Which targets are relevant for therapy of acute ischemic stroke?
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Acute Disease↗
Biomedical subjects
M Fisher
Publications and source records attributed to M Fisher.
The N-methyl-D-aspartate antagonist CNS 1102 protects cerebral gray and white matter from ischemic injury following temporary focal ischemia in rats.
BACKGROUND AND PURPOSE: Cerebral white matter is as sensitive as gray matter to ischemic injury and is probably amenable to pharmacological intervention. In this study we investigated whether an N-methyl-D-aspartate (NMDA) antagonist, CNS 1102, protects not only cerebral gray matter but also white matter from ischemic injury. METHODS: Ten rats underwent 15 minutes of temporary focal ischemia and were blindly assigned to CNS 1102 intravenous bolus injection (1. 13 mg/kg) followed by intravenous infusion (0.33 mg/kg per hour) for 3.75 hours or to vehicle (n=5 per group) immediately after reperfusion. Seventy-two hours after ischemia, the animals were perfusion fixed for histology. The severity of neuronal necrosis in the cortex and striatum was semiquantitatively analyzed. The Luxol fast blue-periodic acid Schiff stain and Bielschowsky's silver stain were used to measure optical densities (ODs) of myelin and axons, respectively, in the internal capsule of both hemispheres, and the OD ratio was calculated to reflect the severity of white matter damage. RESULTS: Neuronal damage in both the cortex and the striatum was significantly better in the drug-treated group than in the placebo group (P<0.05). The OD ratio of both the axons (0.93+/-0.08 versus 0.61+/-0.18; P<0.01) and the myelin sheath (0.95+/-0.07 versus 0.67+/-0.19; P=0.01) was significantly higher in the CNS 1102 group than in the placebo group. The neurological score was significantly improved in the drug-treated group (P<0.05). CONCLUSIONS: The NMDA receptor antagonist CNS 1102 protects not only cerebral gray matter but also white matter from ischemic injury, most probably by preventing degeneration of white matter structures such as myelin and axons.
Animals↗
Sinusitis and carotid artery stroke.
The relationship between sinusitis and ischemic stroke is unexplored. The anatomic proximity between the paranasal sinuses and the internal carotid artery suggests that inflammation of the sinuses could easily extend to the intracranial vasculature. We report 4 patients with acute ischemic stroke and extensive disease of the paranasal sinuses. All patients had large vessel stroke involving the internal carotid artery territory. All patients had extensive disease of the sphenoid and other sinuses. The sinus disease was demonstrated by magnetic resonance imaging. These case report observations suggest a relationship between inflammation of the paranasal sinuses, particularly sphenoid sinusitis, and ischemic stroke.
Carotid Artery, Internal↗
Direct MS-MS identification of isoxsuprine-glucuronide in post-administration equine urine.
Isoxsuprine is routinely recovered from enzymatically-hydrolyzed, post-administration urine samples as parent isoxsuprine in equine forensic science. However, the specific identity of the material in horse urine from which isoxsuprine is recovered has never been established, although it has long been assumed to be a glucuronide conjugate (or conjugates) of isoxsuprine. Using ESI/MS/MS positive mode as an analytical tool, urine samples collected 4-8 h after isoxsuprine administration yielded a major peak at m/z 554 that was absent from control samples and resisted fragmentation to daughter ions. Titration of this material with increasing concentrations of sodium acetate yielded m/z peaks consistent with the presence of monosodium and disodium isoxsuprine-glucuronide complexes, suggesting that the starting material was a dipotassium-isoxsuprine-glucuronide complex. Electrospray ionization mass spectrometry negative mode disclosed the presence of a m/z 476 peak that declined following enzymatic hydrolysis and resulted in the concomitant appearance of peaks at m/z 300 and 175. The resulting peaks were consistent with the presence of isoxsuprine (m/z 300) and a glucuronic acid residue (m/z 175). Examination of the daughter ion spectrum of this putative isoxsuprine-glucuronide m/z 476 peak showed overlap of many peaks with those of similar spectra of authentic morphine-3- and morphine-6-glucuronides, suggesting they were derived from glucuronic acid conjugation. These data suggest that isoxsuprine occurs in post-administration urine samples as an isoxsuprine-glucuronide conjugate and also, under some circumstances, as an isoxsuprine-glucuronide-dipotassium complex.
Animals↗
Secondary decline in apparent diffusion coefficient and neurological outcomes after a short period of focal brain ischemia in rats.
