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Biomedical subjects

S Murphy

Publications and source records attributed to S Murphy.

At least 181 records · Page 10Linked to original sources
PubMed1996

Improved survival for children with B-cell acute lymphoblastic leukemia and stage IV small noncleaved-cell lymphoma: a pediatric oncology group study.

PURPOSE: In an effort to improve outcome for children with advanced B-cell malignancies, a treatment plan based on a published regimen that consists of four courses of fractionated cyclophosphamide (cyclo) given with doxorubicin (doxo) and vincristine (VCR) was intensified by alternating with sequential high-dose methotrexate (MTX) and cytarabine (Ara-C), given in conjunction with intrathecal (IT) MTX and Ara-C. PATIENTS AND METHODS: From October 1986 to October 1992, 133 eligible patients were enrolled: 74 with B-cell (surface immunoglobulin-positive [Slg+] acute lymphoblastic leukemia (B-ALL) and 59 with stage IV small noncleaved-cell lymphoma (SNCCL). The median age was 8 years; there were 103 males and 30 females. Abdominal tumor masses were prominent in 63 cases (33 B-ALL and 30 stage IV SNCCL). RESULTS: Complete remission (CR) was achieved in 66 B-ALL and 57 stage IV patients (93% overall). At 4 years, the estimated event-free survival (EFS) rate is 65% +/- 8% for patients with B-ALL and 79% +/- 9% for those with stage IV SNCCL. Among patients with CNS involvement, 23 of 36 remain in CR (4-year EFS rate, 64% +/- 13%). Relapses occurred early; only 3 patients relapsed after completion of therapy. Thirteen relapses occurred in the marrow, three in the CNS, and six in other sites. Of 11 CNS-positive patients who relapsed, only two recurred primarily in the CNS. CONCLUSION: The results of this study indicate that with intensified chemotherapy an increasing potential for cure exists for patients with B-ALL and stage IV SNCCL.

Adolescent↗
PubMed1996

Deep breathing in children with severe malaria: indicator of metabolic acidosis and poor outcome.

Despite the frequent association of respiratory symptoms and signs with malarial morbidity and mortality in sub-Saharan Africa, the value of individual symptoms and signs has rarely been assessed. We have prospectively examined the association of individual clinical findings with the summary diagnosis of respiratory distress, outcome, and the presence of metabolic acidosis in children admitted with severe malaria to a Kenyan district hospital. Respiratory distress was present in 119 of the 350 children included in the study and in 23 of the 30 deaths (relative risk = 6.5, 95% confidence interval = 2.8-14.4). The features of a history of dyspnea, nasal flaring, and indrawing or deep breathing (Kussmaul's respiration) were individually most closely associated with the summary diagnosis of respiratory distress. Of these, deep breathing, which was sensitive (91%) and specific (83%) for the presence of severe metabolic acidosis (base excess < or = -12), is the best candidate sign to represent the prognostically important syndrome of malarial respiratory distress. Therefore, it warrants further prospective evaluation in different clinical settings and areas of different malaria endemicity.

Acidosis↗
PubMed1996

Chorioamnionitis and early lung inflammation in infants in whom bronchopulmonary dysplasia develops.

OBJECTIVE: The development of bronchopulmonary dysplasia (BPD) often has been attributed to injury from mechanical ventilation and supplemental oxygen. Early lung inflammation in infants with BPD has been thought to be secondary to these factors. The purpose of this study was to evaluate whether preexisting (prenatal) inflammation may be a primary causative factor in the development of BPD. METHODS: Intubated newborns of less than 2,000 g birth weight were prospectively enrolled. The presence or absence of chorioamnionitis was documented. Lung inflammation was evaluated on days 1, 2, and 4 of intubation by assaying concentrations of interleukin 1 beta (IL-1 beta), thromboxane B2, leukotriene B4, and prostaglandin E2 in tracheal lavages. Infants in whom BPD developed were compared with those in whom it did not using these measures. RESULTS: Fifty-three infants were enrolled; 41 survived. Thirty-eight had respiratory distress syndrome; 15 were intubated for other diagnoses. Infants prenatally exposed to chorioamnionitis were less likely to present with respiratory distress syndrome; however, chorioamnionitis was significantly associated with both the presence of IL-1 beta from the first day of intubation and the development of BPD. Tracheal lavage concentrations of IL-1 beta were higher in infants in whom BPD developed. Thromboxane B2 concentrations were similar on day 1 but were higher on days 2 and 4 in infants in whom BPD developed. CONCLUSIONS: In this study, intubated infants weighing less than 2,000 g at birth in whom BPD developed had increased exposure to inflammation prenatally (chorioamnionitis) and evidence of increased lung inflammation from the first postnatal day. We speculate that chorioamnionitis may accelerate lung maturation but that it also causes lung inflammation and subsequent lung injury in intubated infants, fostering the development of BPD.

