Detection of cerebral ischemia in systemic lupus erythematosus by magnetic resonance techniques.
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Brain↗
Biomedical subjects
K M Welch
Publications and source records attributed to K M Welch.
Structure-activity relationships in a series of orally active gamma-hydroxy butenolide endothelin antagonists.
The design of potent and selective non-peptide antagonists of endothelin-1 (ET-1) and its related isopeptides are important tools defining the role of ET in human diseases. In this report we will describe the detailed structure-activity relationship (SAR) studies that led to the discovery of a potent series of butenolide ETA selective antagonists. Starting from a micromolar screening hit, PD012527, use of Topliss decision tree analysis led to the discovery of the nanomolar ET(A) selective antagonist PD155080. Further structural modifications around the butenolide ring led directly to the subnanomolar ETA selective antagonist PD156707, IC50's = 0.3 (ET(A)) and 780 nM (ET(B)). This series of compounds exhibited functional activity exemplified by PD156707. This derivative inhibited the ETA receptor mediated release of arachidonic acid from rabbit renal artery vascular smooth muscle cells with an IC50 = 1.1 nM and also inhibited the ET-1 induced contraction of rabbit femoral artery rings (ETA mediated) with a pA2 = 7.6. PD156707 also displayed in vivo functional activity inhibiting the hemodynamic responses due to exogenous administration of ET-1 in rats in a dose dependent fashion. Evidence for the pH dependence of the open and closed tautomerization forms of PD156707 was demonstrated by an NMR study. X-ray crystallographic analysis of the closed butenolide form of PD156707 shows the benzylic group located on the same side of the butenolide ring as the gamma-hydroxyl and the remaining two phenyl groups on the butenolide ring essentially orthogonal to the butenolide ring. Pharmacokinetic parameters for PD156707 in dogs are also presented.
Administration, Oral↗
Total quality improvement method for reduction of delays between emergency department admission and treatment of acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group.
OBJECTIVE: To develop an approach for reducing time between emergency department (ED) admission and treatment in patients with acute ischemic stroke to meet the challenge of providing tissue plasminogen activator treatment within 180 minutes. DESIGN: An observational study. SETTING: Forty trial-affiliated hospitals, including 30 community hospitals. PARTICIPANTS: A total of 17,324 consecutive patients admitted to trial-affiliated hospital EDs within 24 hours of possible stroke, from January 1991 through October 1994. INTERVENTION: Appraisal of the process of triage, evaluation, diagnosis, and treatment by means of total quality improvement techniques in each hospital. Staff participating in the process identified sources of variation and modifications by flow charting the process. MAIN OUTCOME MEASURE: Time between ED admission and treatment with study medication. RESULTS: Total quality improvement methods identified hospital-specific process improvements. Many improvements were administrative, requiring no additional resources. More than 50% of screened patients arrived too late to be treated. Only 1268 patients were admitted between 0 and 125 minutes from stroke onset with no other trial exclusion criteria; 48% were treated. Of 243 patients admitted between 126 and 170 minutes from stroke onset with no exclusion criteria, 4% were treated. Mean time from ED admission to treatment was similar in teaching and community hospitals. CONCLUSIONS: Total quality improvement methods identified ED-specific sources of process variability and reduced time between ED admission and treatment. Therefore, these methods should be considered in developing and monitoring emergent stroke treatment protocols.
Acute Disease↗
The temporal evolution of MRI tissue signatures after transient middle cerebral artery occlusion in rat.