This study was designed to characterize the initial and secondary changes of the apparent diffusion coefficient (ADC) of water with high temporal resolution measurements of ADC values and to correlate ADC changes with functional outcomes. Fourteen rats underwent 30 minutes of temporary middle cerebral artery occlusion (MCAO). Diffusion-, perfusion-, and T2-weighted imaging was performed during MCAO and every 30 minutes for a total of 12 hours after reperfusion (n = 6). Neurological outcomes were evaluated during MCAO, every 30 minutes for a total of 6 hours and at 24 hours after reperfusion (n = 8). The decreased cerebral blood flow during MCAO returned to normal after reperfusion and remained unchanged thereafter. The decreased ADC values during occlusion completely recovered at 1 hour after reperfusion. The renormalized ADC values started to decrease secondarily at 2.5 hours, accompanied by a delayed increase in T2 values. The ADC-defined secondary lesion grew over time and was 52% of the ADC-defined initial lesion at 12 hours. Histological evaluation demonstrated neuronal damage in the regions of secondary ADC decline. Complete resolution of neurological deficits was seen in 1 rat at 1 hour and in 6 rats between 2.5 and 6 hours after reperfusion; no secondary neurological deficits were observed at 24 hours. These data suggest that (1) a secondary ADC reduction occurs as early as 2.5 hours after reperfusion, evolves in a slow fashion, and is associated with neuronal injury; and (2) renormalization and secondary decline in ADC are not associated with neurological recovery and worsening, respectively.
Animals↗
Identification of lidocaine and its metabolites in post-administration equine urine by ELISA and MS/MS.
Lidocaine is a local anesthetic drug that is widely used in equine medicine. It has the advantage of giving good local anesthesia and a longer duration of action than procaine. Although approved for use in horses in training by the American Association of Equine Practitioners (AAEP), lidocaine is also an Association of Racing Commissioners International (ARCI) Class 2 drug and its detection in forensic samples can result in significant penalties. Lidocaine was observed as a monoprotonated ion at m/z 235 by ESI+ MS/MS (electrospray ionization-positive ion mode) analysis. The base peak ion at m/z 86, representing the postulated methylenediethylamino fragment [CH2N(CH2CH3)2]+, was characteristic of lidocaine and 3-hydroxylidocaine in both ESI+ and EI (electron impact-positive ion mode) mass spectrometry. In addition, we identified an ion at m/z 427 as the principal parent ion of the ion at m/z 86, consistent with the presence of a protonated analog of 3-hydroxylidocaine-glucuronide. We also sought to establish post-administration ELISA-based 'detection times' for lidocaine and lidocaine-related compounds in urine following single subcutaneous injections of various doses (10, 40, 400 mg). Our findings suggest relatively long ELISA based 'detection times' for lidocaine following higher doses of this drug.
Anesthetics, Local↗
Intratracheal clenbuterol in the horse: its pharmacological efficacy and analytical detection.
Clenbuterol, a beta2 agonist/antagonist, is the only bronchodilator approved by the US Food and Drug Administration for use in horses. The Association of Racing Commissioners International classifies clenbuterol as a class 3 agent, and, as such, its identification in post-race samples may lead to sanctions. Anecdotal reports suggest that clenbuterol may have been administered by intratracheal (IT) injection to obtain beneficial effects and avoid post-race detection. The objectives of this study were (1) to measure the pharmacological efficacy of IT dose of clenbuterol and (2) to determine the analytical findings in urine in the presence and absence of furosemide. When administered intratracheally (90 microg/horse) to horses suffering from chronic obstructive pulmonary disease (COPD), clenbuterol had effects that were not significantly different from those of saline. In parallel experiments using a behavior chamber, no significant effects of IT clenbuterol on heart rate or spontaneous locomotor activity were observed. Clenbuterol concentrations in the urine were also measured after IT dose in the presence and absence of furosemide. Four horses were administered i.v. furosemide (5 mg/kg), and four horses were administered saline (5 mL). Two hours later, all horses were administrated clenbuterol (IT, 90 microg), and the furosemide-treated horses received a second dose of furosemide (2.5 mg/kg, i.v.). Three hours after clenbuterol dose (1 h after hypothetical 'post-time'), the mean specific gravity of urine samples from furosemide-treated horses was 1.024, well above the 1.010 concentration at which furosemide is considered to interfere with drug detection. There was no interference by furosemide with 'enhanced' ELISA screening of clenbuterol equivalents in extracted and concentrated samples. Similarly, furosemide had no effect on mass spectral identification or quantification of clenbuterol in these samples. These results suggest that the IT dose of clenbuterol (90 microg) is, in pharmacological terms, indistinguishable from the dose of saline, and that, using extracted samples, clenbuterol dose is readily detectable at 3 h after dosing. Furthermore, concomitant dose of furosemide does not interfere with detection or confirmation of clenbuterol.
