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Biomedical subjects

R F White

Publications and source records attributed to R F White.

At least 37 records · Page 2Linked to original sources
PubMed1998

[Computer assisted neuropsychological testing of children].

The purpose of the study was to examine the feasibility of a computer-assisted neuro-psychological test program, the Neurobehavioral Evaluation System (NES), in six to seven year-old children. We administered three NES tests, Finger Tapping (FT), Continuous Performance Test (CPT) and Hand-Eye Coordination (HEC) to Faroese and Danish children. The FT and CPT were of appropriate difficulty, while the HE was too difficult for the majority of the children. Boys obtained better scores than the girls, and children who were familiar with computers and video games performed better than those without such experience. Older children also obtained better scores than younger ones, especially in the Faroese group. The Danish children performed better than the Faroese in FT and CPT. In HE there was no difference. The NES tests are feasible for children at this age, but appropriate comparison groups must be secured.

Child↗
PubMed1998

Cognitive performance of children prenatally exposed to "safe" levels of methylmercury.

Within a cohort of 1022 consecutive singleton births in the Faroe Islands, we assessed prenatal methylmercury exposure from the maternal hair mercury concentration. At approximately 7 years of age, 917 of the children underwent detailed neurobehavioral examination. Little risk is thought to occur as long as the hair mercury concentration in pregnant women is kept below 10-20 microg/g (50-100 nmol/l). A case group of 112 children whose mothers had a hair mercury concentration of 10-20 microg/g was therefore matched to children with exposure below 3 microg/g, using age, sex, time of examination, and the mother's score on Raven's Progressive Matrices as matching criteria. The two groups were almost identical with regard to other factors that might affect neurobehavioral performance in this community. On six neuropsychological test measures, the case group showed mild decrements, relative to controls, especially in the domains of motor function, language, and memory. Subtle effects on brain function therefore seem to be detectable at prenatal methylmercury exposure levels currently considered to be safe.

Case-Control Studies↗
PubMed1998

Health status of Persian Gulf War veterans: self-reported symptoms, environmental exposures and the effect of stress.

BACKGROUND: Most US troops returned home from the Persian Gulf War (PGW) by Spring 1991 and many began reporting increased health symptoms and medical problems soon after. This investigation examines the relationships between several Gulf-service environmental exposures and health symptom reporting, and the role of traumatic psychological stress on the exposure-health symptom relationships. METHODS: Stratified, random samples of two cohorts of PGW veterans, from the New England area (n = 220) and from the New Orleans area (n = 71), were selected from larger cohorts being followed longitudinally since arrival home from the Gulf. A group of PGW-era veterans deployed to Germany (n = 50) served as a comparison group. The study protocol included questionnaires, a neuropsychological test battery, an environmental interview, and psychological diagnostic interviews. This report focuses on self-reported health symptoms and exposures of participants who completed a 52-item health symptom checklist and a checklist of environmental exposures. RESULTS: The prevalence of reported symptoms was greater in both Persian Gulf-deployed cohorts compared to the Germany cohort. Analyses of the body-system symptom scores (BSS), weighted to account for sampling design, and adjusted by age, sex, and education, indicated that Persian Gulf-deployed veterans were more likely to report neurological, pulmonary, gastrointestinal, cardiac, dermatological, musculoskeletal, psychological and neuropsychological system symptoms than Germany veterans. Using a priori hypotheses about the toxicant effects of exposure to specific toxicants, the relationships between self-reported exposures and body-system symptom groupings were examined through multiple regression analyses, controlling for war-zone exposure and post-traumatic stress disorder (PTSD). Self-reported exposures to pesticides, debris from Scuds, chemical and biological warfare (CBW) agents, and smoke from tent heaters each were significantly related to increased reporting of specific predicted BSS groupings. CONCLUSIONS: Veterans deployed to the Persian Gulf have higher self-reported prevalence of health symptoms compared to PGW veterans who were deployed only as far as Germany. Several Gulf-service environmental exposures are associated with increased health symptom reporting involving predicted body-systems, after adjusting for war-zone stressor exposures and PTSD.