We have developed a multiparameter magnetic resonance imaging (MRI) cluster analysis model of acute ischemic stroke using T2 relaxation times and the diffusion coefficient of water (ADCw). To test the ability of this model to predict cerebral infarction, male Wistar rats (n = 7) were subjected to 2 h of transient middle cerebral artery (MCA) occlusion, and diffusion and T2 weighted MRI were performed on these rats before, during and up to 7 days after MCA occlusion. MRI tissue signatures, specified by values of ADCw and T2 were assigned to tissue histopathology. Significant correlations were obtained between MRI signatures at different time points and histopathologic measurements of lesion area obtained at 1 week. In addition, we compared the temporal evolution of MRI tissue signatures to a separate population of animals at which histological data were obtained at select times of reperfusion. A significant shift (p < or = 0.05) within signatures reflecting tissue histopathology was demonstrated as the ischemic lesion evolved over time. Our data suggest, that the MRI signatures are associated with the degree of ischemic cell damage. Thus, the tissue signature model may provide a noninvasive means to monitor the evolution of ischemic cell damage and to predict final outcome of ischemic cell damage.
Animals↗
Migraine and epilepsy.
The epidemiology of the association between migraine and epilepsy is reviewed. Migraine-related epilepsy is categorized using defined diagnostic criteria. Migraine-induced epilepsy is only one of several migraine-related epileptic syndromes.
Epilepsy↗
Cerebral blood flow in chronic posttraumatic headache.
BACKGROUND AND PURPOSE: Headache is the most common neurologic symptom following minor closed head injury. There is often a lack of objective evidence supporting an organic basis of cerebral pathology in these cases. This pilot study considers the possibility of alterations in cerebral blood flow, indicating evidence of an organic disorder in posttraumatic headache. METHODS: Regional cerebral blood flow studies of 35 patients with chronic posttraumatic headache (PTH) (International Headache Society criteria), identified retrospectively from our cerebral blood flow data base, were compared with those of 49 nonheadache controls and 92 migraineurs (Ad Hoc Committee criteria). Regional cerebral blood flow (initial slope index method) was measured using the xenon Xe 133 inhalation technique. RESULTS: Compared to migraineurs and controls, and after adjusting for differences (analysis of covariance) in baseline variables such as blood pressure, hematocrit, and PCO2, patients with PTH had: (1) significantly lower mean initial slope indices (P < 0.001, P = 0.002, respectively); (2) regional interhemispheric flow differences (rIFD), with higher distribution of regional asymmetrical probe pairs (rIFD > or = 7%: P[PTH versus control] = 0.006, P[PTH versus migraine] = 0.016: rIFD > or = 10%; P[PTH versus control] = 0.011, P[PTH versus migraine] = 0.003); and (3) more hemispheric asymmetries (P[PTH versus control] = 0.023, P[PTH versus migraine] = 0.57). Lower mean initial slope indices and hemispheric asymmetry (mean interhemispheric flow difference > or = 3.2%) predicted PTH over control (P = 0.023 and 0.002, respectively). Lower mean initial slope indices predicted PTH over migraine (P = 0.002). CONCLUSIONS: Patients with PTH have reduced regional cerebral blood flow, and regional and hemispheric asymmetries. These cerebral hemodynamic alterations support an organic basis to chronic posttraumatic headache.
Adult↗
Pathogenesis of migraine.
Prevailing hypotheses for the mechanisms of migraine are reviewed. Models of aura mechanisms include transient cerebral ischemia and spreading depression. Models of headache involve trigeminovascular and brainstem mechanisms. The ability to trigger an attack may depend on a threshold of brain excitability. Mitochondrial disorder, magnesium deficiency, and abnormality of presynaptic calcium channels may be responsible for neuronal hyperexcitability between attacks. It remains to be determined whether cortical or brainstem centers generate the attack.
Calcium Channels↗
Imaging the brain of migraine sufferers.
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Brain↗
Migraine and ovarian steroid hormones.
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Estrogens↗
Pitfalls and potential of clinical diffusion-weighted MR imaging in acute stroke.
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Acute Disease↗
Effects of ramipril and enalapril on cerebral blood flow in elderly patients with asymptomatic carotid artery occlusive disease.