Bronchoalveolar Lavage↗
PubMed1996

Using HL7 and the World Wide Web for unifying patient data from remote databases.

W3-EMRS is an architecture designed to access clinical data from remote heterogeneous electronic medical record system (EMRS) databases. We describe the technologies used in an experimental implementation of W3-EMRS that concurrently collects data from several sources and presents them in an integrated set of views. After describing some of the organizational constraints, the architectural decision, implementation methodology, and operation of the completed project are discussed.

Computer Communication Networks↗
PubMed1996

Haemagglutination properties of Moraxella (Branhamella) catarrhalis.

The ability of 30 isolates of Moraxella (Branhamella) catarrhalis to haemagglutinate erythrocytes of five species was examined. Two haemagglutination phenotypes of M. catarrhalis were observed: phenotype I isolates (n = 10) agglutinated human erythrocytes, while phenotype II isolates (n = 7) agglutinated both human and rabbit erythrocytes. No haemagglutination was observed with chick, sheep or horse erythrocytes. Haemagglutination by both phenotype I and II isolates was abolished following treatment of these isolates with pronase and trypsin, while heat treatment at 70 degrees C markedly reduced the level of haemagglutination by both sets of isolates. Haemagglutination by phenotype II isolates was inhibited by galactose, whereas haemagglutination by phenotype I isolates was not inhibited by this carbohydrate. Transmission electron microscopy (TEM) studies showed that very close cell-surface interactions occurred when both phenotypes of M. catarrhalis adhered to the human erythrocyte. Fimbrial attachment was not apparent. Haemagglutinating isolates of both phenotypes had a trypsin-sensitive outer fibrillar coat when examined by TEM.

Animals↗
PubMed1995

Platelet storage for transfusion in synthetic media: further optimization of ingredients and definition of their roles.

Currently, most platelet concentrates (PC) are stored for transfusion at 20 degrees C to 24 degrees C in autologous plasma. There are potential advantages in replacing some of this plasma with a synthetic medium. In this study, our major goals were to define the optimal ingredients and their concentrations in such a medium and to gain insight into the mechanism by which each ingredient confers benefit. In addition, we wished to validate a new polyvinyl chloride container plasticized with di-n-decyl phthalate (DnDP) for PC storage. PC derived from donations of whole blood were stored for 7 days in autologous plasma or a basic synthetic medium (BSM) containing 15 mmol/L glucose, 21 mmol/L citrate, and physiologic concentrations of salts other than bicarbonate within either the DnDP container or a licensed polyolefin container, PL-732. Metabolic events were characterized and a panel of in vitro tests were used to monitor platelet quality as systematic changes in the BSM were made. Platelet quality was as least as good, if not better, after storage in DnDP in comparison to PL-732. pH consistently decreased to less than 6.0 because of inadequate buffering of lactic acid in BSM alone. However, pH and the in vitro tests were well maintained by either the serial addition of bicarbonate (BSM + B) or the addition of at least 15 mmol/L acetate and 10 mmol/L phosphate (BSM + AP). The benefits of BSM + AP were traced to a decrease in lactic acid production by 33% and 19% relative to plasma and BSM + B, respectively, and the vigorous oxidation of acetate (0.66 +/- 0.09 mmol/d/10(12 platelets). The rates of lactate production and acetate consumption were similar and the pH during storage correlated with difference between the two rates, suggesting that acetate oxidation has an alkalinizing effect equivalent on a molar basis to the acidifying effect of production of lactate and a hydrogen ion. When pyruvate replaced acetate, it was also metabolized vigorously (0.52 +/- 0.06 mmol/d/10(12) platelets). Its presence suppressed lactic acid production by 44% relative to BSM + B and allowed maintenance of pH and platelet quality similar to what is achieved with acetate. The results strongly suggest that the benefit from acetate (or pyruvate) is derived from its oxidation and the use of a hydrogen ion during that oxidation. For reasons that are not yet clear, the omission of phosphate resulted in pH decrease to less than 6.0 in 3 of 9 PC even with acetate present.(ABSTRACT TRUNCATED AT 400 WORDS)

Acetates↗
PubMed1995

Functional redundancy of promoter elements ensures efficient transcription of the human 7SK gene in vivo.

