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Biomedical subjects

R F White

Publications and source records attributed to R F White.

At least 19 recordsLinked to original sources
PubMed2001

SB 239063, a novel p38 inhibitor, attenuates early neuronal injury following ischemia.

The aim of the present study was to evaluate p38 MAPK activation following focal stroke and determine whether SB 239063, a novel second generation p38 inhibitor, would directly attenuate early neuronal injury. Following permanent middle cerebral artery occlusion (MCAO), brains were dissected into ischemic and non-ischemic cortices and Western blots were employed to measure p38 MAPK activation. Neurologic deficit and MR imaging were utilized at various time points following MCAO to monitor the development and resolution of brain injury. Following MCAO, there was an early (15 min) activation of p38 MAPK (2.3-fold) which remained elevated up to 1 h (1.8-fold) post injury compared to non-ischemic and sham operated tissue. Oral SB 239063 (5, 15, 30, 60 mg/kg) administered to each animal 1 h pre- and 6 h post MCAO provided significant (P<0.05) dose-related neuroprotection reducing infarct size by 42, 48, 29 and 14%, respectively. The most effective dose (15 mg/kg) was further evaluated in detail and SB 239063 significantly (P<0.05) reduced neurologic deficit and infarct size by at least 30% from 24 h through at least 1 week. Early (i.e. observed within 2 h) reductions in diffusion weighted imaging (DWI) intensity following treatment with SB 239063 correlated (r=0.74, P<0.01) to neuroprotection seen up to 7 days post stroke. Since increased protein levels for various pro-inflammatory cytokines cannot be detected prior to 2 h in this stroke model, the early improvements due to p38 inhibition, observed using DWI, demonstrate that p38 inhibition can be neuroprotective through direct effects on ischemic brain cells, in addition to effects on inflammation.

Animals↗
PubMed2001

Neuropsychological function in Gulf War veterans: relationships to self-reported toxicant exposures.

BACKGROUND: The present study was aimed at (1) exploring evidence of central nervous system (CNS) dysfunction among Gulf War (GW) veterans on neuropsychological tests and (2) examining whether performance on neuropsychological tests was related to specific neurotoxicant exposures experienced in the Gulf. METHODS: The GW-deployed groups were selected using stratified random sampling methods from two distinct cohorts of GW veterans. A comparison group that had been called up for GW service but deployed to Germany rather than the Gulf also was examined. Neuropsychological function was assessed using a pre-determined battery chosen to include tests known to be highly sensitive to the behavioral effects of the neurotoxicants thought to have been present in the Gulf. RESULTS: Self-reported exposures were related to neuropsychological test performance controlling for post-traumatic stress disorder, major depression, and other known covariates of neuropsychological test performance. Results showed that GW-deployed veterans performed more poorly than the Germany-deployed veterans on several specific neuropsychological tests, but after adjustment for multiple comparisons, only the differences in mood complaints remained significant. Within the GW-deployed group, self-reported exposure to chemical warfare agents was associated with poorer performance on cognitive tests involving specific functional domains. CONCLUSIONS: Results provide evidence that there are subtle differences in CNS function among GW-deployed veterans who report chemical warfare agent exposure while in the GW theater.

Adult↗
PubMed2001

Chemical sensitivity and chronic fatigue in Gulf War veterans: a brief report.

The foci of this brief report are to (1) describe the prevalence of chemical sensitivity (CS) and chronic fatigue (CF) symptomatology and of presumptive multiple CS and CF syndrome diagnoses, and (2) explore the potential overlap between one purported case definition (i.e., chronic multi-symptom illness) and these unexplained symptom syndromes in a well-characterized group of Gulf War veterans. The number of subjects with CS and CF symptomatology and presumptive multiple CS and CF syndrome diagnoses was higher in the Gulf War-deployed group compared with a group deployed to Germany during the Gulf War. However, the percent differences were not significant when comparing the presumptive diagnoses of multiple CS and CF syndrome. The characteristic differences between the groups and the overlap with chronic multi-symptom illness are also discussed.