Administration, Inhalation↗
Decreased morbidity and use of hospital services in English HIV-infected individuals with increased uptake of anti-retroviral therapy 1996-1997. National Prospective Monitoring System Steering Group.
OBJECTIVE: To investigate the relationship between changing morbidity patterns, the use of hospital services by HIV-infected patients and the uptake of antiretroviral therapy (ART) in England. DESIGN: Prospective serial cross-sectional analyses based on data collected through the National Prospective Monitoring System (NPMS), a multi-centre prospective monitoring system. SETTING: HIV-infected patients seen in 10 clinics, five London and five non-London, during the three semesters, 1 January 1996 to 30 June 1997. MAIN OUTCOME MEASURES: The mean use of hospital services per patient-year, mean new HIV-related opportunistic illnesses per 1000 patient-years and percentage uptake of ART. RESULTS: The use of inpatient services changed particularly among AIDS patients. The mean number of inpatient days for AIDS patients decreased from 19.7 [95% confidence interval (CI) 13.7-25.7] in 1996 to 11.2 (95% CI 6.1-15.6) per patient-year in 1997. Concurrently the number of new AIDS-defining events decreased significantly from 567 (95% CI 529-607) to 203 (95% CI 183-225) per 1000 patient-years. The overall uptake of ART increased significantly from 33% (95% CI 31-35%) to 50% (95% CI 48-52%), and a switch from mono or dual to triple therapy or quadruple or more therapy was observed. However, by mid-1997 only 29% (95% CI 26-32%) of asymptomatic patients and 51% (95% CI 49-54%) of patients with symptomatic non-AIDS were on ART, compared with 69% (95% CI 66-71%) of AIDS patients. CONCLUSION: The observed reduction in new AIDS-defining events has led to a reduction in the need for inpatient hospital care and has been associated with an increased uptake of ART, including a switch to triple therapy. All of these factors are likely to have contributed to the observed reduction in mortality among English AIDS patients. As the overall uptake of ART remained relatively low in English centres further improvements can be anticipated. However, the medium to long-term effects of these treatment regimens will need to be closely monitored.
Anti-HIV Agents↗
Novel cationic amphiphiles as delivery agents for antisense oligonucleotides.
There has been great interest recently in therapeutic use of nucleic acids including genes, ribozymes and antisense oligonucleotides. Despite recent improvements in delivering antisense oligonucleotides to cells in culture, nucleic acid-based therapy is still often limited by the poor penetration of the nucleic acid into the cytoplasm and nucleus of cells. In this report we describe nucleic acid delivery to cells using a series of novel cationic amphiphiles containing cholic acid moieties linked via alkylamino side chains. We term these agents 'molecular umbrellas' since the cationic alkylamino chains provide a 'handle' for binding of nucleic acids, while the cholic acid moieties are likely to interact with the lipid bilayer allowing the highly charged nucleic acid backbone to traverse across the cell membrane. Optimal gene and oligonucleotide delivery to cells was afforded by a derivative (amphiphile 5) containing four cholic acid moieties. With this amphiphile used as a constituent in cationic liposomes, a 4-5 log increase in reporter gene delivery was measured. This amphiphile used alone provided a 250-fold enhancement of oligo-nucleotide association with cells as observed by flow cytometry. A substantial fraction of cells exposed to complexes of amphiphile 5 and fluorescent oligo-nucleotide showed nuclear accumulation of the fluorophore. Enhanced pharmacological effectiveness of antisense oligonucleotides complexed with amphiphile 5 was observed using an antisense splicing correction assay that activates a Luciferase reporter. Intracellular delivery, nuclear localization and pharmacological effectiveness of oligonucleotides using amphiphile 5 were similar to those afforded by commercial cytofectins. However, in contrast to most commercial cytofectins, the umbrella amphiphile showed substantial delivery activity even in the presence of high concentrations of serum.
3T3 Cells↗
Applications of diffusion-perfusion magnetic resonance imaging in acute ischemic stroke.
Diffusion-weighted imaging (DWI) and perfusion imaging (PI) are two new magnetic resonance technologies that are becoming increasingly available for evaluation of acute ischemic stroke patients. DWI provides information about the location of acute focal ischemic brain injury at early time points and PI can document the presence of disturbances in microcirculatory perfusion. DWI and PI are now being used in clinical practice and in clinical trials of potential acute stroke therapies to assess their utility. In the future, DWI and PI may aid in the development of effective acute stroke therapies and help identify which stroke patients are most likely to benefit from specific agents.