Deletion and mutation studies of the human 7SK gene transfected into HeLa cells have identified three functional regions of the promoter corresponding to the TATA box at -25, the proximal sequence element (PSE) between -49 and -65 and the distal sequence element (DSE) between -243 and -210. These elements show sequence homology to equivalent regions in other snRNA genes and are functionally analogous. Unlike the DSEs of many snRNA genes however, the 7SK DSE does not contain a consensus binding site for the transcription factor Oct-1 but rather, contains two non-consensus Oct-1 binding sites that can function independently of one another to enhance transcription. Unusually, the 7SK PSE can retain function even after extensive mutation and removal of the conserved TGACC of the PSE has little effect in the context of the whole promoter. However, the same mutation abolishes transcription in the absence of the DSE suggesting that protein/protein interactions between DSE and PSE binding factors can compensate for a mutant PSE. Mutation of the 7SK TATA box allows snRNA type transcription by RNA polymerase II to occur and this is enhanced by the DSE, indicating that both the DSE and the PSE can also function with pol II. In addition, mutation of the TATA box does not abolish pol III dependent transcription, suggesting that other sequence elements may also play a role in the determination of polymerase specificity. Although the human 7SK gene is transcribed efficiently in Xenopus oocytes, analysis of the 7SK wild-type gene and mutants in Xenopus oocytes gives significantly different results from the analysis in HeLa cells indicating that the recognition of functional elements is not the same in the two systems.

Amino Acid Sequence↗
PubMed1995

Activation of astrocytes in the spinal cord of mice chronically infected with a neurotropic coronavirus.

Mice infected with the neurotropic JHM strain of mouse hepatitis virus (MHV-JHM) develop a demyelinating encephalomyelitis several weeks after infection. Astrogliosis and infiltration of inflammatory cells are prominent findings in the brains and spinal cords of infected mice. In this report, astrocytes in infected spinal cords were analyzed for expression of three pleiotropic cytokines, TNF-alpha, IL-1 beta, and IL-6; Type 2 nitric oxide synthase (iNOS); and MHC class I and II antigen. The data show that all three cytokines and iNOS are expressed by astrocytes in chronically infected spinal cords. These activated astrocytes are localized to areas of virus infection and demyelination, although most of the astrocytes expressing these proteins are not MHV-infected. MHC class I and II antigen can be detected in these spinal cords as well, but not in cells with the typical morphology of astrocytes. TNF-alpha, IL-6, and iNOS are also evident in the brains of mice with MHV-induced acute encephalitis, but in marked contrast to the results obtained with the chronically infected mice, most of the cells expressing these cytokines or iNOS had the morphology of macrophages or other mononuclear cells and very few appeared to be astrocytes. Additionally, astrocytes and, most likely, oligodendrocytes are infected in the spinal cords of mice with chronic demyelination. These results are consistent with a role for both viral infection of glial cells and high localized levels of proinflammatory cytokines and nitric oxide in the demyelinating process in mice infected with MHV-JHM. They also show that analogously to the human demyelinating disease, multiple sclerosis, astrocytes are a major cellular source for these cytokines in mice with chronic, but not acute disease.

Acute Disease↗
PubMed1995

Factor VNew Brunswick: Ala221-to-Val substitution results in reduced cofactor activity.

