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Biomedical subjects

S Murphy

Publications and source records attributed to S Murphy.

At least 55 records · Page 3Linked to original sources
PubMed2000

Production of nitric oxide by glial cells: regulation and potential roles in the CNS.

Roles proposed for nitric oxide (NO) in CNS pathophysiology are increasingly diverse and range from intercellular signaling, through necrotic killing of cells and invading pathogens, to the involvement of NO in apoptosis and tissue remodeling. In vitro evidence and observations from experimental animal models of a variety of human neuropathologies, including stroke, indicate that glial cells can produce NO. Regulation of at least one of the NO synthase genes (NOS-2) in glia has been well described; however, apart from hints emerging out of co-culture studies and extrapolation based upon the reactivity of NO, we are a long way from identifying functions for glial-derived NO in the CNS. Although the assumption is that NO is very often cytotoxic, it is evident that NO production does not always equate with tissue damage, and that both the cellular source of NO and the timing of NO production are important factors in terms of its effects. With the development of strategies to transfer or manipulate expression of the NOS genes in specific cells in situ, the ability to deliver NO into the CNS via long-lived chemical donors, and the emergence of more selective NOS inhibitors, an appreciation of the significance of glial-derived NO will change.

Animals↗
PubMed2000

Pericyte migration from the vascular wall in response to traumatic brain injury.

Any perturbation of the blood brain barrier, whether from changes in cell physiology or from direct injury, may result in microvascular dysfunction and disease. We examined, at the ultrastructural level, microvascular pericyte responses in a well-defined model of traumatic brain injury in the rat. In areas close to the site of impact cortical pericytes underwent a number of changes within the first hour. Approximately 40% of pericytes migrated from their microvascular location. Migration occurred concomitant with a thinning of the abluminal surface of the basal lamina and an accumulation of the receptor for the urokinase plasminogen activator on the leading surface of the migrating cell. Migrated pericytes appeared viable and remained in a perivascular location in the adjacent neuropil. Nonmigrating pericytes in the same section displayed cytoplasmic alterations and nuclear chromatin changes consistent with a rapid degenerative process.

Animals↗
PubMed2000

Long-term results of treatment studies for childhood acute lymphoblastic leukemia: Pediatric Oncology Group studies from 1986-1994.

This paper presents the long-term results of treatment for children with acute lymphoblastic leukemia (ALL) as conducted by the Pediatric Oncology Group (POG) from 1986 to 1994. The data are presented using standard NCI/Rome risk criteria. The overall event-free survival (EFS) at 5 and 10 years were 70.9% and 67.3% for children with B-precursor ALL, 51.0% and 50.2% for patients with T cell ALL, and 22.4% and 20.9% for infants with ALL. Concomitant biologic studies found that in B-precursor ALL a DNA index (DI) of > or =1.16 and trisomies of both chromosomes 4 and 10 were good prognostic indicators for patients with B-precursor ALL. The traditional prognostic indicators (age and white count), DI and trisomies did not predict outcome in patients with T cell disease. Infants continued to do poorly overall despite more intensive therapy with rotating pairs of chemotherapy. We recommend continued reporting of study results using common risk criteria in order to facilitate comparisons both within and across study groups.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2000

Unexpected Ebola virus in a tertiary setting: clinical and epidemiologic aspects.

OBJECTIVES: To describe the clinical manifestations of viral hemorrhagic fever, and to increase clinicians' awareness and knowledge of these illnesses. DESIGN: Retrospective study of the clinical and laboratory data and management of two cases of Ebola virus infection with key epidemiologic data provided. SETTING: Two tertiary care hospitals. PATIENTS: Two adult patients, the index case and the source patient, both identified as having Ebola, one of whom originated in Gabon. INTERVENTIONS: One patient was admitted to the intensive care unit. The other was managed in a general ward. MEASUREMENT AND MAIN RESULTS: Clinical and laboratory data are reported. One patient, a healthcare worker who contracted this illness in the course of her work, died of refractory thrombocytopenia and an intracerebral bleed. The source patient survived. Despite a long period during which the diagnosis was obscure, none of the other 300 contacts contracted the illness. CONCLUSIONS: Identification of high-risk patients and use of universal blood and body fluid precautions will considerably decrease the risk of nosocomial spread of viral hemorrhagic fevers.