We wished to determine in asymptomatic hypertensive patients with > or = 70% stenosis of an internal carotid artery the change in regional cerebral blood flow (rCBF) produced by ramipril and enalapril and to evaluate the influence of age on drug-induced changes in rCBF. In a prospective, randomized, single-blind, placebo-controlled investigation, using the 133Xenon inhalation technique, we assessed baseline rCBF in 15 patients (9 men and 6 women aged 60-79 years) after a 24-h antihypertensive drug-free period. All patients then received a single 5-mg oral dose of ramipril, enalapril, or placebo. rCBF was reassessed 2 h postdose. There was no significant change in the median rCBF in any of the three treatment groups. Neither did we observe any lateralization of BF to any specific cerebral region in any of the three groups. There were no observed or patient-reported adverse events (AE). Single 5-mg oral doses of either ramipril or enalapril did not decrease CBF significantly in asymptomatic hypertensive patients with > or = 70% stenosis of an internal carotid artery and are probably safe starting doses in such patients. In addition, this effect was not modified by age.
Age Factors↗
Pharmacological differences between rat and human endothelin B receptors.
Cloned rat and human endothelin-B receptors (ETBR) were utilized to determine if there are significant pharmacological differences between highly homologous ETBR from different species. Recombinant rat and human ETBR were expressed in CHO-K1 cells, and radioligand binding studies were carried out with [125I]-ET-3 to determine the affinities of various ET receptor agonists and antagonists for rat and human ETBR. These receptors had similar affinities for a number of ETBR agonists (ET-1, ET-3, S6C, BQ 3020) and antagonists (Ro 47-0203, PD 142893). However, several peptide (PD 147452, PD 151583, BQ 788) and non-peptide (PD 156707, SB 209670) antagonists had different affinities for rat and human ETBR, with differences in Ki values between species ranging from 4.1- to 53.4-fold. The ETBR-selective agonist IRL 1620 also had a 5.7-fold higher affinity for rat ETBR than human ETBR. Thus despite their high degree of homology, rat and human ETBR show significant pharmacological differences with respect to both antagonist and agonist binding.
Amino Acid Sequence↗
Preliminary observations of transverse relaxation rates obtained at 3 tesla from the substantia nigra of adult normal human brain.
The transverse relaxation rates R2 and R2* were measured at 3 T in the substantia nigra of the midbrain of adult normal human controls. The relaxation rate arising from magnetic inhomogeneities, R2', was calculated from the relationship R2* = R2 + R2'. No significant differences were found for any parameters between left and right side substantia nigra regions, however, a significant inverse correlation was found between R2 and R2' (r = 0.70, p = 0.035). Water diffusion, in the presence of paramagnetic metal ions, may play a role in determining the relative contributions to reversible and irreversible transverse relaxation and may explain the inverse correlation demonstrated here.
Aged↗
Adhesive glycoproteins CD11a and CD18 are upregulated in the leukocytes from patients with ischemic stroke and transient ischemic attacks.
Leukocytes may have an important role in the pathogenesis of brain injury after ischemia. Expression of adhesion molecules on leukocytes and/or endothelia is needed for leukocytes to adhere to endothelia and infiltrate into the injured brain. The purpose of the present pilot study is to delineate whether the expression of leukocyte adhesion molecules, CD11a and CD18, are upregulated in patients with ischemic stroke and transient ischemic attack. Ten patients with ischemic stroke, 6 with transient ischemic attack (TIA), and 11 age and risk factor matched controls were studied. Using immunofluorescence phenotyping and flow cytometry, leukocyte membrane expression of CD11a and CD18 were measured within 72 h after onset of ischemia. Follow-up measurements were performed at 5-7 days after ictus in 6 patients with stroke, and at 3-5 days after ictus in 3 patients with TIA. CD11a immunofluorescence (IF) was significantly increased within 72 h after onset of symptoms in patients with stroke as well as TIA compared with the control group (p < 0.017). IF of CD18 also increased in both patient groups, but significance was reached only in the TIA group (p < 0.05). No difference of CD11a and CD18 IF was detected between stroke and TIA groups. Follow-up measurement of CD11a and CD18 showed a trend of decrease, but CD11a IF remained significantly elevated compared with the control group (p < 0.017). Expression of leukocyte adhesion molecules CD11a, and CD18 are upregulated in patients with ischemic stroke and TIA. Although these data are preliminary, our data suggest that these molecules are associated with cerebrovascular disorders including ischemic stroke and TIA.