Adult↗
PubMed2001

SB 239063, a second-generation p38 mitogen-activated protein kinase inhibitor, reduces brain injury and neurological deficits in cerebral focal ischemia.

The stress-activated mitogen-activated protein kinase (MAPK) p38 has been linked to the production of inflammatory cytokines/mediators/inflammation and death/apoptosis following cell stress. In these studies, a second-generation p38 MAPK inhibitor, SB 239063 (IC(50) = 44 nM), was found to exhibit improved kinase selectivity and increased cellular (3-fold) and in vivo (3- to 10-fold) activity over first-generation inhibitors. Oral SB 239063 inhibited lipopolysaccharide-induced plasma tumor necrosis factor production (IC(50) = 2.6 mg/kg) and reduced adjuvant-induced arthritis (51% at 10 mg/kg) in rats. SB 239063 reduced infarct volume (48%) and neurological deficits (42%) when administered orally (15 mg/kg, b.i.d.) before moderate stroke. Intravenous SB 239063 exhibited a clearance of 34 ml/min/kg, a volume of distribution of 3 l/kg, and a plasma half-life of 75 min. An i.v. dosing regimen that provided effective plasma concentrations of 0.38, 0.75, or 1.5 microg/ml (i.e., begun 15 min poststroke and continuing over the initial 6-h p38 activation period) was used. Significant and dose-proportional brain penetration of SB 239063 was demonstrated during these infusion periods. In both moderate and severe stroke, intravenous SB 239063 produced a maximum reduction of infarct size by 41 and 27% and neurological deficits by 35 and 33%, respectively. No effects of the drug were observed on cerebral perfusion, hemodynamics, or body temperature. Direct neuroprotective effects from oxygen and glucose deprivation were also demonstrated in organotypic cultures of rat brain tissue. This robust in vitro and in vivo SB 239063-induced neuroprotection emphasizes the potential role of MAPK pathways in ischemic stroke and also suggests that p38 inhibition warrants further study, including protection in other models of nervous system injury and neurodegeneration.

Animals↗
PubMed2001

Health-related quality of life in Persian Gulf War Veterans.

OBJECTIVE: The objective of this investigation is to describe the health-related quality of life of Persian Gulf War (GW) veterans and to examine the effects of current chronic medical conditions and psychiatric status on physical functioning. METHODS: To measure health-related quality of life, the Medical Outcomes Short Form Survey (SF36) was administered approximately 4 years after the GW to a stratified, random sample of New England-area GW-deployed veterans and a group of military personnel deployed to Germany during the GW. The SF36 scores for the GW-deployed study population (N = 141) were compared with those for the Germany-deployed group (N = 46) and with published U.S. population norms. Multiple linear regression analyses were performed to identify risk factors associated with lower physical health functioning in the GW-deployed study group. RESULTS: Functional health status was significantly lower in the GW-deployed group compared with the Germany-deployed group for each of the SF36 subscales and the two summary scores (Physical Component Summary [PCS] and Mental Component Summary). Compared with the general U.S. population, the GW-deployed group median was between the 25th and 50th percentile for the Physical Functioning subscale and the PCS score. Within the GW-deployed group, lower education, psychological symptomatology, and a higher number of chronic self-reported medical conditions were significant predictors of the PCS score. CONCLUSION: GW-deployed veterans report lower functional health status compared with a group of Germany-deployed veterans and published general U.S. population norms. Within the group of GW-deployed veterans, several current medical and psychological conditions predictive of lower physical functioning levels were identified.

Adult↗
PubMed2000

Characterisation of SB-221420-A - a neuronal Ca(2+) and Na(+) channel antagonist in experimental models of stroke.

