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Biomedical subjects

C L Murray

Publications and source records attributed to C L Murray.

At least 19 recordsLinked to original sources
PubMed2005

Automated external defibrillators for home use.

The Philips HeartStart Home Defibrillator is an automated external defibrillator (AED) that is approved for home use by untrained users. Most cardiac arrests occur in the home, so a rapid response with cardiopulmonary resuscitation (CPR) and defibrillation is critical for survival. No prospective studies demonstrate that the use of AEDs in the home by untrained persons improves health outcomes. Further investigation is needed to determine the benefit and harm of AEDs in the home.

Adult↗
PubMed2001

Crystallographic phasing of myristoyl-CoA-protein N-myristoyltransferase using an iodinated analog of myristoyl-CoA.

Myristoyl-CoA-protein N-myristoyltransferase (Nmt; E.C. 2.1.3.97) catalyzes the covalent attachment of myristate to the N-terminal glycine amine of many eukaryotic and viral proteins. The molecular structure of the ternary complex of Saccharomyces cerevisiae Nmt1p with a bound non-hydrolyzable myristoyl-CoA analog, S-(2-oxopentadecyl)-CoA, and a competitive peptidomimetic inhibitor, SC-58272, was solved to 2.9 A resolution by X-ray crystallography. The structure determination utilized diffraction data from an iodinated ternary complex in which a newly designed and synthesized compound, S-(13-iodo-2-oxotridecyl)-CoA, was substituted for S-(2-oxopentadecyl)-CoA. Replacing the two terminal fatty acid C atoms of myristate by iodine produced, under the same crystallization conditions, heavy-atom-derivatized crystals of defined site occupancy that were isomorphous to the native complex. This approach for obtaining experimental phase information can be extended to other crystal structures of protein-fatty acyl complexes. The synthesis of S-(13-iodo-2-oxotridecyl)-CoA and the phasing procedure are described.

Acyl Coenzyme A↗
PubMed2000

Cerebral perfusion in chronic fatigue syndrome and depression.

BACKGROUND: Patients with chronic fatigue syndrome (CFS) and depressive illness share many, but not all, features. AIMS: To test the hypothesis that patients with CFS have abnormal cerebral perfusion, that differs from that in patients with depressive illness. METHOD: We recruited 30 patients with CFS who were not depressed, 12 depressed patients and 15 healthy volunteers. Regional cerebral perfusion at rest was assessed using region of interest (ROI) and voxel-based statistical parametric mapping (SPM) techniques. RESULTS: On SPM analysis there was increased perfusion in the right thalamus, pallidum and putamen in patients with CFS and in those with depressive illness. CFS patients also had increased perfusion in the left thalamus. Depressed patients differed from those with CFS in having relatively less perfusion of the left prefrontal cortex. The results were similar on ROI analysis. CONCLUSIONS: Abnormal cerebral perfusion patterns in CFS subjects who are not depressed are similar but not identical to those in patients with depressive illness. Thalamic overactivity may be a correlate of increased attention to activity in CFS and depression; reduced prefrontal perfusion in depression may be associated with the greater neuropsychological deficits in that disorder.

Adult↗
PubMed1999

Evidence from cultured rat cortical neurons of differences in the mechanism of ischemic preconditioning of brain and heart.

Ca2+ influx and activation of protein kinase C (PKC) and mitogen-activated protein kinase (MAPK) during nonlethal ischemic preconditioning have been implicated in the protection of the heart against subsequent lethal ischemic injury. Thus, we determined if Ca2+ influx, PKC and MAPK also mediate ischemic preconditioning-induced protection in neurons. Preconditioning by exposure of E18 rat cortical cultures to 90 min of nonlethal oxygen-glucose deprivation (OGD) 24 h prior to 180-240 min of lethal OGD was neuroprotective. Exposure to nominally free Ca2+, or blockade of the alpha-amino-hydroxy-5-methyl-isoxazolepropionate (AMPA) receptor with CNQX did not eliminate protection. MAPK activity did not change and PKC activity decreased by 50% relative to normal baseline levels at 0 and 24 h following preconditioning. The sustained decrease in PKC activity was not due to a loss of enzyme as determined from immunoblots using pan and epsilon-, beta- and zeta-specific PKC antibodies. Neuroprotection was maintained with pharmacological inhibition of PKC activity by staurosporine, chelerythrine and calphostin C and MAPK activity by PD 98059 during preconditioning, indicating that activation of these enzymes during preconditioning was not necessary for protection. Therefore, in contrast to cardiac tissue, ischemic preconditioning of neurons does not require activation of PKC and MAP kinase, and protection is maintained with substantial removal of extracellular Ca2+ or blockade of the AMPA receptor.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1999

Follow-up study of depression in the elderly. Clinical and SPECT data.

