready for case management. Analysis of the SWOT data revealed that the environment was favorable for a population-based approach to case management. Results of this initial study are encouraging. The new longitudinal geriatric assessment form has assisted family practice residents in organizing problems and data while seeing elderly patients. As a direct result, higher-risk frail elders have been identified for closer evaluation and follow-up. Future goals are to measure outcomes-based data and to refine the geriatric assessment process.

Aged↗
PubMed1999

Down-regulation of the stathmin/Op18 and FKBP25 genes following p53 induction.

The p53 tumor suppressor protein can function as an activator and a repressor of gene transcription. Currently, the mechanism of transcriptional repression by p53 is poorly understood. To aid in clarifying this mechanism, we carried out studies designed to identify specific target genes that are down-regulated following p53 induction. Among the negative p53-response genes revealed by our screening protocols are those encoding stathmin (Op18), a tubulin-associated protein implicated in cell signaling pathways, and an FK506/rapamycin-binding protein, FKBP25. Stathmin and FKBP25 exhibit decreased expression in both human and murine immortalized and transformed cell lines following induction of wild-type p53 by several stimuli that result in DNA damage. Candidate p53-repressed genes such as these provide the necessary markers to delineate the mechanism and biological consequences of transcriptional repression mediated by p53.

Animals↗
PubMed1999

Transcriptional repression by wild-type p53 utilizes histone deacetylases, mediated by interaction with mSin3a.

There is growing evidence that the p53 tumor suppressor protein not only can function to activate gene transcription but also to repress the expression of specific genes. Although recent studies have implicated the transcriptional repression function of p53 in the pathway of apoptosis, the molecular basis of this activity remains poorly understood. This study takes a first step toward elucidating this mechanism. We report that trichostatin A (TSA), an inhibitor of histone deacetylases (HDACs), abrogates the ability of p53 to repress the transcription of two genes that it negatively regulates, Map4 and stathmin. Consistent with this finding, we report that p53 physically associates in vivo with HDACs. This interaction is not direct but, rather, is mediated by the corepressor mSin3a. Both wild-type p53 and mSin3a, but not mutant p53, can be found bound to the Map4 promoter at times when this promoter preferentially associates with deacetylated histones in vivo. Significantly, inhibition of p53-mediated transcriptional repression with TSA markedly inhibits apoptosis induction by p53. These data offer the first mechanistic insights for p53-mediated transcriptional repression and underscore the importance of this activity for apoptosis induction by this protein.

Animals↗
PubMed1999

DNA damage increases sensitivity to vinca alkaloids and decreases sensitivity to taxanes through p53-dependent repression of microtubule-associated protein 4.

Taxanes and Vinca alkaloids are among the most active classes of drugs in the treatment of cancer. Yet, fewer than 50% of previously untreated patients respond, and clinicians have few ways of predicting who will benefit from treatment and who will not. Mutations in p53 occur in more than half of human malignancies and may alter the sensitivity to a variety of anticancer therapies. We have shown that the transcriptional status of p53 determines the sensitivity to antimicrotubule drugs and that this is mediated through the regulation of microtubule-associated protein 4 (MAP4). Expression of MAP4 is transcriptionally repressed by wild-type p53. Increased expression of MAP4, which occurs when p53 is transcriptionally inactive, increases microtubule polymerization, paclitaxel binding, and sensitivity to paclitaxel, a drug that stabilizes polymerized microtubules. In contrast, overexpression of MAP4 decreases microtubule binding and sensitivity to Vinca alkaloids, which promotes microtubule depolymerization. To determine whether induction of endogenous wild-type p53 by DNA-damaging agents alters the expression of MAP4 and changes the sensitivity to antimicrotubule drugs, we assayed cell lines with wild-type or mutant p53 for the expression of MAP4 and drug sensitivity before and after DNA damage. UV irradiation, bleomycin, and doxorubicin increased wild-type p53 expression and decreased MAP4 expression. These changes were associated with decreased sensitivity to paclitaxel and increased sensitivity to vinblastine. These changes in drug sensitivity were no longer observed when p53 and MAP4 returned to baseline levels. Changes in drug sensitivity following DNA-damaging agents were associated with decreased binding of paclitaxel and increased binding of Vinca alkaloids. In contrast, DNA damage did not alter the sensitivity to non-microtubule-active drugs, such as 1-beta-D-arabinofuranosylcytosine and doxorubicin. Changes in drug sensitivity following DNA-damaging drugs were not observed in cells with mutant p53. These studies demonstrate that induction of wild-type p53 by DNA-damaging agents can affect the sensitivity to antimicrotubule drugs through the regulation of MAP4 expression and may have implications for the design of clinical anticancer therapies.