For progression to clinical trials in stroke, putative neuroprotective compounds should show robust efficacy post-ischaemia in several experimental models of stroke. This paper describes the characterisation of (+)(1S, 2R)-cis-1-[4-(1-methyl-1-phenylethyl)phenoxy]-2-methylamino indane hydrochloride (SB-221420-A), a Ca(2+) and Na(+) channel antagonist. SB-221420-A inhibited (IC(50)=2.2 microM) N-type voltage-operated Ca(2+) channel currents in cultured superior cervical ganglion neurons, which were pretreated with 10 microM nimodipine to block L-type voltage-operated Ca(2+) channel currents. In dorsal root ganglion neurons pretreated with 1 microM omega-conotoxin GVIA to block N-type voltage-operated Ca(2+) channel currents, SB-221420-A inhibited the residual Ca(2+) current with an IC(50) of 7 microM. SB-221420-A also inhibited Na(+) currents in dorsal root ganglion neurons with an IC(50) of 8 microM. In rats, the pharmacokinetic profile of SB-221420-A shows that it has a half-life of 6.4 h, a high volume of distribution, is highly brain penetrating, and has no persistent metabolites. Following bilateral carotid artery occlusion in gerbils, SB-221420-A significantly reduced the level of ischaemia-induced hyperlocomotor activity and the extent of hippocampal CA1 cell loss compared to the ischaemic vehicle-treated group. SB-221420-A was also effective in focal models of ischaemia. In the mouse permanent middle cerebral artery occlusion model, SB-221420-A (10 mg/kg) administered intravenously, post-ischaemia significantly (P<0.05) reduced lesion volume compared to the ischaemic vehicle-treated group. In the normotensive rat permanent middle cerebral artery occlusion model, SB-221420-A (10 mg/kg) administered intravenously over 1 h, beginning 30 min postmiddle cerebral artery occlusion, significantly (P<0.05) reduced lesion volume from 291+/-16 to 153+/-30 mm(3), compared to ischaemic vehicle-treated controls when measured 24 h postmiddle cerebral artery occlusion. Efficacy was maintained when the same total dose of SB-221420-A was infused over a 6-h period, beginning 30 min postmiddle cerebral artery occlusion. SB-221420-A also significantly (P<0.05) reduced lesion volume following transient middle cerebral artery occlusion in normotensive rats and permanent middle cerebral artery occlusion in spontaneously hypertensive rats (SHR). Investigation of the side effect profile using the Irwin screen in mice revealed that, at neuroprotective doses, there were no overt behavioural or cardiovascular changes. These data demonstrate that robust neuroprotection can be seen post-ischaemia with SB-221420-A in both global and focal ischaemia with no adverse effects at neuroprotective doses, and indicate the potential utility of a mixed cation blocker to improve outcome in cerebral ischaemia.

Anesthesia↗
PubMed2000

Benign focal ischemic preconditioning induces neuronal Hsp70 and prolonged astrogliosis with expression of Hsp27.

We have established a focal preconditioning (PC) paradigm that produces significant and prolonged ischemic tolerance (IT) of the brain to subsequent permanent middle cerebral artery occlusion (MCAO). PC using 10 min of MCAO induces brain tolerance at 1-7 days of reperfusion that requires active protein synthesis. The protective protein(s) involved are unknown. In these studies the increased transcription and translation of the inducible 70-kDa heat shock protein (Hsp70) and the 27-kDa heat shock protein (Hsp27), and astrogliosis/glial fibrillary acidic protein (GFAP) were determined by Northern analysis and immunohistochemistry following PC. Cellular localization of proteins was determined by double labeling. PC produced no brain injury but did increase Hsp70 mRNA transiently at 6 h and increased Hsp27 mRNA later at 24 h for at least 5 days. Protein expression induced by PC exhibited a similar profile. Hsp70 protein was primarily expressed in neurons from 1 to 5 days post-PC throughout the PC cortex. Hsp27 protein expression was initiated later for a much longer period of time. A remarkable astroglyosis was verified with increased astrocytic Hsp27 from 1 to 7 days after PC. Gliosis with increased Hsp27 in the PC cortex was still present but reduced 4 weeks after PC. Therefore, PC that results in brain tolerance/neuroprotection increases neuronal Hsp70 in the PC cortex and activated astrocytic Hsp27 in the PC cortex in a temporal fashion associated with developing IT. The short duration of benign ischemia (PC) that produces IT produces a robust, long-lived cellular and protein synthetic response that extends throughout the entire cortex (i.e. well beyond the MCA perfusion territory). The resulting IT is associated with changes in astrocyte-activation that might provide increased support and protection from injury. Although both Hsp70 and Hsp27 may participate in the neuroprotection/brain tolerance induced by PC, the temporal expression patterns of these proteins indicate that they are not solely responsible for the tolerance to brain injury.