We have characterized the factor V protein and cDNA of a patient displaying factor V deficiency (parahemophilia) and correlated the reduced activity with a missense mutation of Ala221-to-Val. Plasma from the subject individual (C1) presented reduced factor V antigen (39% of normal) that displayed reduced activity (approximately 26% of normal). Factor V purified from this individual by standard techniques shows normal migration on sodium dodecyl sulfate gels and a normal pattern of activation by thrombin. Purified antigen from sibling C2 gives a much reduced specific activity of 263 U/mg (17% of normal). Sibling C3, the mother, and the father have antigen within the normal range (57% to 200%) that has approximately normal specific activity. The cDNA encoding the factor Va heavy and light chains of the subject individual was polymerase chain reaction-amplified and sequenced and revealed an A-to-G substitution at position 3 of codon 51 (silent mutation), a C-to-T substitution in position 2 of codon 221 (Ala221-Val), a T-to-C substitution at position 3 of codon 708 (silent mutation), and a G-to-A substitution at position 1 of codon 2185 (Thr2185-Ala). The latter mutation was also observed in control individuals and is proposed to be a possible polymorphism. Restriction analyses demonstrated the presence of one mutant and one normal allele in the father. The subject individual (C1) and sibling C2 carry only the mutant allele. The mother and sibling C3 carry only the normal allele. The inheritance pattern suggests the presence of a missing or nonexpressed allele in the mother that is passed on to all the siblings. Expression of only the mutant allele by the subject individual (C1) and sibling C2 is consistent with reduced factor V antigen and activity in these patients. We have designated this mutant as Factor VNew Brunswick.

Adolescent↗
PubMed1995

Sp1 functions in a chromatin-dependent manner to augment human alpha-globin promoter activity.

The 5' flanking region of the human alpha-globin gene is highly G + C rich and contains multiple copies of the consensus sequence for the Sp1 binding site. We investigated the role of this G + C-rich region in augmenting alpha-globin promoter activity in the presence of the far-upstream alpha-globin enhancer, HS-40. We show that in transiently transfected erythroid cells, deletion of the alpha-globin G + C-rich 5' flanking region has no effect on alpha-globin promoter activity. However, upon stable integration into chromatin, deletion of this region causes a nearly 90% decrease in promoter activity compared with expression from an alpha-globin promoter retaining this region. These results suggest that the alpha-globin G + C-rich 5' flanking region augments alpha-globin promoter activity in a chromatin-dependent manner. We further show that this G + C-rich region is required for the activation of alpha-globin gene expression during erythroid differentiation. Finally, we show by both footprint analysis and functional assays that the ability of the G + C-rich region to increase alpha-globin promoter activity from a stably integrated alpha-globin gene is mediated by its multiple binding sites for the transcription factor Sp1.

Animals↗
PubMed1995

The oxidation of exogenously added organic anions by platelets facilitates maintenance of pH during their storage for transfusion at 22 degrees C.

Previous studies of platelet metabolism during the storage of platelet concentrates (PCs) at 22 degrees C for transfusion have shown high rates of both oxygen consumption and aerobic glycolysis with little oxidation of pyruvate produced by glycolysis. During storage in plasma, free fatty acids are major oxidative fuels. Glutamine is also present as a potential fuel but relatively little is metabolized beyond glutamate. In synthetic media, acetate is oxidized and provides a poorly understood buffering function. In the current work, acetate and pyruvate (6 to 25 mmol/L, sometimes with their 14-C-labeled counterparts) were added to PCs stored in plasma. They were both vigorously metabolized, predominantly to CO2 (0.51 +/- 0.08 and 0.31 +/- 0.06 mmol/d/10(12) platelets for acetate and pyruvate, respectively). The metabolism of these exogenous substrates was associated with significantly increased oxygen consumption and decreased glucose consumption, fatty acid oxidation, and bicarbonate utilization for buffering. In a more limited number of studies, similar findings were observed with addition of beta-hydroxy-butyrate. Superior maintenance of pH in the presence of these additives could be attributed to the fact that the metabolism of an organic anion requires that a proton be brought with the anion into the metabolic pathway, thus providing an alkalinizing effect. Pyruvate (but not acetate) also stimulated the metabolism of glutamate. Studies with 14-C-labeled glucose suggested significant activity of the hexose-monophosphate shunt during PC storage and confirmed that little, if any, pyruvate derived from glucose was fully oxidized. Taken together, the results provide a relatively complete picture of the pathways of energy metabolism used by platelets during PC storage and suggest a strategy by which organic anions such as acetate can be used to improve the results of such storage.