Adult↗
PubMed2000

Results of treatment with hyper-CVAD, a dose-intensive regimen, in adult acute lymphocytic leukemia.

PURPOSE: To evaluate the efficacy and toxicity of Hyper-CVAD (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone), a dose-intensive regimen, in adult acute lymphocytic leukemia (ALL). PATIENTS AND METHODS: Adults with newly diagnosed ALL referred since 1992 were entered onto the study; treatment was initiated in 204 patients between 1992 and January 1998. No exclusions were made because of older age, poor performance status, organ dysfunction, or active infection. Median age was 39.5 years; 37% were at least 50 years old. Mature B-cell disease (Burkitt type) was present in 9%, T-cell disease in 17%. Leukocytosis of more than 30 x 10(9)/L was found in 26%, Philadelphia chromosome-positive disease in 16% (20% of patients with assessable metaphases), CNS leukemia at the time of diagnosis in 7%, and a mediastinal mass in 7%. Treatment consisted of four cycles of Hyper-CVAD alternating with four cycles of high-dose methotrexate (MTX) and cytarabine therapy, together with intrathecal CNS prophylaxis and supportive care with antibiotic prophylaxis and granulocyte colony-stimulating factor therapy. Maintenance in patients with nonmature B-cell ALL included 2 years of treatment with mercaptopurine, MTX, vincristine, and prednisone (POMP). RESULTS: Overall, 185 patients (91%) achieved complete remission (CR) and 12 (6%) died during induction therapy. Estimated 5-year survival and 5-year CR rates were 39% and 38%, respectively. The incidence of CNS relapse was low (4%). Compared with 222 patients treated with vincristine, doxorubicin, and dexamethasone (VAD) regimens, our patients had a better CR rate (91% v 75%, P <.01) and CR rate after one course (74% v 55%, P <.01) and better survival (P <.01), and a smaller percentage had more than 5% day 14 blasts (34% v 48%, P =.01). Previous prognostic models remained predictive for outcome with Hyper-CVAD therapy. CONCLUSION: Hyper-CVAD therapy is superior to our previous regimens and should be compared with established regimens in adult ALL.

Adolescent↗
PubMed2000

The determinants of time off work after childbirth.

Relatively little is known about the role that leave policies--family, parental, or maternity-leave policies--play in facilitating time off work after childbirth. Yet time off is a critical element of leave policies, as it facilitates the mother's recovery from childbirth and promotes maternal-infant attachment. Using data from Minnesota, the state with the highest rate of female labor force participation, we examine the extent to which policies, relative to personal, job, and workplace characteristics, determine the duration of women's childbirth-related leaves from work. A random sample of women identified from vital statistics records is used to estimate the relationship between leave policies and time off work after childbirth. Of our sample 85 percent had access to some paid leave benefits, although only 46 percent had paid maternity leave benefits. The difference in duration of leave between women with and without paid leave policies was approximately four weeks, a substantial difference for most women and their infants. Paid leave policies and spousal earnings as primary determinants of maternal time off work, suggest problems in the use of unpaid leave for economically vulnerable women.

Costs and Cost Analysis↗
PubMed2000

Longitudinal study of the influence of life events and personality status on diagnostic change in three neurotic disorders.