BACKGROUND: Imaging studies in depression of the elderly are often small and highly selective. AIMS: To investigate a large group of elderly depressed patients in order to assess changes in clinical, imaging and neuropsychological variables at follow-up. METHOD: Patients (n = 175, age range 65-91 years) with clinical depression were identified from consecutive local referrals. Clinical interviews, neuropsychological tests and SPECT scans were carried out at referral and at two-year follow-up. RESULTS: Of 84 re-examined patients, 46.5% were well, 9.5% were ill, 33% partially recovered and 11% had developed dementia. Duration of illness before index assessment was the only factor to predict outcome. Thirty-nine patients could be scanned and followed up. There were no differences between patients with good or poor depressive outcome on SPECT. Ten clinically improved patients could be re-examined with SPECT. There were relative increases in right cingulate gyrus and right cerebellum at follow-up. CONCLUSIONS: The patients group was comparable with other studies showing high levels of residual depressive symptoms. Activity changes in limbic cortex are implicated in depression of old age.

Aged↗
PubMed1999

AR-R15896AR blocks the early NMDA-induced loss of MAP2 in primary cortical cultures.

The low-affinity use-dependent N-methyl-D-aspartate (NMDA) receptor antagonist AR-R15896AR is neuroprotective in primary rat cortical cultures exposed to toxic concentrations of NMDA and reduces the magnitude of NMDA-triggered increases in [Ca2+]i. Here we show using fluorescence staining and measurements of microtubule-associated protein-2 (MAP2) levels, that AR-R15896AR inhibits the NMDA-induced loss of MAP2 that occurs within 2 min following NMDA exposure. Understanding the multiple, Ca(2+)-triggered intracellular events that occur following NMDA receptor stimulation is important to the development of safe and effective neuroprotective agents.

Animals↗
PubMed1999

Differences in degree of trapping of low-affinity uncompetitive N-methyl-D-aspartic acid receptor antagonists with similar kinetics of block.

This study characterizes the trapping of block of N-methyl-D-aspartic acid (NMDA)-induced currents by three structurally distinct, use-dependent NMDA receptor antagonists with similar rapid on-off rates. The antagonism of whole-cell currents in cultured rat cortical neurons by AR-R15896AR, ketamine, and memantine was examined. All three compounds produced a steady-state block after a 30-s coapplication, which was fully relieved after 50 s of NMDA exposure. The amplitudes of block caused by 50 microM AR-R15896AR, 10 microM ketamine, or 10 microM memantine were not significantly different, being 82 +/- 1%, 80 +/- 2%, and 81 +/- 2%, respectively. All three NMDA receptor antagonists exhibited trapping of block that was not significantly increased by extending the agonist/antagonist coapplication beyond 30 s. Although the initial blocks were similar, after 120 s of washout without agonist present, there were significant differences in trapping of block between antagonists, as only 54 +/- 3% of the AR-R15896AR block, 86 +/- 1% of the ketamine block, and 71 +/- 4% of the memantine block remained trapped. The lack of complete trapping is consistent with closed-channel egress by these compounds. Higher antagonist concentrations produced larger initial blocks, but the degree of trapping block was not significantly different from that at lower antagonist concentrations. The results demonstrate that differences in the degree of trapping exist among use-dependent NMDA receptor antagonists even when on and off rates are similar. These differences are correlated with measures of therapeutic index.

Animals↗
PubMed1998

Brain derived neurotrophic factor induction of N-methyl-D-aspartate receptor subunit NR2A expression in cultured rat cortical neurons.