Acetates↗
PubMed1995

Cytokine-induced expression of type II nitric oxide synthase in astrocytes is downregulated by ATP and glutamate.

Combinations of cytokines and/or phorbol ester induce expression of Type II nitric oxide synthase (NOS) mRNA in astrocyte cultures via protein kinase mediated pathways (Simmons and Murphy: GLIA 11:227, 1994; Fernstein et al.: J Neurochem 62:811, 1994). Agonists that activate receptors linked to protein kinases did not reproduce this effect of cytokines in astrocytes. On the contrary, ATP and glutamate treatment of astrocytes prior to a combination of interleukin-1 beta and interferon-gamma markedly reduced (30-50%) subsequent NOS mRNA expression. The effect was not seen if treatment coincided with or followed cytokine activation, suggesting that ATP and glutamate were not destabilizing NOS mRNA. The effects of ATP and glutamate were additive and could be mimicked by selective receptor agonists, but were insensitive to a specific inhibitor of protein kinase C. The inhibition of cytokine-induced NOS mRNA expression caused by these agents was not the result of interference with the activation/translocation of nuclear factor-Kappa Beta by interleukin-1 beta. These results suggest that exposure of astrocytes to ATP and glutamate, both of which increase markedly in a variety of neuropathologies, could modulate the subsequent responsiveness of these cells to NOS-inducing stimuli. As such, this may be an important regulatory mechanism in the expression of Type II NOS in vivo.

Adenosine Triphosphate↗
PubMed1995

Psychology, health promotion and aesthemiology. Paper one: Social cognition models as a framework for health promotion: necessary, but not sufficient.

Much of health promotion is premised on the notion that health-related behaviours are under individual control, and strongly influenced by intra-psychic factors, including knowledge and attitudes. The emphasis placed on such factors has led to a neglect of the social and material context in which the individual is situated. This paper describes a number of psychological theories which have influenced health promotion, and suggests ways in which a wider set of psychological theories and methods, which take into account social and material factors, may more usefully inform health promotion initiatives.

Cognition↗
PubMed1995

Involvement of nitric oxide in IFN-gamma-mediated reduction of microvessel smooth muscle cell proliferation.

Previous studies in our laboratory demonstrated that murine cerebral microvessel smooth muscle cells (SMC) activate syngeneic CD4+ T-cells in vitro. These T-cells, or their culture supernatants, in turn, strongly inhibit proliferation of the SMC. The present study focuses on IFN-gamma as a mediator of inhibition of SMC proliferation, and addresses the molecular mechanism of this inhibition. IFN-gamma profoundly reduced the proliferation of murine brain microvessel smooth muscle cells in vitro. Three lines of evidence indicate that nitric oxide contributed to this effect: (1) IFN-gamma-mediated inhibition of proliferation correlated with the quantity of nitrite, a stable breakdown product of nitric oxide, in culture supernatants; (2) the addition of N(g)- monomethyl-l-arginine, and inhibitor of nitric oxide synthesis, restored proliferation to control or near control levels; and (3) the addition of hemoglobin, which has a high affinity for, and thus sequesters nitric oxide, also resulted in significant restoration of the proliferative response. However, the nitric oxide donating chemical sodium nitro-prusside, at concentrations up to 100 microM, had no direct cytostatic effect. These results suggest that nitric oxide is a necessary but insufficient component in IFN-gamma-mediated inhibition of microvessel smooth muscle cell proliferation. TNF-alpha also stimulated nitric oxide production by the smooth muscle cells, but was not as potent as IFN-gamma at inhibiting proliferation. Knowledge of the physiological effects of lymphokines on cells of the brain microvasculature will contribute towards a better understanding of inflammatory processes in diseases such as multiple sclerosis and infectious encephalitis.

Animals↗
PubMed1995

Stimulation of cyclic GMP production via a nitrosyl factor in sensory neuronal cultures by algesic or inflammatory agents.