It has been known for many years that diagnosis within the neurotic spectrum of disorders is temporally unstable and also that life events can be major precipitants of change in symptoms. Reasons for this instability could include inherent inadequacy of current diagnostic practice, the influence of life events as an agent of diagnostic shift, and an innate course of disorder with features dependent on the stage at which disorder presents (e.g., development of panic to agoraphobia). These possibilities were examined in a prospective study that was initially a randomised controlled trial. Two hundred ten patients recruited from primary care psychiatric clinics with DSM-III diagnosed dysthymic, generalised anxiety, and panic disorders were randomly allocated to either drug treatment (mainly antidepressants), cognitive-behaviour therapy, or self-help therapy over a 2 year period, irrespective of original diagnosis. Life events were recorded by using a standard procedure over the period 6 months before starting treatment and at five occasions over 2 years; 181 (86%) of the patients had follow-up data and 76% maintained compliance with the original treatment allocated over the 2 years; and 155 of the 181 patients (86%) had at least one diagnostic change in this period. There was no difference in the number of diagnostic changes between the three original diagnostic groups, but dysthymic disorder changed more frequently to major depressive episode than did GAD or panic disorder (20; 11; 12) (%) and panic disorder changed more frequently to agoraphobia (with or without panic) than did dysthymia or GAD (18; 8; 6) (%). There was no relationship between loss events and depressive diagnoses or between addition events and anxiety diagnoses, but greater numbers of conflict events were associated with diagnostic change. More life events were associated with the flamboyant and dependent personality disorders, reinforcing other evidence that many life events are internally generated by personality characteristics and cannot be regarded as truly independent.

Cognitive Behavioral Therapy↗
PubMed2000

Age-related risk for HIV infection in men who have sex with men: examination of behavioral, relationship, and serostatus variables.

The study examined behavioral, relationship, and serostatus variables that potentially contribute to HIV infection risk in three age groups of men who have sex with men (MSM). MSM recruited in West Hollywood, California self-administered a questionnaire measuring unprotected insertive anal intercourse (UIAI) and unprotected receptive anal intercourse (URAI) with primary and nonprimary partners. The following relationship/serostatus variables were also assessed: recency of HIV testing, knowledge of own HIV serostatus, perception of partner's serostatus, seroconcordance (self and partner seronegative), and self-reported monogamy status. The prevalence of UIAI and URAI was higher with primary than nonprimary partners. These sexual risk behaviors with primary partners were substantially more prevalent among men younger than 25 years of age than among men aged 25 to 30 or over age 30. UIAI and URAI with nonprimary partners were uncommon in each age group, and there were no significant age differences on the serostatus and relationship variables. The findings suggest that young MSM may be at elevated risk for contracting HIV by virtue of their sexual risk behavior with primary partners. Targeted interventions for MSM need to address sexual risk in the context of primary relationships.

AIDS Serodiagnosis↗
PubMed1999

Determinants of coronary blood flow after thrombolytic administration. TIMI Study Group. Thrombolysis in Myocardial Infarction.

OBJECTIVES: This study evaluated the determinants of coronary blood flow following thrombolytic administration in a large cohort of patients. BACKGROUND: Tighter residual stenoses following thrombolysis have been associated with slower coronary blood flow, but the independent contribution of other variables to delayed flow has not been fully explored. METHODS: The univariate and multivariate correlates of coronary blood flow at 90 min after thrombolytic administration were examined in a total of 2,195 patients from the Thrombolysis in Myocardial Infarction (TIMI) 4, 10A, 10B and 14 trials. The cineframes needed for dye to first reach distal landmarks (corrected TIMI frame count, CTFC) were counted as an index of coronary blood flow. RESULTS: The following were validated as univariate predictors of delayed 90-min flow in two cohorts of patients: a greater percent diameter stenosis (p < 0.0001 for both cohorts), a decreased minimum lumen diameter (p = 0.0003, p = 0.0008), a greater percent of the culprit artery distal to the stenosis (p = 0.03, p = 0.02) and the presence of any of the following: delayed achievement of patency (i.e., between 60 and 90 min) (p < 0.0001 for both cohorts), a culprit location in the left coronary circulation (left anterior descending or circumflex) (p = 0.02, p < 0.0001), pulsatile flow (i.e., reversal of flow in systole, a marker of heightened microvascular resistance, p = 0.0003, p < 0.0001) and thrombus (p = 0.002, p = 0.03). Despite a minimal 16.4% residual stenosis following stent placement, the mean post-stent CTFC (25.8 +/- 17.2, n = 181) remained significantly slower than normal (21.0 +/- 3.1, n = 78, p = 0.02), and likewise 34% of patients did not achieve a CTFC within normal limits (i.e., <28 frames, the upper limit of the 95th percent confidence interval previously reported for normal flow). Those patients who failed to achieve normal CTFCs following stent placement had a higher mortality than did those patients who achieved normal flow (6/62 or 9.7% vs. 1/118 or 0.8%, p = 0.003). CONCLUSIONS: Lumen geometry is not the sole determinant of coronary blood flow at 90 min following thrombolytic administration. Other variables such as the location of the culprit artery, the duration of patency, a pulsatile flow pattern and thrombus are also related to slower flow. Despite a minimal 16% residual stenosis, one-third of the patients treated with adjunctive stenting still have a persistent flow delay following thrombolysis, which carries a poor prognosis.