Adult↗
PubMed1998

Subtractive cloning identifies tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) increased gene expression following focal stroke.

BACKGROUND AND PURPOSE: Differential gene expression has been reported following the onset of focal stroke. To identify de novo expression of ischemia-induced genes, we applied subtractive cDNA library strategy to identify the genes that are selectively upregulated by focal stroke. METHODS: Spontaneously hypertensive rats were subjected to permanent occlusion of the middle cerebral artery (MCAO). mRNAs prepared from ischemic and nonischemic cortex 2 and 12 hours after MCAO were subtracted, and a subtractive cDNA library was constructed. A cDNA that encodes for tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) was identified in the subtractive cDNA library. The temporal expression of cortical TIMP-1 mRNA was further characterized in ischemic cortex subjected to permanent or temporary (160-minute) MCAO. RESULTS: A panel of genes isolated from the subtractive cDNA library was subjected to Southern analysis to confirm ischemia-induced gene expression. TIMP-1 demonstrated robust induction after ischemic injury. Time-course studies revealed that TIMP-1 mRNA was induced threefold over controls at 12 hours (P<.001, n=4 animals) and reached a peak level at 2 days after permanent MCAO (sevenfold increase, P<.001). Similar induction profile of TIMP-1 mRNA was observed in the ischemic cortex after temporary MCAO followed by reperfusion. CONCLUSIONS: This work demonstrated the utility of subtractive cDNA library strategy for discovery of genes differentially expressed in focal stroke. Furthermore, our data implicate TIMP-1 in ischemia-induced brain injury.

Animals↗
PubMed1998

Matrix metalloproteinase expression increases after cerebral focal ischemia in rats: inhibition of matrix metalloproteinase-9 reduces infarct size.

BACKGROUND AND PURPOSE: Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes that degrade the extracellular matrix and are implicated in numerous pathological conditions including atherosclerosis, inflammation, and tumor growth and metastasis. In the brain, the endothelial cell wall, strengthened by tight junctions, defines the blood-brain barrier (BBB). The extracellular matrix molecules constitute the basement membrane underlying the vasculature and play a critical role in maintaining the integrity of the BBB. After focal stroke, there is a breakdown of the BBB with an associated increase in vascular permeability, inflammatory cell influx, and neuronal cell death. The present study was designed to investigate the effects of MMP expression after stroke. METHODS: Focal stroke was produced by permanent middle cerebral artery occlusion (MCAO) in the rat, and MMP protein expression was measured by Western blot and zymogram analysis over a time course ranging from 6 hours to 30 days (n=32). Immunohistochemistry at 1 and 5 days (n=8 and 6, respectively) was also utilized to characterize the expression of several MMPs and related proteins after stroke, including their cellular source. To test the hypothesis that early increased MMP-9 expression is involved in ischemic brain injury, a neutralizing monoclonal antibody directed against MMP-9 was administered intravenously (n=7 per group) 1 hour before MCAO, and infarct size was measured 24 hours later. RESULTS: MMP expression increased progressively over time after stroke. After 12 hours, significant (P<0.05) MMP-9 activity was observed that reached maximum levels by 24 hours (P<0.001), then persisted for 5 days at this level and returned to basal (zero) levels by 15 days. On the basis of morphological criteria, MMP-9 appeared to stain with endothelial cells and neutrophils identified both within and at the periphery of the infarct within 24 hours of focal ischemia. After 5 days, MMP-9 appeared to stain with macrophages present within the infarcted brain. MMP-2 activity was significantly (P<0.001) increased by 24 hours and was maximum after 5 days following MCAO. MMP-2 appeared to stain with macrophages present within the infarcted region. Unlike MMP-9 and MMP-2, tissue inhibitor of metalloproteinase-1 was identified at comparable levels in both control and ischemic tissue after MCAO. MMP-1 and MMP-3 could not be detected in the brain after focal stroke. When an MMP-9-neutralizing monoclonal antibody was administered systemically, animals exhibited significantly reduced infarct size (ie, a 30% reduction compared with non-immune antibody controls; P<0.05). CONCLUSIONS: These results demonstrate that early increased MMP-9 expression in endothelial cells and infiltrating neutrophils is a significant response to cerebral focal ischemia and that selective inhibition of MMP-9 activity can significantly reduce brain injury after stroke.