Animals↗
PubMed1999

Pax-3 regulates neurogenesis in neural crest-derived precursor cells.

The peripheral nervous system consists of multiple neural lineages derived from the neural crest (NC). Pax-3 is expressed in the NC and when mutated in the splotch mouse (Sp) results in the loss of derivatives from this precursor cell population. We have investigated the role of Pax-3 in regulating the generation of neurons from NC-derived precursor cells in vitro. Pax-3 mRNA in NC cultures is initially expressed in all NC but is subsequently only retained in neurons, suggesting a role in their generation. To determine whether Pax-3 is involved in neuron development, we first examined the generation of sensory-like neurons in NC cultures from Sp mice. Fivefold less sensory-like neurons were generated in NC cultures from Sp homozygous mice as compared to wild-type littermates. The role of Pax-3 in sensory neuron generation was then directly examined in dorsal root ganglia cultures by down-regulating the expression of Pax-3 protein with antisense oligonucleotides. It was found that antisense oligonucleotides inhibited 80-90% of newly generated sensory neurons; however, there was no significant effect on the survival of sensory neurons or the precursor population. These results suggest that Pax-3 has a role in regulating the differentiation of peripheral neurons.

Animals↗
PubMed1999

Gene expression and production of the monokine induced by IFN-gamma (MIG), IFN-inducible T cell alpha chemoattractant (I-TAC), and IFN-gamma-inducible protein-10 (IP-10) chemokines by human neutrophils.

Monokine induced by IFN-gamma (MIG), IFN-inducible T cell alpha chemoattractant (I-TAC), and IFN-gamma-inducible protein of 10 kDa (IP-10) are related members of the CXC chemokine subfamily that bind to a common receptor, CXCR3, and that are produced by different cell types in response to IFN-gamma. We have recently reported that human polymorphonuclear neutrophils (PMN) have the capacity to release IP-10. Herein, we show that PMN also have the ability to produce MIG and to express I-TAC mRNA in response to IFN-gamma in combination with either TNF-alpha or LPS. While IFN-gamma, alone or in association with agonists such as fMLP, IL-8, granulocyte (G)-CSF and granulocyte-macrophage (GM)-CSF, failed to influence MIG, IP-10, and I-TAC gene expression, IFN-alpha, in combination with TNF-alpha, LPS, or IL-1beta, resulted in a considerable induction of IP-10 release by neutrophils. Furthermore, IL-10 and IL-4 significantly suppressed the expression of MIG, IP-10, and I-TAC mRNA and the extracellular production of MIG and IP-10 in neutrophils stimulated with IFN-gamma plus either LPS or TNF-alpha. Finally, supernatants harvested from stimulated PMN induced migration and rapid integrin-dependent adhesion of CXCR3-expressing lymphocytes; these activities were significantly reduced by neutralizing anti-MIG and anti-IP-10 Abs, suggesting that they were mediated by MIG and IP-10 present in the supernatants. Since MIG, IP-10, and I-TAC are potent chemoattractants for NK cells and Th1 lymphocytes, the ability of neutrophils to produce these chemokines might contribute not only to the progression and evolution of the inflammatory response, but also to the regulation of the immune response.

Apoptosis↗
PubMed1999

Sonic hedgehog promotes neuronal differentiation of murine spinal cord precursors and collaborates with neurotrophin 3 to induce Islet-1.

Sonic hedgehog (Shh) is strongly implicated in the development of ventral structures in the nervous system. Addition of Sonic hedgehog protein to chick spinal cord explants induces floor plate and motoneuron development. Whether Shh acts directly to induce these cell types or whether their induction is mediated by additional factors is unknown. To further investigate the role of Shh in spinal neuron development, we have used low-density cultures of murine spinal cord precursor cells. Shh stimulated neuronal differentiation; however, it did not increase the proportion of neurons expressing the first postmitotic motoneuron marker Islet-1. Moreover, Shh did induce Islet-1 expression in neural tube explants, suggesting that it acts in combination with neural tube factors to induce motoneurons. Another factor implicated in motoneuron development is neurotrophin 3 (NT3), and when assayed in isolated precursor cultures, it had no effect on Islet-1 expression. However, the combination of N-terminal Shh and NT3 induced Islet-1 expression in the majority of neurons in low-density cultures of caudal intermediate neural plate. Furthermore, in explant cultures, Shh-mediated Islet-1 expression was blocked by an anti-NT3 antibody. Previous studies have shown expression of NT3 in the region of motoneuron differentiation and that spinal fusimotor neurons are lost in NT3 knock-out animals. Taken together, these findings suggest that Shh can act directly on spinal cord precursors to promote neuronal differentiation, but induction of Islet-1 expression is regulated by factors additional to Shh, including NT3.

Animals↗