Angioplasty, Balloon, Coronary↗
PubMed1999

Heat shock protein expression in target cells infected with low levels of replication-competent virus contributes to the immunogenicity of adenoviral vectors.

A significant limitation of adenoviral vectors is their associated immunogenicity. Since we, and others, have shown that the immunogenicity of cells can be increased by the induction of heat shock proteins (hsp), and because infection with several viruses induces hsp, we investigated whether the immunogenicity of adenoviral gene transfer might be mediated through induction of hsp expression. Neither plasmid DNA nor a recombinant retroviral vector induced hsp expression in transduced B16 melanoma cells. However, hsp70 was upregulated after infection with two of six adenoviral vectors; this induction of hsp70 did not correlate with the adenoviral transgene or with the viral backbone (Ad2 or Ad5). In previous assays, no replication-competent adenovirus (RCA) had been detected in any of these viruses. However, using sensitive assays for RCA, induction of hsp70 was found to correlate with the transfer of E1A and low levels of RCA. Moreover, target cells expressing hsp70 at levels similar to those induced by RCA infection protected syngeneic mice against rechallenge with parental cells, demonstrating that cells induced to express hsp70 by inadvertant transfer of RCA will become immunogenic. These results reveal a novel mechanism contributing to the immunogenicity of adenoviral vectors. If careful screening for RCA is not used when using laboratory-prepared viral stocks, the validity of the resulting experimental data might be significantly affected, especially when the immune stimulatory effects of the transgene are being studied.

Adenoviruses, Human↗
PubMed1999

Expression of nitric oxide synthase (NOS)-2 following permanent focal ischemia and the role of nitric oxide in infarct generation in male, female and NOS-2 gene-deficient mice.

Considerable evidence implicates nitric oxide (NO) in the pathological events following cerebral ischemia and, depending on the enzyme/cell source, NO is considered to be either damaging or protective. As a role for the enzyme nitric oxide synthase (NOS)-2 in permanent focal ischemia is not clear, we examined its expression following permanent middle cerebral artery occlusion in mice. At 24 h after occlusion, NOS-2 was expressed in cells infiltrating the infarct, while at later times, there was also expression in astrocytes around the infarct. To reveal a role for NO derived from this source, we compared infarct size in male and female mice with littermates in which the NOS-2 gene was disrupted. No differences were found between gender and genotype at 24 h. At 72 h, the infarct was increased in male mice, but not in females or in either gender with the gene disruption. These results suggest that NOS-2 plays a role in the later development of the infarct in male mice. Female mice are protected either against the damaging effects of NO, or because NOS-2 expression/activity is modulated by steroids.

Animals↗
PubMed1999

Transcription of the human U2 snRNA genes continues beyond the 3' box in vivo.