Animals↗
PubMed1998

Ischemic preconditioning and brain tolerance: temporal histological and functional outcomes, protein synthesis requirement, and interleukin-1 receptor antagonist and early gene expression.

BACKGROUND AND PURPOSE: A short duration of ischemia (ie, ischemic preconditioning [PC]) can provide significant brain protection to subsequent ischemic events (ie, ischemic tolerance [IT]). The present series of studies was conducted to characterize the temporal pattern of a PC paradigm, to systematically evaluate the importance of protein synthesis in PC-induced IT, and to explore candidate gene expression changes associated with IT. METHODS: Temporary middle cerebral artery occlusion (MCAO) (10 minutes) was used for PC. Various periods of reperfusion (ie, 2, 6, and 12 hours and 1, 2, 7, 14, and 21 days) were allowed after PC and before permanent MCAO (PMCAO) (n=7 to 9 per group) to establish IT compared with non-PC (sham-operated) rats (n=22). Infarct size, forelimb and hindlimb motor function, and cortical perfusion (laser-Doppler flowmetry; n=9 per group) were measured after PMCAO. The effects of the protein synthesis inhibitor cycloheximide administered just before PC (n= 13 to 17) or administered long after PC but just before PMCAO (n=7 to 8) on IT were also determined. Interleukin- receptor antagonist mRNA (reverse transcriptase and polymerase chain reactions [n=20] and Northern analysis [n=50]) and protein expression (immunohistochemistry [n=16]) after PC and early response gene expression (Northern analysis [n=16]) after PMCAO in PC animals were determined. RESULTS: Hemispheric infarct was significantly (P<0.01) reduced only if PC was performed 1 day (decreased 58.4%), 2 days (decreased 58.1%), or 7 days (decreased 59.4%) before PMCAO. PC significantly (P<0.01) reduced neurological deficits (similar to reductions in infarct size). Cycloheximide eliminated ischemic PC-induced IT effects on both brain injury and neurological deficits if administered before PC (P<0.05) but not if administered long after PC but before PMCAO. PC did not produce any significant brain injury, alter cortical blood flow after PMCAO, or produce contralateral cortical neuroprotection. Interleukin-1 receptor antagonist mRNA and protein expression were increased significantly (P<0.01) only during the IT period. PC rats also exhibited a significant (P<0.01) reduction in c-fos and zif268 mRNA expression after PMCAO. CONCLUSIONS: PC is a powerful inducer of ischemic brain tolerance as reflected by preservation of brain tissue and motor function. PC induces IT that is dependent on de novo protein synthesis. New protein(s) that occurs at the PC brain site 1 to 7 days after PC contributes to the neuroprotection. Those proteins that are produced after the more severe PMCAO in PC animals apparently do not contribute to IT. The PC-induced IT is also associated with increased expression of the neuroprotective protein interleukin-1 receptor antagonist and a reduced postischemic expression of the early response genes c-fos and zif268. (Stroke. 1998;29:1937-1951.)

Animals↗
PubMed1997

Solvents and neurotoxicity.

We describe the clinical evaluation of the nervous-system effects of solvent exposure. We review the current evidence in the epidemiological literature on neurotoxicological effects of solvents, and outline methods and issues to be taken into account in assessment of the patient whose symptoms may be related to solvent toxicity. Primary prevention of these disorders is essential, because treatment options are limited.

Central Nervous System Diseases↗
PubMed1997

Hazardous waste and neurobehavioral effects: a developmental perspective.