Animals↗
PubMed2000

Benchmark dose calculations of methylmercury-associated neurobehavioural deficits.

Prenatal methylmercury exposure is associated with neuropsychological deficits in Faroese children at age 7 years. Lower confidence bounds of benchmark doses (BMDLs) have now been calculated. With the cord-blood mercury concentration as the dose parameter, a logarithmic dose-response model tended to show a better fit than a linear dose model for the attention, language and verbal memory tests. The lowest BMDLs averaged approximately 5 microgram/l cord blood, which corresponds to a maternal hair concentration of approximately 1 microgram/g. However, most BMDLs for hair mercury concentrations were higher. Thus, the results of the benchmark calculations depend on the assumed dose-response model.

Biomarkers↗
PubMed2000

The preclinical phase of alzheimer disease: A 22-year prospective study of the Framingham Cohort.

OBJECTIVES: To relate performance on tests of cognitive ability to the subsequent development of probable Alzheimer disease (pAD) and to identify the pattern of earliest changes in cognitive functioning associated with a diagnosis of pAD. DESIGN: From May 1975 to November 1979, a screening neuropsychological battery was administered to Framingham Study participants. They were followed up prospectively for 22 years and examined at least every 2 years for the development of pAD. SETTING: A community-based center for epidemiological research. PARTICIPANTS: Subjects were 1076 participants of the Framingham Study aged 65 to 94 years who were free of dementia and stroke at baseline (initial) neuropsychological testing. MAIN OUTCOME MEASURE: Presence or absence of pAD during a 22-year surveillance period was related to test performance at initial neuropsychological testing. RESULTS: Lower scores for measures of new learning, recall, retention, and abstract reasoning obtained during a dementia-free period were associated with the development of pAD. Lower scores for measures of abstract reasoning and retention predicted pAD after a dementia-free period of 10 years. CONCLUSIONS: The "preclinical phase" of detectable lowering of cognitive functioning precedes the appearance of pAD by many years. Measures of retention of information and abstract reasoning are among the strongest predictors of pAD when the interval between initial assessment and the development of pAD is long. Arch Neurol. 2000.

Aged↗
PubMed2000

Validity of a computer-assisted neurobehavioral test battery in toxicant encephalopathy.

The computer-assisted Neurobehavioral Evaluation System 2 (NES2) test battery provides an efficient method of measuring neurobehavioral effects in epidemiological studies, and a newer computer-assisted battery, NES3, has been developed to assist in neuropsychological assessment. This study assesses the validity of some NES2 and NES3 tests in patients diagnosed with toxicant encephalopathy (TE) following exposure to lead or to mixed solvents. This information can be used to improve the interpretation of NES test results in research studies and clinical evaluations examining central nervous system function. Performance on a battery of computer-assisted tests, consisting of several NES2 and NES3 tasks, by persons diagnosed with TE was compared to that of control subjects to determine if performance differences reflected a priori hypothesized brain-behavior relationships. Performance on the NES2 and NES3 tests was also correlated with performance on analogous standard neuropsychological tests. Significant performance differences between the patient cases and controls were observed in most of the predicted domains on the NES tests. Overall, moderate correlations were obtained between standard neuropsychological tests and NES2 and NES3 tests from the same functional domains. The results suggest that a test battery composed of NES2 and NES3 tests can identify clinically significant performance deficits in solvent-exposed patients who have been diagnosed with TE using traditional clinical neuropsychological test methods. The results with lead-exposed TE patients are less robust. Possible explanations for these differences are discussed.