Brain Ischemia↗
Neuroprotective effects of a novel broad-spectrum cation channel blocker, LOE 908 MS, on experimental focal ischemia: a multispectral study.
Thirty-four rats undergoing 90 minutes of temporary middle cerebral artery occlusion were randomly and blindly assigned to vehicle or (RS)-(3,4-dihydro-6, 7-dimethoxyisoquinoline-1-gamma1)-2-phenyl-N,N-di-2-(2, 3, 4-trimethoxyphenyl)ethyl acetamide (LOE 908 MS; 0.5 mg/kg) i.v. bolus at 30 minutes after arterial occlusion followed by a 5 mg/kg/hr i.v. infusion for 3.8 hours (n =17/group). Perfusion-, diffusion- and T(2)-weighted magnetic resonance imaging was performed before treatment and repeatedly after treatment. Multispectral analysis was used to define ischemic abnormalities. The size of the ischemic abnormalities, including the ischemic core and penumbra, was not different between the two groups before treatment. However, a significant difference in ischemic lesion size was detected beginning 1.5 hours after treatment. The size of the ischemic core was significantly smaller in the treatment group, while the size of the ischemic penumbra was similar in the two groups at 85 minutes after arterial occlusion. Postmortem infarct size at 24 hours was significantly smaller in the drug-treated group than in the placebo group. These results demonstrate that LOE 908 MS can reduce ischemic lesion size, which is probably attributable to inhibition of expansion of the ischemic core. J. Magn. Reson. Imaging 1999;10:138-145.
Acetamides↗
Reversal of acute apparent diffusion coefficient abnormalities and delayed neuronal death following transient focal cerebral ischemia in rats.
Twenty-two rats were subjected to 8, 15, 30, or 60 minutes of temporary middle cerebral artery occlusion (n = 5 per group) or sham occlusion (n = 2) in the magnetic resonance imaging unit. Diffusion-, perfusion-, and T2-weighted imaging were acquired before and during occlusion, and after reperfusion. A coregistration method was used to correlate the acute changes of the average apparent diffusion coefficient (ADCav) with the histology after 72 hours at the same topographic sites. The initially reduced ADCav values recovered completely in both the lateral caudoputamen and upper frontoparietal cortex in the 8-, 15-, and 30-minute groups, partially in the cortex, and not at all in the caudoputamen in the 60-minute group. The histology showed that the caudoputamen was either normal or had mild neuronal injury in the 8-minute group and invariably had some degree of neuronal death in the 15-, 30-, and 60-minute groups, whereas the cortex was either normal or had varying degrees of neuronal injury in all groups. No histological abnormalities were seen in the sham-operated rats. Our data suggest that acute ADCav reversal does not always predict tissue recovery from ischemic injury and that temporary focal ischemia for even 8-minute duration can cause delayed neuronal death that is more severe in the caudoputamen where the initial ADCav decline was greater than in the cortex.
Animals↗
A generic digital imaging and communications in medicine solution for a bidirectional interface between the modality and the radiology information system.
The Relay is a generic Digital Imaging and Communications in Medicine (DICOM)-compliant software package. It is a bidirectional interface between the modality and the radiology information system (RIS) that uses DICOM modality worklist and modality-performed procedure step services. This device can eliminate discrepancies between patient demographic information contained in the RIS and that entered at the imaging modality. The Relay receives the worklist for a modality from the RIS. It verifies the accession number (ACC#) and medical record number (MRN) received from the RIS for a study against the ACC# and MRN entered at the modality after that study is pushed to the Relay by the modality. If the values for the ACC# and MRN contained in the image header coincide with the values stored on the RIS, the patient demographics and study protocol contained in the RIS is downloaded into the image header. The study is then automatically routed to the specified destination without technologist intervention. Images whose header does not coincide with data on the RIS are flagged for subsequent reconciliation by the technologist. When the study is completed, the Relay updates the status of the study in the RIS, if the RIS provides DICOM performed procedure step service. When required, the Relay is able to split a single study into two or more series and assign each an ACC#. Other Relay functionality includes sending studies to multiple DICOM devices, adding comments to the image header, and DICOM print service. Should the archive be unavailable to receive images for whatever reason, the Relay can store studies so image acquisition can continue without interruption or it can divert studies directly to a diagnostic workstation. This Relay provides redundancy and fault-tolerance capabilities for picture archiving and communications systems. It is vendor-independent and will function with any DICOM modality, RIS, or archive.
Computer Communication Networks↗
Menstrual and premenstrual issues in female military cadets: a unique population with significant concerns.