This paper summarizes the findings gleaned from detailed clinical examinations of three groups of residents who were exposed to trichloroethylene in well water. Also summarized are diagnostic findings for peripheral neuropathy. A detailed description of the neuropsychological test results is included, as well as a summary of domain-specific findings and diagnostic outcomes. A high rate of cognitive deficits of the type seen in patients with central nervous system dysfunction attributable to solvent exposure was seen. In addition, there was a clear developmental trend: subjects who were younger at the time of TCE exposure showed deficits in a larger variety of cognitive realms than did subjects who had already reached adulthood by the time of exposure. In particular, language deficits were seen in the younger, but not older, exposed subjects.

Adolescent↗
PubMed1997

Asymptomatic sequelae to acute sarin poisoning in the central and autonomic nervous system 6 months after the Tokyo subway attack.

Six to eight months after the Tokyo subway attack in March 1995, the neurophysiological effects of acute sarin poisoning were investigated in 18 passengers exposed to sarin (sarin cases) in the subways to ascertain the focal or functional brain deficits induced by sarin. The event-related and visual evoked potentials (P300 and VEP), brainstem auditory evoked potential, and electrocardiographic R-R interval variability (CVRR), together with the score on the posttraumatic stress disorder (PTSD) checklist, were measured in the sarin cases and the same number of control subjects matched for sex and age. None of the sarin cases had any obvious clinical abnormalities at the time of testing. The P300 and VEP (P100) latencies in the sarin cases were significantly prolonged compared with the matched controls. In the sarin cases, the CVRR was significantly related to serum cholinesterase (ChE) levels determined immediately after exposure; the PTSD score was not significantly associated with any neurophysiological data despite the high PTSD score in the sarin cases. These findings suggest that asymptomatic sequelae to sarin exposure, rather than PTSD, persist in the higher and visual nervous systems beyond the turnover period of ChE; sarin may have neurotoxic actions in addition to the inhibitory action on brain ChE.

Acute Disease↗
PubMed1997

Brain cooling during transient focal ischemia provides complete neuroprotection.

A review of the effects of reducing brain temperature on ischemic brain injury is presented together with original data describing the systematic evaluation of the effects of brain cooling on brain injury produced by transient focal ischemia. Male spontaneously hypertensive rate were subjected to transient middle cerebral artery occlusion (TMCAO; 80, 120 or 160 min) followed by 24 h of reperfusion. During TMCAO, the exposed skull was bathed with isotonic saline at various temperatures to control skull and deeper brain temperatures. Rectal temperature was always constant at 37 degrees C. Initial studies indicated that skull temperature was decreased significantly (i.e. to 32-33 degrees C) just as a consequence of surgical exposure of the artery. Subsequent studies indicated that maintaining skull temperature at 37 degrees C compared to 32 degrees C significantly (p < 0.05) increased the infarct size following 120 or 160 min TMCAO. In other studies, 80 min TMCAO was held constant, but deeper brain temperature could be varied by regulating skull temperature at different levels. At 36-38 degrees C brain temperature, infarct volumes of 102 +/- 10 to 91 +/- 9 mm3 occurred following TMCAO. However, at a brain temperature of 34 degrees C, a significantly (p < 0.05) reduced infarct volume of 37 +/- 10 mm3 was observed. Absolutely no brain infarction was observed if the brain was cooled to 29 degrees C during TMCAO. Middle cerebral artery exposure and maintaining brain temperature at 37 degrees C without artery occlusion did not produce any cerebral injury. These data indicated the importance of controlling brain temperature in cerebral ischemia and that reducing brain temperature during ischemia produces a brain temperature-related decrease in focal ischemic damage. Brain cooling of 3 degrees C and 8 degrees C can provide dramatic and complete, respectively, neuroprotection from transient focal ischemia. Multiple mechanisms for reduced brain temperature-induced neuroprotection have been identified and include reduced metabolic rate and energy depletion, decreased excitatory transmitter release, reduced alterations in ion flux, and reduced vascular permeability, edema, and blood-brain barrier disruption. Cerebral hypothermia is clearly the most potent therapeutic approach to reducing experimental ischemic brain injury identified to date, and this is emphasized by the present data which demonstrate complete neuroprotection in transient focal stroke. Certainly all available information warrants the evaluation of brain cooling for potential implementation in the treatment of human stroke.