N-methyl-D-aspartate (NMDA) receptor subunit expression changes during development and following injury in several brain regions. These changes may be mediated by neurotrophic factors, such as brain derived neurotrophic factor (BDNF). Exposure of cultured cortical neurons to BDNF (100 ng/ml) for 24 h produced a significant decrease in the NMDA-induced whole-cell currents sensitive to the NR2B subunit selective NMDA receptor antagonist, CP-101,606, suggesting a relative decrease in NR2B subunit expression. There was a significant increase in NR2A by Western blot analysis. Consistent with the electrophysiology and Western blot analysis, reverse transcriptase-polymerase chain reaction (RT-PCR) amplification revealed that BDNF caused a significant increase in relative NR2A subunit expression, a significant decrease in relative NR2B subunit expression and no change in relative NR2C subunit expression. These results suggest that BDNF enhances NMDA receptor maturation, warranting further study of the mechanism of BDNF effects on NMDA receptor subunit expression and the role these effects play in development and neuronal injury.

Animals↗
PubMed1998

Neuroprotective effects of a novel AMPA receptor antagonist, YM872.

Quinoxalinediones such as NBQX are neuroprotective in most models of cerebral ischemia but their poor solubility results in nephrotoxicity limiting their clinical utility. We have investigated the neuroprotective effects of a water soluble AMPA receptor antagonist, YM872, using two in vitro models. The viability of cortical cultures exposed to 400 microM AMPA for 15 min (16.4 +/- 2.6%; n = 10) was significantly (p < 0.05) increased (84.7 +/- 4.6%; n = 6) with YM872 (10 microM) in a concentration-dependent manner. Evoked post-synaptic response amplitudes in oxygen-glucose deprived hippocampal slices treated with 10 microM YM872 (3.5 +/- 0.3 mV; n = 27) were significantly different from untreated deprived slices (0.3 +/- 0.1 mV; n = 31, p < 0.05) and the CA1 neurons appeared viable using a confocal live/dead fluorescence assay with confocal microscopy. The neuroprotection seen with YM872 in vitro warrants further investigation in vivo.

Animals↗
PubMed1998

Structure of N-myristoyltransferase with bound myristoylCoA and peptide substrate analogs.

N-myristoyltransferase (Nmt) attaches myristate to the N-terminal glycine of many important eukaryotic and viral proteins. It is a target for anti-fungal and anti-viral therapy. We have determined the structure, to 2.9 A resolution, of a ternary complex of Saccharomyces cerevisiae Nmt1p with bound myristoylCoA and peptide substrate analogs. The model reveals structural features that define the enzyme's substrate specificities and regulate the ordered binding and release of substrates and products. A novel catalytic mechanism is proposed involving deprotonation of the N-terminal ammonium of a peptide substrate by the enzyme's C-terminal backbone carboxylate.

Acyl Coenzyme A↗
PubMed1998

Evidence that functional glutamate receptors are not expressed on rat or human cerebromicrovascular endothelial cells.

Excitatory amino acids can modify the tone of cerebral vessels and permeability of the blood-brain barrier (BBB) by acting directly on endothelial cells of cerebral vessels or indirectly by activating receptors expressed on other brain cells. In this study we examined whether rat or human cerebromicrovascular endothelial cells (CEC) express ionotropic and metabotropic glutamate receptors. Glutamate and the glutamate receptor agonists N-methyl-d-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA), and kainate failed to increase [Ca2+]i in either rat or human microvascular and capillary CEC but elicited robust responses in primary rat cortical neurons, as measured by fura-2 fluorescence. The absence of NMDA and AMPA receptors in rat and human CEC was further confirmed by the lack of immunocytochemical staining of cells by antibodies specific for the AMPA receptor subunits GluR1, GluR2/3, and GluR4 and the NMDA receptor subunits NR1, NR2A, and NR2B. We failed to detect mRNA expression of the AMPA receptor subunits GluR1 to GluR4 or the NMDA receptor subunits NR1(1XX); NR1(0XX), and NR2A to NR2C in both freshly isolated rat and human microvessels and cultured CEC using reverse transcriptase polymerase chain reaction (RT-PCR). Cultured rat CEC expressed mRNA for KA1 or KA2 and GluR5 subunits. Primary rat cortical neurons were found to express GluR1 to GluR3 and NR1, NR2A, and NR2B by both immunocytochemistry and RT-PCR and KA1, KA2, GluR5, GluR6, and GluR7 by RT-PCR. Moreover, the metabotropic glutamate receptor agonist 1-amino-cyclopentyl-1S, 3R-dicorboxylate (1S,3R-trans-ACPD), while eliciting both inositol trisphosphate and [Ca2+]i increases and inhibiting forskolin-stimulated cyclic AMP in cortical neurons, was unable to induce either of these responses in rat or human CEC. These results strongly suggest that both rat and human CEC do not express functional glutamate receptors. Therefore, excitatory amino acid-induced changes in the cerebral microvascular tone and BBB permeability must be affected indirectly, most likely by mediators released from the adjacent glutamate-responsive cells.