The 3' box of the human class II snRNA genes is required for proper 3' processing of transcripts, but how it functions is unclear. Several lines of evidence suggest that termination of transcription occurs at the 3' box and the terminated transcript is then a substrate for processing. However, using nuclear run-on analysis of endogenous genes, we demonstrate that transcription continues for at least 250 nucleotides beyond the 3' box of the U2 genes. Although in vivo footprinting analysis of both the U1 and U2 genes detects no protein-DNA contacts directly over the 3' box, a series of G residues immediately downstream from the 3' box of the U1 gene are clearly protected from methylation by dimethylsulfate. In conjunction with the 3' box of the U1 gene, this in vivo footprinted region causes termination of transcription of transiently transfected U2 constructs, whereas a 3' box alone does not. Taken together, these results indicate that the 3' box is not an efficient transcriptional terminator but may act as a processing element that is functional in the nascent RNA.

Base Sequence↗
PubMed1999

Transcriptional activation following cerebral ischemia in mice of a promoter-deleted nitric oxide synthase-2 gene.

Nitric oxide synthase (NOS)-2 is transcriptionally activated in a wide variety of injurious conditions, including cerebral ischemia, and the resulting nitric oxide is implicated both in tissue damage and recovery. Studies in vitro suggest that the proximal region of the NOS-2 promoter is obligatory for gene activation by proinflammatory cytokines. However, following cerebral ischemia in a NOS-2 gene-deficient mouse in which this region and exons 1-4 have been deleted, we find temporal and spatial expression, identical to wild-type, from a previously unidentified promoter region. The resulting protein is predicted to lack the first 113 amino acids and is NOS-2-incompetent. Fortuitously, this gene-deficient mouse presents a unique opportunity to determine more about the mechanisms of NOS-2 gene regulation in vivo.

Animals↗
PubMed1999

Exhaled nitric oxide measurements in childhood asthma: techniques and interpretation.

In this review, we outline the role of nitric oxide in airway inflammation in children with asthma. We also discuss the various methods reported for measuring exhaled nitric oxide and provide some insight as to the pros and cons and pitfalls of these techniques. Guidelines for measurements of exhaled nitric oxide based on our experience are provided, as well as suggestions for the use of this technique as a new "airway inflammation test."

Asthma↗
PubMed1999

Methodologic drift in the assessment of TIMI grade 3 flow and its implications with respect to the reporting of angiographic trial results. The TIMI Study Group.

BACKGROUND: The Thrombolysis in Myocardial Infarction (TIMI) Study Group originally defined TIMI grade 3 flow (complete perfusion) as antegrade flow into the bed distal to the obstruction that occurs as promptly as antegrade flow into the bed proximal to the obstruction. Recently, several groups have defined TIMI grade 3 flow as opacification of the coronary artery within 3 cardiac cycles. METHODS AND RESULTS: On the basis of heart rate data at the time of the cardiac catheterization and the time for dye to go down the artery (TIMI frame count/30 = seconds), we estimated the number of patients who would meet the 3 cardiac cycle criterion and compared this with the number of patients with TIMI grade 3 flow by using the original definition in 1157 patients from 3 recent TIMI trials (10 A, 10B, and 14). In 74 patients without acute myocardial infarction and normal coronary arteries, the fraction of a cardiac cycle required for dye to traverse the artery was a mean of 0.93 +/- 0.34 cardiac cycles (n = 74) (median 0.80, minimum 0.44, maximum 2.1, none >3.0 cycles). The mean heart rate at 90 minutes after thrombolysis in the TIMI 14 trial was 79.6 +/- 16.8 beats/min (n = 194), and the duration of 3 cardiac cycles was a mean of 2.36 seconds, or a TIMI frame count of 70.8 frames. In all trials, the rate of TIMI grade 3 flow was 57.3% (n = 663/1157) with the original definition and 66.8% (n = 743/1113) with the <3 cardiac cycle definition (P <.001). CONCLUSIONS: A duration of 3 cardiac cycles for dye to traverse the artery lies approximately 6 SD above that observed in normal coronary arteries. A 3 cardiac cycle definition of TIMI grade 3 flow results in rates of normal perfusion that are approximately 10% higher than if the original definition of TIMI grade 3 flow is applied. Application of this simple correction factor may help place data reported with the 3 cardiac cycle definition of TIMI grade 3 flow in context.

Cineangiography↗