Animals↗
PubMed1997

Tumor necrosis factor-alpha. A mediator of focal ischemic brain injury.

BACKGROUND AND PURPOSE: Tumor necrosis factor-alpha (TNF-alpha) is a pleiotropic cytokine that rapidly upregulates in the brain after injury. The present study was designed to explore the pathophysiological significance of brain TNF-alpha in the ischemic brain by systematically evaluating the effects of lateral cerebroventricular administration of exogenous TNF-alpha and agents that block the effects of TNF-alpha on focal stroke and by examining the potential direct toxic effects of TNF-alpha on cultured neurons to better understand how TNF-alpha might mediate stroke injury. METHODS: TNF-alpha (2.5 or 25 pmol) was administered intracerebroventricularly to spontaneously hypertensive rats 24 hours before permanent or transient (80 minutes and 160 minutes) middle cerebral artery occlusion (MCAO). Animals were examined 24 hours later for neurological deficits and ischemic hemisphere necrosis and swelling. In some of these studies, neutralizing anti-TNF-alpha monoclonal antibody (mAb) (60 pmol) was injected intracerebroventricularly 30 minutes before exogenous TNF-alpha (25 pmol). In addition, the effects of blocking endogenous TNF-alpha on permanent focal ischemic injury were determined with the use of either mAb (60 pmol) or soluble TNF receptor I (sTNF-RI) (0.3 or 0.7 nmol) administered intracerebroventricularly 30 minutes before and 3 and 6 hours after MCAO. Finally, the direct neurotoxic effects of TNF-alpha were studied in cultured rat cerebellar granule cells exposed to TNF-alpha (10 to 2000 U/mL for 6 to 24 hours), and neurotransmitter release, glutamate toxicity, and oxygen radical toxicity were studied. RESULTS: TNF-alpha increased the percent hemispheric infarct induced by permanent MCAO in a dose-related manner from 13.1 +/- 1.3% (vehicle) to 18.9 +/- 1.7% at 2.5 pmol (P < .05) and 27.1 +/- 1.3% at 25 pmol (P < .0001). The high dose of TNF-alpha increased ischemia-induced forelimb deficits from 1.6 +/- 0.2 to 2.3 +/- 0.2 (P < 0.1). TNF-alpha (2.5 pmol) also increased the infarction induced by 80 or 160 minutes of transient MCAO from 1.9 +/- 0.9% to 4.3 +/- 0.4% (P < .01) and from 14.2 +/- 1.3% to 21.6 +/- 2.2% (P < .05), respectively. The exacerbation of infarct size, swelling, and neurological deficit after exogenous TNF-alpha was reversed by preinjection of 60 pmol mAb. Blocking endogenous TNF-alpha also significantly reduced focal ischemic brain injury. Treatment with 60 pmol mAb before and after permanent MCAO significantly reduced infarct size compared with control (nonimmune) antibody treatment by 20.2% (P < .05). Reduced brain infarction also was produced by brain administration of 0.3 nmol (decreased 18.2%) or 0.7 nmol (decreased 26.1%, P < .05) sTNF-RI before and after focal stroke. The intracerebroventricular administration of TNF-alpha or sTNF-RI did not alter brain or body temperature, blood gases or pH, blood pressure, blood glucose, or general blood chemistry. In cultured cerebellar granule cells, the application of TNF-alpha did not directly affect neurotransmitter release or glutamate or oxygen free radical toxicity. CONCLUSIONS: These studies demonstrate that exogenous TNF-alpha exacerbates focal ischemic injury and that blocking endogenous TNF-alpha is neuroprotective. The specificity of the action(s) of TNF-alpha was demonstrated by antagonism of its effects with specific anti-TNF-alpha tools (ie, mAb and sTNF-RI). TNF-alpha toxicity does not appear to be due to a direct effect on neurons or modulation of neuronal sensitivity to glutamate or oxygen radicals and apparently is mediated through nonneuronal cells. These data suggest that inhibiting TNF-alpha may represent a novel pharmacological strategy to treat ischemic stroke.