Aged↗
Mitochondria, magnesium and migraine.
The evidence for disordered mitochondrial oxidative phosphorylation and reduced intracellular free magnesium in brain and body tissue of migraine suffers both between and during an attack is reviewed. We propose that between attacks these metabolic shifts cause instability of neuronal function which enhances the susceptibility of brain to develop a migraine attack.
Brain↗
Expression of monocyte chemoattractant protein-1 and macrophage inflammatory protein-1 after focal cerebral ischemia in the rat.
Chemoattractant cytokines, the chemokines, play an important role in early events of inflammation at the site of tissue damage. We examined the expression of mRNA and the protein products of two such chemokines; i.e. monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1 alpha (MIP-1 alpha) in the ischemic brain tissue following middle cerebral artery occlusion (MCAo). The mRNA transcripts of MCP-1 and MIP-1 alpha were detected by Northern hybridization and reverse transcriptase polymerase chain reaction (RT/PCR), respectively, and the anatomic distribution of specific proteins was analyzed by immunohistochemistry. We found that MCP-1 mRNA was not expressed in the brains of normal rats or rats sacrificed 2 h after MCAo. 6 h after the induction of cerebral ischemia, weak expression of both mRNAs was detected in the ischemic tissue. mRNAs were expressed up to 48 h, and were markedly attenuated at 96 h. In the rats subjected to MCA occlusion, MCP-1 immunoreactivity was diffusely expressed and localized to the ischemic area, and was most intense at 48 h after MCA occlusion. Endothelial cells and macrophage-like cells expressed MCP-1 protein in the ischemic brain. The distribution and morphology of MIP-1 alpha immunoreactive cells were identical with activated astrocytes. We conclude that MCP-1 and MIP-1 alpha mRNAs and proteins are induced after cerebral ischemia in the rat. They may have a role in promoting inflammatory and/or repair processes in the ischemic brain, possibly by attracting or modulating inflammatory cells in the ischemic area.
Animals↗
Platelet and plasma levels of glutamate and glutamine in migraine with and without aura.
We evaluated plasma and platelet glutamate and glutamine levels in migraine with and without aura during headache-free periods and compared the results with those of normal controls. The plasma and platelet levels of glutamine in migraine with and without aura were normal. Migraine without aura patients had higher glutamate levels in plasma, and normal platelet levels. In migraine with aura patients, glutamate levels were high in platelets, but not in plasma. This suggests different profiles of excitatory amino acid metabolism in migraine with and without aura.
Adolescent↗
Metabolism and menstrual cycle rhythmicity of serotonin in primary headaches.
We investigated the platelet and plasma levels of serotonin and its metabolite, 5-hydroxyindoleacetic acid, in patients suffering from episodic tension-type headache and migraine with and without aura, during a headache-free period. In female subjects, blood samples were drawn during the follicular, ovulatory, and late luteal phases of the menstrual cycle. In tension headache and migraine with aura, the group mean values of serotonin and 5-hydroxyindoleacetic acid in platelets and plasma were significantly increased, but migraine without aura patients' levels were normal. The pattern of menstrual cycle-related fluctuations in platelet serotonin levels were similar in female patients with tension headache and in controls, with a maximum value in the follicular phase. In both migraine groups, in contrast, the peak occurred in the ovulatory phase. The results are discussed in view of whether these aberrations in peripheral markers of the metabolism and menstrual cycle-related rhythmicity of serotonin may reflect similar alterations in the central nervous system.
Adolescent↗