Adult↗
PubMed1999

Methylmercury exposure biomarkers as indicators of neurotoxicity in children aged 7 years.

The mercury concentration in blood or scalp hair has been widely used as a biomarker for methylmercury exposure. Because of the increased risks associated with exposures during prenatal and early postnatal development, biomarker results must be interpreted with regard to the age-dependent susceptibility. The authors compared regression coefficients for five sets of exposure biomarkers in 917 children from the Faroe Islands examined at birth, 1 year, and 7 years. Outcome variables were the results of neuropsychologic examination carried out in 1993-1994 at age 7 years. After adjustment for covariates, the cord-blood concentration showed the clearest associations with deficits in language, attention, and memory. Fine-motor function deficits were particularly associated with the maternal hair mercury at parturition. Mercury concentrations in the child's blood and hair at age 7 years were significant predictors only of performance on memory for visuospatial information. These findings emphasize the usefulness of the cord-blood mercury concentration as a main risk indicator. They also support the notion that the greatest susceptibility to methylmercury neurotoxicity occurs during late gestation, while early postnatal vulnerability is less, and they suggest that the time-dependent susceptibility may vary for different brain functions.

Biomarkers↗
PubMed1999

Use of diffusion-weighted MRI and neurological deficit scores to demonstrate beneficial effects of isradipine in a rat model of focal ischemia.

The neuroprotective effects of isradipine, a 2,4-dihydropyridine calcium channel blocker, has been well studied in the rat model of focal ischemia (induced by middle cerebral artery occlusion, MCAO). The present study was designed to evaluate whether isradipine pretreatment caused early (0-3 h after stroke) ischemic changes in diffusion- weighted magnetic resonance imaging (DWI) and if such changes were predictive of previously documented protection in brain infarction. An initial dose-response study using neurological deficit scores and estimates of protection from brain infarction (by histology) showed that isradipine reduced cortical infarctions compared to vehicle-treated animals at most doses (between 1.25 and 5 mg/kg/day s.c. for 6 days) with the best results obtained at 5 mg/kg/day, where a 78.5% reduction was observed. This dose was utilized to perform the DWI study. Early quantitative estimates of infarct size, as measured by DWI at 1, 2 and 3 h after MCAO, were similar to those obtained with late histology at 24 h. These data indicate that in pretreatment protocols, DWI can be used to quantitatively predict areas at risk of permanent damage. This work also demonstrates that neurological deficits, developing from the damaged forebrain following focal stroke, may provide an index of isradipine's neuroprotective activity.

Animals↗
PubMed1999

Methylmercury neurotoxicity in Amazonian children downstream from gold mining.

In widespread informal gold mining in the Amazon Basin, mercury is used to capture the gold particles as amalgam. Releases of mercury to the environment have resulted in the contamination of freshwater fish with methylmercury. In four comparable Amazonian communities, we examined 351 of 420 eligible children between 7 and 12 years of age. In three Tapajós villages with the highest exposures, more than 80% of 246 children had hair-mercury concentrations above 10 microg/g, a limit above which adverse effects on brain development are likely to occur. Neuropsychological tests of motor function, attention, and visuospatial performance showed decrements associated with the hair-mercury concentrations. Especially on the Santa Ana form board and the Stanford-Binet copying tests, similar associations were also apparent in the 105 children from the village with the lowest exposures, where all but two children had hair-mercury concentrations below 10 microg/g. Although average exposure levels may not have changed during recent years, prenatal exposure levels are unknown, and exact dose relationships cannot be generated from this cross-sectional study. However, the current mercury pollution seems sufficiently severe to cause adverse effects on brain development.

Adult↗