Animals↗
PubMed1997

Corticobasal degeneration: neuropsychological and clinical correlates.

A comprehensive neuropsychological test battery was administered to 3 patients who met the clinical criteria of corticobasal degeneration (CBD). The pattern of neuropsychological deficits in CBD appears to be a distinctive mixture of posterior cortical dysfunction and frontal-subcortical system impairment.

Aged↗
PubMed1996

Apolipoprotein E epsilon4 association with dementia in a population-based study: The Framingham study.

Apolipoprotein E type 4 allele (apoE epsilon4) is associated with Alzheimer's disease (AD) in the late-onset familial form and in sporadic cases, but the age-associated risk in a randomly sampled elderly population is not established. We examined the association of apoE epsilon4 with AD and other dementias (mainly multi-infarct or dementia following stroke) in 1,030 persons aged 71 to 100 years in the population-based Framingham Study cohort. Kaplan-Meier survival analysis revealed that 55% of the apoE epsilon4/epsilon4 homozygotes developed AD by age 80, whereas 27% of apoE epsilon3/epsilon4 heterozygotes developed AD by age 85, and 9% of those without a 4 allele developed AD by age 85 years. In comparison with persons without a 4 allele, the risk ration for AD was 3.7 (95% CI = 1.9 to 7.5) for apoE epsilon3/epsilon4 heterozygotes and 30.1 (95% CI = 10.7 to 84.4) for apoE epsilon4 homozygotes. ApoE epsilon2 (2/2, 2/3, or 2/4 genotypes) was associated with an absence of AD. One-half (n=21) of the 43 AD patients were either homozygous or heterozygous for apoE epsilon4. We found evidence for an association of apoE epsilon4 with other dementia, primarily multi-infarct dementia and stroke. The risk ratio was 2.3 (95% CI = 0.9 to 6.1) for non-AD dementias among persons with apoE epsilon3/epsilon4. Although the apoE epsilon4 allele is a potent risk factor for AD and may be associated with other forms of dementia, most apoE epsilon4 carriers do not develop dementia, and about one-half of AD is not apoE epsilon4 associated. The low positive predictive value of this marker (0.10) suggest that use of apoE genotyping as a screening test for AD is not supported.

Adult↗
PubMed1996

Role of the neurologist in hazard identification and risk assessment.

This review describes strategies used by a clinical neurologist in the investigation of neurotoxic disease. It emphasizes the need for a high level of suspicion that environmental substances are capable of producing impairments in neurologic and neurobehavioral functions. Because of the difficulties in differentiating neurotoxic from nonneurotoxic disease when presented with common neurological symptoms, it is necessary to rely upon corroborative evidence from past medical records, work and environmental histories, and exposure data, as well as detailed neurological examinations, to reach a conclusion about causation. Sensitive electrophysiologic and neuropsychologic test batteries are useful in identifying subclinical impairments and in providing objective confirmation of abnormalities in the central and peripheral nervous systems. Combining scientific and epidemiologic information with experience and clinical judgment, these sources of information are used in the formulation of a clinical diagnosis. When many patients among a group of people are exposed to neurotoxicants, the effects of the exposure may vary from one to another because of differences in susceptibility, duration of exposure and dosage of neurotoxicant, and other possible risk factors. Group statistics may obscure a significant effect for the larger group, despite clinically obvious effects in an individual. The neurologist applies clinical skills and refers to the accumulated neurotoxicologic literature as a frame of reference to make a diagnosis about an individual patient or a group of patients who have been exposed to particular neurotoxicants. The Boston University Environmental Neurology Assessment (BUENA) is a scheme that attempts to combine epidemiologic methodology and clinical approaches to detect effects of neurotoxic exposure. The advantages and limitations of such a strategy are discussed.

Electrophysiology↗
PubMed1996

Neurobehavioral epidemiology: application in risk assessment.

Neurobehavioral epidemiology may contribute information to risk assessment in relation to a) characterization of neurotoxicity and its time course; b) the dose-effect relationship; c) the dose-response relationship; and d) predisposing factors. The quality of this information relies on the validity of the exposure data, the validity and sensitivity of neurobehavioral function tests, and the degree to which sources of bias are controlled. With epidemiologic studies of methylmercury-associated neurotoxicity as an example, the field of research involves numerous uncertainties that should be taken into account in the risk assessment process.

Animals↗
PubMed1996

Effect of overtime work on cognitive function in automotive workers.

OBJECTIVE: The present investigation examined whether increased overtime work predicts impairment in cognitive performance in the domains of attention, executive function, and mood. METHODS: The behavioral and cognitive functions of 248 automotive workers were measured by a neurobehavioral test performance. Overtime, defined as number of hours worked greater than 8 h a day or greater than 5 d a week, was calculated from company payroll records for the week before the test day. The number of consecutive days worked before the test day was also determined. RESULTS: Cross-sectional data analysis by multiple linear regression, after adjustment for the effects of age, education, gender, alcohol intake, repeated grade in school, acute petroleum naphtha exposure, shift worked, job type, number of consecutive days worked before the test day, and number of hours worked on the test day before the testing, demonstrated that increased overtime was significantly associated with impaired performance on several tests of attention and executive function. Increased feelings of depression, fatigue, and confusion were also associated with increased overtime work. In addition significant interaction effects were observed for job type but not for naphtha exposure. CONCLUSIONS: The findings support the hypothesis that overtime work results in impaired cognitive performance in the areas of attention and executive function and that both overtime hours and the number of consecutive days worked prior to a test day affect mood.

Adult↗
PubMed1995

Discovery of adrenomedullin in rat ischemic cortex and evidence for its role in exacerbating focal brain ischemic damage.

Focal brain ischemia is the most common event leading to stroke in humans. To understand the molecular mechanisms associated with brain ischemia, we applied the technique of mRNA differential display and isolated a gene that encodes a recently discovered peptide, adrenomedullin (AM), which is a member of the calcitonin gene-related peptide (CGRP) family. Using the rat focal stroke model of middle cerebral artery occlusion (MCAO), we determined that AM mRNA expression was significantly increased in the ischemic cortex up to 17.4-fold at 3 h post-MCAO (P < 0.05) and 21.7-fold at 6 h post-MCAO (P < 0.05) and remained elevated for up to 15 days (9.6-fold increase; P < 0.05). Immunohistochemical studies localized AM to ischemic neuronal processes, and radioligand (125I-labeled CGRP) displacement revealed high-affinity (IC50 = 80.3 nmol) binding of AM to CGRP receptors in brain cortex. The cerebrovascular function of AM was studied using synthetic AM microinjected onto rat pial vessels using a cranial window or applied to canine basilar arteries in vitro. AM, applied abluminally, produced dose-dependent relaxation of preconstricted pial vessels (P < 0.05). Intracerebroventricular (but not systemic) AM administration at a high dose (8 nmol), prior to and after MCAO, increased the degree of focal ischemic injury (P < 0.05). The ischemia-induced expression of both AM mRNA and peptide in ischemic cortical neurons, the demonstration of the direct vasodilating effects of the peptide on cerebral vessels, and the ability of AM to exacerbate ischemic brain damage suggests that AM plays a significant role in focal ischemic brain injury.

Adrenomedullin↗