CONTEXT: There is a strong need to determine what effect, if any, menstruation has on the performance of duty as a Cadet at the United States Military Academy (USMA) at West Point, and to determine what impact, if any, the USMA environment has on the menstrual cycle. STUDY OBJECTIVES: To study menstrual function and premenstrual symptoms in a structured, rigorous military environment; determine the perceived impact of menstrual and premenstrual symptoms on academic, physical, and military activities; and evaluate the difficulties inherent to menstruation in a military setting. DESIGN, SETTING, AND PARTICIPANTS: A survey about high school menstrual and premenstrual function, and the Premenstrual Assessment Form (PAF), were completed by all 158 freshman female Cadets in July 1991. In May 1992, 83 participants completed a survey assessing menstrual and premenstrual symptoms, including interference with activities during the year. MAIN OUTCOME MEASURES: Menstrual regularity, premenstrual symptoms, interference with activities. RESULTS: Participants reported menstrual patterns and premenstrual symptoms in high school similar to other females their age. Most (62%) predicted a change in menstruation at the USMA, half were worried that physical symptoms would interfere with activities, one-fourth were worried that premenstrual symptoms would interfere with activities, and one-fourth were worried that obtaining and changing menstrual materials would interfere with activities. Almost all respondents (91%) reported changes in menstruation during the year, most commonly less regular, less frequent, shorter, lighter, and less crampy periods. Menstrual and premenstrual symptoms interfered with physical activities (66.2%, 61.4% respectively) more so than academic (50.6%, 45.7% respectively) or military activities (39.8%, 47.0% respectively). Female Cadets described significant difficulties with changing (62.6%), obtaining (51.8%), and disposing of (38.5%) menstrual materials. CONCLUSIONS: The data demonstrate major changes in menstrual function in over 90% of female Cadets; a significant perceived impact of menstrual and premenstrual symptoms on academic, physical, and military activities; and difficulties in obtaining, changing, and disposing of menstrual materials in a military setting. These findings have implications for females in the military, as well as for young women generally.
Adolescent↗
Antithrombotic and thrombolytic therapy for ischemic stroke.
Anthithrombotic therapy is widely used as primary and secondary preventative treatment for ischemic cerebrovascular disease. Aspirin modestly reduces the risk for subsequent ischemic stroke after a transient ischemic attack or initial stroke. Adding dipyridamole may enhance this benefit. Ticlopidine confers a small additional benefit, but with more side effects and cost. The best dose of aspirin remains unsettled, but recent studies support the concept of very early initiation of treatment. Intravenous and subcutaneous heparin or low-molecular-weight heparin is not recommended because of enhanced bleeding side effects, unless venous thrombosis in debilitated patients is a concern. Thrombolytic therapy with rt-PA was recently demonstrated to improve outcome in ischemic stroke patients treated within 3 hours of onset. However, the risk-benefit ratio is narrow because of the substantial risk for intracerebral hemorrhage with rt-PA. An enhanced ability to identify patients at risk for bleeding and newer thrombolytic drugs may expand the utility of this therapy, as would extending the time window beyond the current 3-hour period. Clinicians should anticipate continued advances in the fields of antithrombotic and thrombolytic therapy for ischemic stroke over the next few years.
Aspirin↗
ICU admission in patients infected with the human immunodeficiency virus - a multicentre survey.
We conducted a retrospective study to assess the reasons for admission to the intensive care unit, and subsequent outcome, in patients infected with the human immunodeficiency virus (HIV). Four hospitals in the south of England participated, all with specialist HIV units. Data were collected on 127 patients admitted to ICU on 133 separate occasions between June 1993 and October 1997. The mean age on admission was 38 years (range 23-60 years). Ninety-four patients (70.7%) were documented HIV-positive before admission and 36 (27%) were diagnosed HIV-positive for the first time during admission; 36.1% were admitted with Pneumocystis carinii pneumonia. Overall ICU mortality was 33%, in-hospital mortality was 56% and the eventual mortality at the end of follow-up (March 1998) was 72%. Survival was highest in those admitted with respiratory HIV-related disease or HIV-unrelated illness. Associations with poor outcome included a prior AIDS-defining illness, a CD4 cell count of less than 100 cells.ml-1 and admission secondary to sepsis.
AIDS-Related Opportunistic Infections↗
Interventional cardiology in people with diabetes.
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Angioplasty, Balloon, Coronary↗
Diabetes and myocardial infarction.
Myocardial infarction (MI) is a common cause of mortality in people with diabetes. The case fatality from MI is high and may be reduced by thrombolysis and treatment with aspirin, beta-blockers and angiotensin-converting enzyme inhibitors. Poor metabolic control is common among diabetic patients with MI, but the importance of controlling blood glucose during and following an MI is debatable. