Pharmacological therapy for acute stroke.
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Acute Disease↗
Biomedical subjects
S J Read
Publications and source records attributed to S J Read.
No evidence of hypoxic tissue on 18F-fluoromisonidazole PET after intracerebral hemorrhage.
We studied six patients after intracerebral hemorrhage (ICH) and eight controls using positron emission tomography (PET) with to determine whether a zone of tissue hypoxia, possibly representing "penumbral" tissue, exists surrounding an intracerebral hemorrhage. None of the stroke patients, studied 24 to 43 hours after symptom onset, nor any of the controls exhibited areas of tissue hypoxia on 18F-fluoromisonidazole PET images. These findings may have implications for the treatment of intracerebral hemorrhage with neuroprotective strategies.
Aged↗
Effects of sumatriptan on nitric oxide and superoxide balance during glyceryl trinitrate infusion in the rat. Implications for antimigraine mechanisms.
Infusion of glyceryl trinitrate (GTN) into patients with migraine precipitates the onset of a migraine attack several hours after completion of the infusion. Using an infusion of GTN into anaesthetised rats, this study investigates the relationship of regional cerebral blood flux rCBF(ldf), cortical nitric oxide (NO) and cortical superoxide concentrations and the effect of sumatriptan on each variable. In saline treated animals, a 30 min infusion of GTN (2 microgram kg(-1) min(-1), i.v.) was found to markedly increase cortical rCBF(ldf) (133+/-3% of baseline) and NO concentrations (141+/-13% of baseline). Superoxide levels exhibited an inverse relationship to NO levels, decreasing below basal to 48+/-14% of baseline. It is hypothesised that high NO levels during GTN infusion may decrease the detectable superoxide due to "leeching" of the superoxide into low level peroxynitrite formation. In the presence of sumatriptan, a decrease below baseline in cortical rCBF(ldf) (82+/-5% of baseline) and NO concentration (64+/-13% of baseline) was observed throughout GTN infusion, although superoxide levels significantly increased above baseline by 105+/-14 nM (p<0.05, ANOVA post hoc LSD test). The mechanism for this action of sumatriptan is unknown but may include; modulation of cell redox state, NO scavenging or direct manipulation of superoxide release.
Animals↗
Identification of (-)-cis-6-acetyl-4S-(3-chloro-4-fluoro-benzoylamino)- 3,4-dihydro-2,2-dimethyl-2H-benzo[b]pyran-3S-ol as a potential antimigraine agent.
Optimisation of novel cis- and trans-4-(substituted-amido)benzopyran-3-ol derivatives has led to the identification of SB-220453 20 with an in vivo pre-clinical CNS profile predictive of potential antimigraine activity.
Animals↗
Plasticizers increase adhesion of the deteriogenic fungus Aureobasidium pullulans to polyvinyl chloride.
Initial adhesion of fungi to plasticized polyvinyl chloride (pPVC) may determine subsequent colonization and biodeterioration processes. The deteriogenic fungus Aureobasidium pullulans was used to investigate the physicochemical nature of adhesion to both unplasticized PVC (uPVC) and pPVC containing the plasticizers dioctyl phthalate (DOP) and dioctyl adipate (DOA). A quantitative adhesion assay using image analysis identified fundamental differences in the mechanism of adhesion of A. pullulans blastospores to these substrata. Adhesion to pPVC was greater than that to uPVC by a maximum of 280% after a 4-h incubation with 10(8) blastospores ml(-1). That plasticizers enhance adhesion to PVC was confirmed by incorporating a dispersion of both DOA and DOP into the blastospore suspension. Adhesion to uPVC was increased by up to 308% in the presence of the dispersed plasticizers. Hydrophobic interactions were found to dominate adhesion to uPVC because (i) a strong positive correlation was observed between substratum hydrophobicity (measured by using a dynamic contact angle analyzer) and adhesion to a range of unplasticized polymers including uPVC, and (ii) neither the pH nor the electrolyte concentration of the suspension buffer, both of which influence electrostatic interactions, affected adhesion to uPVC. In contrast, adhesion to pPVC is principally controlled by electrostatic interactions. Enhanced adhesion to pPVC occurred despite a relative reduction of 13 degrees in the water contact angle of pPVC compared to that of uPVC. Furthermore, adhesion to pPVC was strongly dependent on both the pH and electrolyte concentration of the suspension medium, reaching maximum levels at pH 8 and with an electrolyte concentration of 10 mM NaCl. Plasticization with DOP and DOA therefore increases adhesion of A. pullulans blastospores to pPVC through an interaction mediated by electrostatic forces.
Ascomycota↗
Laboratory diagnosis of common viral infections of the central nervous system by using a single multiplex PCR screening assay.
A multiplex PCR assay that detects the four commonest causes of viral meningitis and encephalitis in the United Kingdom (herpes simplex virus [HSV] type 1 [HSV-1], HSV type 2 [HSV-2], varicella-zoster virus [VZV], and enteroviruses) was developed, and its sensitivity was compared with those of similar assays described previously for this application. Compared to the previous assays, this single multiplex PCR assay had higher molecular sensitivities for the detection for each of the viruses and improved utility for routine use in a diagnostic laboratory. The assay was used to test a series of 1,683 consecutive cerebrospinal fluid (CSF) samples between June 1997 and March 1998 inclusively. Viral nucleic acid was detected in 138 (8.2%) of the CSF samples, including enteroviruses in 51 samples, HSV-2 in 33 samples, VZV in 28 samples, and HSV-1 in 25 samples. Compared to the accepted relative incidence of viral etiologies, aseptic meningitis due to HSV-2 infection was high, and in adult female patients with symptoms of aseptic meningitis, HSV-2 was the virus most commonly detected in the CSF.
Adult↗
Limiting neurological damage after stroke: a review of pharmacological treatment options.
Acute ischaemic stroke is a leading cause of death and a major cause of long term disability worldwide. Effective treatments for limiting the neurological damage after stroke have proven elusive. An improved understanding of the complicated cascade of cellular events following the onset of cerebral ischaemia has led to exploration of a number of avenues for early intervention. Reperfusion of the ischaemic territory using thrombolytic drugs has shown promise in clinical trials as a method for achieving tissue salvage. Antithrombotic and antiplatelet agents have not demonstrated efficacy as acute therapies, although the early use of aspirin (acetylsalicylic acid) appears to produce a reduction in early stroke recurrence. A wide variety of drugs which interfere at various points in the ischaemic cascade, so-called 'neuroprotective agents', have also been studied, but with mixed success. Of these, antagonists of voltage-gated calcium channels, antagonists at the N-methyl-D-aspartate (NMDA) receptor and scavengers of free radicals have been most extensively studied. Despite proving effective in animal models of cerebral ischaemia, these drugs have largely failed to fulfil their promise in clinical trials. While individual compounds have proven ineffective, combinations of drugs with different mechanisms of action may yet provide the best treatment for acute ischaemic stroke.
Cerebrovascular Disorders↗
Nitric oxide does not mediate cerebral blood flow changes during cortical spreading depression in the anaesthetised rat.
To date, the role of nitric oxide (NO) in mediation of cerebrovascular regulation during spreading depression (SD) in rats remains controversial. Studies are compromised by indirect assay of 'regional' nitric oxide synthase activity (NOS) and/or inappropriate doses of antagonists. The present study utilises direct electrochemical detection in the pia to demonstrate a local, biphasic release of NO associated with each wave of cortical depolarisation. The mean peak of SD-induced NO release was 0.35 microM, which was significantly inhibited by L-N(G)-nitroarginine methyl ester (L-NAME) pre-treatment. Changes in cerebrovascular flux remained intact following treatment with L-NAME, indicating little role for NO in mediation of rat SD blood-flux changes. Mean peak NO release was found to be lower than that observed in rat cerebral ischaemia studies (approximately 4 microM) and in SD in the cat gyrencephalic brain (approximately 0.8 microM).
Anesthesia↗
Identifying hypoxic tissue after acute ischemic stroke using PET and 18F-fluoromisonidazole.
OBJECTIVE: To show that PET with 18F-fluoromisonidazole (18F-FMISO) can detect peri-infarct hypoxic tissue in patients after ischemic stroke. BACKGROUND: PET with (15)O-labeled oxygen and water is the only established method for identifying the ischemic penumbra in humans. We used PET with 18F-FMISO in patients after ischemic stroke to identify hypoxic but viable peri-infarct tissue likely to represent the ischemic penumbra, and to determine how long hypoxic tissues persist after stroke. METHODS: Patients with acute hemispheric ischemic stroke were studied using PET with 18F-FMISO either within 48 hours or 6 to 11 days after stroke onset. The final infarct was defined by CT performed 6 to 11 days after stroke. Tracer uptake was assessed objectively by calculating the mean activity in the contralateral (normal) hemisphere, then identifying pixels with activity greater than 3 SDs above the mean in both hemispheres. Positive studies were those with high-activity pixels ipsilateral to the infarct. RESULTS: Fifteen patients were studied; 13 within 48 hours of stroke, 8 at 6 to 11 days, and 6 during both time periods. Hypoxic tissue was detected in 9 of the 13 patients studied within 48 hours of stroke, generally distributed in the peripheries of the infarct and adjacent peri-infarct tissues. None of the 8 patients studied 6 to 11 days after stroke exhibited increased 18F-FMISO activity. All 6 patients studied both early and late exhibited areas of increased activity during the early but not the late study. CONCLUSIONS: PET with 18F-FMISO can detect peri-infarct hypoxic tissue after acute ischemic stroke. The distribution of hypoxic tissue suggests that it may represent the ischemic penumbra. Hypoxic tissues do not persist to the subacute phase of stroke (6 to 11 days).
Acute Disease↗
The dynamics of nitric oxide release measured directly and in real time following repeated waves of cortical spreading depression in the anaesthetised cat.
Cortical application of crystalline KCl in male cats anaesthetised with alpha-chloralose induced four transient negative deflections in cortical direct current (d.c.) potential. In vehicle treated animals d.c. shifts were associated with a hyperaemia and a multiphasic nitric oxide (NO) release. In these animals, the first negative shift in d.c. potential produced a significantly larger NO electrode current, when compared to subsequent cortical depolarisations. However, regional cerebrovascular laser Doppler flux (rCBF[LDF]) increases were similar for each event. In L-N(G)-nitro-L-arginine (L-NAME; 10 mg/kg i.v. infused over 30 min) treated animals, d.c. shifts were also associated with NO release following a multiphasic waveform and increase in rCBF(LDF), but were significantly attenuated when compared to controls.
Anesthesia↗
Diagnosis of viral infections of the central nervous system: clinical interpretation of PCR results.
BACKGROUND: Standard laboratory techniques, such as viral culture and serology, provide only circumstantial or retrospective evidence of viral infections of the central nervous system (CNS). We assessed the diagnostic accuracy of PCR of cerebrospinal fluid (CSF) in the diagnosis of viral infections of the CNS. METHODS: We examined all the CSF samples that were received at our diagnostic virology laboratory between May, 1994, and May, 1996, by nested PCR for viruses associated with CNS infections in the UK. We collected clinical and laboratory data for 410 patients from Oxford city hospitals (the Oxford cohort) whose CSF was examined between May, 1994, and May, 1995. These patients were classified according to the likelihood of a viral infection of the CNS. We used stratified logistic regression analysis to identify the clinical factors independently associated with a positive PCR result. We calculated likelihood ratios to estimate the clinical usefulness of PCR amplification of CSF. FINDINGS: We tested 2233 consecutive CSF samples from 2162 patients. A positive PCR result was obtained in 143 patients, including 22 from the Oxford cohort. Logistic regression analysis of the Oxford cohort showed that fever, a virus-specific rash, and a CSF white-cell count of 5/microL or more were independent predictors of a positive PCR result. The likelihood ratio for a definite diagnosis of viral infection of the CNS in a patient with a positive PCR result, relative to a negative PCR result, was 88.2 (95% CI 20.6-378). The likelihood ratio for a possible diagnosis of viral infection of the CNS in a patient with a negative PCR result, relative to a positive PCR result, was 0.10 (0.03-0.39). INTERPRETATION: A patient with a positive PCR result was 88 times as likely to have a definite diagnosis of viral infection of the CNS as a patient with a negative PCR result. A negative PCR result can be used with moderate confidence to rule out a diagnosis of viral infection of the CNS. We believe that PCR will become the first-line diagnostic test for viral meningitis and encephalitis.
Adolescent↗
Enhanced nitric oxide release during cortical spreading depression following infusion of glyceryl trinitrate in the anaesthetized cat.
Intravenous infusion of glyceryl trinitrate (GTN) into migraineurs induces an immediate headache followed by migraine. We studied the effect of GTN (0.25 microgram kg-1 min-1) on local cerebrovascular laser Doppler flux (rCBFLDF), artery diameter and NO concentration (selective NO microelectrode) in the pial middle cerebral artery perfusion territory of the anaesthetized cat, at rest and during cortical spreading depression (SD). GTN infusion induced a significant increase in pial artery diameter, rCBFLDF, and NO concentration. Following termination of infusion, NO concentrations remained significantly elevated above controls for 60 min, other parameters returned to baseline within 10 min (p < 0.05, ANOVA, post hoc Dunnett's multiple comparison procedure). Two hours after termination of infusion KCl-evoked SD was initiated. GTN-treated animals exhibited significantly (p < 0.05, Kruskal-Wallis) elevated SD-induced NO release compared to controls. All other parameters remained unaffected. Our results demonstrate that GTN induces a prolonged increase in local NO concentrations and enhances SD-induced NO release.
Anesthesia↗
Furosemide inhibits regenerative cortical spreading depression in anaesthetized cats.
Ionic perturbations occur during cortical spreading depression (SD), a phenomenon implicated in migraine pathophysiology. We studied the effect of 0.2, 2 and 20 mg kg-1 i.v. (n=4) furosemide on cortical direct current (d.c.) potential, cerebrovascular laser Doppler flux (rCBF[LDF]), artery diameter and NO concentration in the parietal cortex of the anaesthetized cat during repetitive SD. In vehicle-treated animals (n=4), SD activity was sustained for 50+/-1.8 min. However, duration of SD activity was significantly reduced when compared to vehicle to 39+/-6.6 (n=4), 34+/-8.5 (n=4) and 27.3+/-11.3 min (n=4), at 0.2, 2 and 20 mg kg-1 i.v. furosemide respectively. It is hypothesized that the mechanism of inhibition of SD d.c. activity by furosemide may be through alterations in cortical ion buffering capacity or inhibition of cell swelling in neurones or glia. These mechanisms may represent potential novel drug targets in future migraine therapy.
Analysis of Variance↗
Aseptic meningitis and encephalitis: the role of PCR in the diagnostic laboratory.
In this study we have devised a simple and robust PCR strategy to detect a wide range of viruses, bacteria, and parasites, all of which are capable of causing aseptic meningitis and encephalitis. The techniques developed have been used in a routine diagnostic virology laboratory to test prospectively 2,233 cerebrospinal fluid specimens. A virus was detected in 147 specimens of cerebrospinal fluid from 143 patients. Four sets of primers were sufficient to detect the virus in 135 (94%) of the PCR-positive patients. We conclude that with appropriate primers, PCR can be systematically and economically applied to test for a range of organisms in a routine diagnostic laboratory. In our opinion, PCR will soon become the "gold standard" test for viral infections of the central nervous system.
Algorithms↗
Connectionism, parallel constraint satisfaction processes, and gestalt principles: (re) introducing cognitive dynamics to social psychology.
We argue that recent work in connectionist modeling, in particular the parallel constraint satisfaction processes that are central to many of these models, has great importance for understanding issues of both historical and current concern for social psychologists. We first provide a brief description of connectionist modeling, with particular emphasis on parallel constraint satisfaction processes. Second, we examine the tremendous similarities between parallel constraint satisfaction processes and the Gestalt principles that were the foundation for much of modem social psychology. We propose that parallel constraint satisfaction processes provide a computational implementation of the principles of Gestalt psychology that were central to the work of such seminal social psychologists as Asch, Festinger, Heider, and Lewin. Third, we then describe how parallel constraint satisfaction processes have been applied to three areas that were key to the beginnings of modern social psychology and remain central today: impression formation and causal reasoning, cognitive consistency (balance and cognitive dissonance), and goal-directed behavior. We conclude by discussing implications of parallel constraint satisfaction principles for a number of broader issues in social psychology, such as the dynamics of social thought and the integration of social information within the narrow time frame of social interaction.
Journal Article↗
Human cytomegalovirus infection is not increased in common variable immunodeficiency.
It has been postulated that human cytomegalovirus (HCMV) infection may have a role in the pathogenesis of common variable immunodeficiency (CVID). Many patients have a lymphocyte phenotype similar to that seen in HCMV infection, HCMV mononucleosis may precipitate hypogammaglobulinaemia, and a previous small study of common variable immunodeficient patients reported a high rate of active HCMV infection. This study investigated the presence and activity of HCMV infection in 102 CVID patients. Buffy coats were examined for the presence of HCMV IE and glycoprotein B genes using highly sensitive nested PCR. 30 blood donors of known HCMV serologic status were used as controls. There was no significant difference in HCMV positivity by PCR between patients and controls. Enrichment for mononuclear cells prior to PCR had no effect on sensitivity. Twenty-five patients were also examined for HCMV antigenaemia by staining buffy coat cytospins with monoclonal antibodies directed against the HCMV pp65 lower matrix protein, a technique widely used for diagnosis of active HCMV disease. Only one patient was positive (and also positive by PCR). Whilst these results do not exclude prior infection contributing to antibody deficiency in a small proportion of CVID patients, this study refutes the previously reported increase in active HCMV infection in CVID.
Adolescent↗
Present versus future time perspective and HIV risk among heterosexual college students.
Because safer sex behaviors require planning and forethought and their primary motivations lie in the future, the hypothesis that behaviors that might reduce exposure to HIV would positively correlate with future time orientation, whereas risky behaviors would correlate with present time orientation, was tested in a survey of 188 heterosexual college students. As expected, those high in future time orientation were less likely to be sexually experienced and had fewer sexual partners. In contrast, present time orientation positively related to those measures. Those high in future orientation were more likely to use alternate methods of reducing exposure to HIV (e.g., inquiring about partner's sexual history, delaying or abstaining from sex). Time perspective also interacted with both gender and fear of AIDS. The responses of women and individuals low in fear were more related to time orientation.
Adolescent↗
How time dependent is the threshold for cerebral infarction?
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Brain↗