Animals↗
PubMed1998

Transepithelial transport of nicotine and vinblastine in isolated malpighian tubules of the tobacco hornworm (Manduca sexta) suggests a P-glycoprotein-like mechanism.

We have examined the accumulative transport properties of the Malpighian (excretory) tubules of the tobacco hornworm Manduca sexta to test the hypothesis that a P-glycoprotein-like multidrug transporter is active and is responsible for the excretion of dietary nicotine in this tissue. Isolated tubules were cannulated and exposed to radiolabelled forms of either nicotine (5 min exposure) or the P-glycoprotein substrate vinblastine (60 min exposure) in the bathing (basal surface) fluid. The luminal (apical) contents were then flushed, and lumen-to-bath ratios were measured. Although these ratios provide conservative estimates of the physiological ability of Malpighian tubules to move compounds from blood to lumen, tubules concentrated nicotine 10-fold from an initial bath concentration of 0.5 mmol l-1 and vinblastine threefold (from an initial concentration of 1 micromol l-1). Vectorial transport of vinblastine and nicotine was eliminated by 25 micromol l-1 verapamil (a P-glycoprotein inhibitor) and was not dependent on the presence of a transepithelial electrical potential. Nicotine transport was inhibited by atropine (3 mmol l-1), while nicotine (> or = 50 micromol l-1) significantly reduced vinblastine transport. Verapamil was effective at reducing vinblastine transport when applied to the basal side alone, but not when applied to the apical side alone. Taken together, these results are consistent with the idea that the active excretion of nicotine and other alkaloids by the tobacco hornworm is mediated by a P-glycoprotein-like mechanism.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

Survival of women ages 40-49 years with breast carcinoma according to method of detection.

BACKGROUND: The value of mammographic screening in reducing breast carcinoma mortality among women younger than 50 years continues to be controversial. Previous randomized clinical trials have not been definitive because of inadequate sample sizes, prolonged screening intervals, questionable randomization, and/or cross-contamination between intervention groups. This study uses a historical prospective cohort design to examine differences in prognostic factors at the time of breast carcinoma diagnosis and differences in overall survival among patients ages 40-49 years, according to the method of breast carcinoma detection. METHODS: Women (n = 971) ages 40-49 years diagnosed with invasive breast carcinoma between 1986 and 1992 were identified by TUMORS (The Upper Midwest Oncology Registry Services). Measures of tumor size, lymph node status, and overall survival were compared with breast carcinoma patients whose tumors were detected by breast self-exam (BSE), clinical breast exam (CBE), patient incidental finding (PI), or mammography. RESULTS: Mean tumor size among women in the mammography group was smaller than that among women in the BSE, CBE, and PI groups (P < 0.002). Tumors detected by mammography were significantly more likely to be localized than those detected by other methods (P < 0.0001). Patients whose tumors were detected by mammography had significantly better survival than patients in the other detection method groups, especially among those with smaller tumors (P < 0.0001). This difference persisted even after adjustment for lead time bias. CONCLUSIONS: Women ages 40-49 years whose invasive breast carcinoma is detected by mammography have significantly smaller tumors, more localized disease, and may have a lower risk of mortality than women whose tumors are detected by other methods.

Adult↗
PubMed1997

Quality of life and treatment outcomes: prostate carcinoma patients' perspectives after prostatectomy or radiation therapy.