Capsaicin stimulates cyclic GMP production via nitric oxide (NO) (or another nitrosyl factor) in dorsal root ganglion (DRG) neurons maintained in culture. The purpose of the present study was to characterize further capsaicin stimulation of cyclic GMP production in DRG cells maintained in culture, investigate other algesic and/or inflammatory agents for effects on cyclic GMP production, and examine cells responsible for NO production and cyclic GMP production. Capsaicin stimulation of cyclic GMP production in DRG cells was dose dependent, receptor mediated, and attenuated by hemoglobin. Prostaglandin E2, substance P, and calcitonin gene-related peptide did not affect basal, capsaicin-stimulated, or bradykinin-stimulated cyclic GMP production. Other inflammatory or algesic agents, including serotonin, histamine, ATP, glutamate, aspartate, and NMDA, did not affect cyclic GMP production. Pretreatment of DRG cells with lipopolysaccharide increased basal cyclic GMP production in neuronal but not in nonneuronal cultures and facilitated stimulation of cyclic GMP production by L-arginine. Capsaicin pretreatment of neuronal DRG cultures, which destroys capsaicin-sensitive (small diameter) afferent neurons, attenuated capsaicin- and bradykinin-stimulated cyclic GMP production but did not affect basal or sodium nitroprusside-stimulated cyclic GMP production. These results indicate that capsaicin elicits production of a nitrosyl factor via capsaicin-sensitive (small diameter) neurons. Capsaicin evoked cyclic GMP production in nonneuronal DRG cultures in the presence but not in the absence of apposed neuronal DRG cultures. Overall, these findings suggest that specific exogenous (or endogenous) substances may stimulate production of a nitrosyl factor(s) by a subset of DRG neurons, and nitrosyl factors produced by these neurons may affect cyclic GMP production in neighboring neuronal or non-neuronal cells.

Animals↗
PubMed1995

Relationships of dopamine, cortical oxygen pressure, and hydroxyl radicals in brain of newborn piglets during hypoxia and posthypoxic recovery.

The present study describes the relationships of extracellular striatal dopamine, cortical oxygen pressure, and striatal hydroxyl radicals in brain of newborn piglets during hypoxia and posthypoxic reoxygenation. Hypoxia was induced by reducing the fraction of inspired oxygen (FiO2) from 22% (control) to 7% for 1 h. The FiO2 was then returned to the control value and measurements were continued for 2 h. Cerebral oxygen pressure was measured by the oxygen dependent quenching of phosphorescence and extracellular levels of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and hydroxy radicals in the striatum were determined by in vivo microdialysis. Hypoxia decreased the cortical oxygen pressure from 47 +/- 2 to 9 +/- 1.3 torr (p < 0.001); the levels of extracellular dopamine in the striatum increased to 16,000 +/- 3,270% of control (p < 0.01), whereas the levels of DOPAC and HVA decreased to 25.3 +/- 6% (p < 0.001) and 36 +/- 5% (p < 0.01) of control, respectively. Compared with control, the hydroxyl radical levels at each time point were not significantly increased during hypoxia, although the sum of the measured values was significantly increased (p < 0.05). During the first 5 min after FiO2 was returned to 22%, the cortical oxygen pressure increased to control values and stayed at this level for the remainder of the measurement period. The extracellular level of dopamine declined to values not statistically different from control during 40 min of reoxygenation. During the first 10 min of reoxygenation, DOPAC and HVA further decreased and then began to slowly increase. By 70 min of reoxygenation, the values were not significantly different from control.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dihydroxyphenylacetic Acid↗
PubMed1995

Expression of inducible nitric oxide synthase in cerebral endothelial cells is regulated by cytokine-activated astrocytes.

A nitric oxide (NO) synthase (NOS) can be induced in both astrocytes and cerebral endothelial cells with a combination of interleukin-1 beta/interferon-gamma or lipopolysaccharide/interferon-gamma, respectively. Exogenous NO, either from the chemical donor spermine NONOate or from activated astrocytes, affected the expression of inducible NOS in cerebral endothelial cells. In cerebral endothelial cells pretreated with spermine NONOate the induction of NOS was reduced, as revealed by mRNA expression and nitrite accumulation. Cytokine-treated astrocytes generating NO and placed in close proximity to endothelial cells decreased the expression of NOS induced by cytokines in endothelial cells. In addition, it was apparent that cytokine-activated astrocytes released a factor(s) that initiated transcriptional induction of NOS in cerebral endothelium. This suggests that astrocytes activated by cytokines in vivo could influence expression of inducible NOS in cells of the adjacent microvasculature.

Amino Acid Oxidoreductases↗