BACKGROUND: Of the estimated 317,000 men in the United States diagnosed with prostate carcinoma in 1996, 57% will have localized disease, and their 5-year relative survival rate will be 98%. Limited information exists on patient-reported quality of life (QOL) and the incidence and severity of treatment-related side effects. The purpose of this study was to identify and compare patients' self-reported QOL and treatment side effects 1-5 years after radical prostatectomy or radiotherapy. METHODS: Data collection for this cross-sectional study included a mailed, self-administered survey with three parts: a demographic survey, the Functional Assessment of Cancer Therapy-General (FACT-G), and a newly developed Prostate Cancer Treatment Outcome Questionnaire (PCTO-Q). The FACT-G measured the effect of prostate carcinoma on overall QOL in the two treatment groups. The PCTO-Q assessed the patients' perceptions of the incidence and severity of specific changes in bowel, urinary, and sexual functions. The test-retest reliability of the PCTO-Q in a pilot study was 91.2%. RESULTS: Two hundred seventy-four eligible men completed the questionnaires; 132 (48%) reported having undergone prostatectomy and 142 (52%) reported having undergone radiotherapy. After age adjustment, the radiotherapy group reported more bowel dysfunction (P = 0.001), whereas the prostatectomy group reported more urinary problems (P = 0.03) and more sexual dysfunction (P = 0.001). Scores for the FACT-G were similar in the two treatment groups. CONCLUSIONS: Men undergoing treatment for clinically localized prostate carcinoma continue to experience difficulty long after treatment. In this study, the prostatectomy group fared worse in regard to sexual and urinary functions, whereas the radiotherapy group experienced more bowel dysfunction. Survivor-reported QOL and treatment outcomes can assist physicians in counseling patients in the selection of the preferred course of treatment.

Age Factors↗
PubMed1997

Conspiring to succeed: the process of a joint military health care merger.

Congress has mandated that the military services improve their health care systems to improve access, assure high-quality care, provide more choices, and contain costs. In response, the Department of Defense established the TRICARE system, organizing it geographically into 12 health services regions. This paper tracks the efforts of one of those 12--region IV--to plan for this change using strategic planning. Region IV's board of governors represents military facilities in Mississippi, Florida, Alabama, Tennessee, and Louisiana, including one clinic managed by the U.S. Coast Guard, Department of Transportation. Strategic planning usually involves people who know each other and work together. Because of the joint nature of this effort, the members were unfamiliar with one another and with the others' systems. There were also physical distances to overcome. This paper documents that unique experience, likened to a "corporate merger," and the lessons learned from it.

Delivery of Health Care↗
PubMed1995

Evaluation of oncology registry follow-up methods.

BACKGROUND: The accuracy and completeness of oncology (tumor) registry patient follow-up information directly affects the validity of the oncology registry system for determining outcomes, as a quality assurance measure, and for research activities. At this institution, if a hospital-based patient encounter has not been identified during the previous year, a follow-up letter is sent to the attending physician to obtain current information about the patient. Difficulties using this method include (1) correct identification of the appropriate physician (2) constraints on physician and staff time to provide information, and (3) accuracy, currentness, and completeness of information provided. METHODS: A study was conducted to compare the accuracy and completeness of the oncology registry patient follow-up information obtained from three sources: responses from the patient, responses from the physician, and affiliated clinic chart reviews. Seven hundred ninety-one patient and physician letters were sent during a 2-month period, and 122 clinic charts were reviewed. RESULTS: Physicians responded more frequently than patients (82% vs. 58%) (P < 0.003). From the responses received, requested information regarding recurrence, treatment, quality of survival, and survival was obtained most frequently from patients. However, it was difficult to ascertain information about cancer status from patient responses. Patients supplied more current follow-up information than physicians or the clinic chart reviews. CONCLUSIONS: A follow-up system that delivers accurate and complete information while maintaining efficiency is a critical aspect of an oncology registry. Requesting follow-up information from the patient before physician contact or chart review allows for more current information while maintaining accuracy regarding cancer recurrence, treatment, quality of survival, and survival. Consequently, staff time required for obtaining follow-up information from physicians and/or chart reviews is lessened and costs decreased.

Data Collection↗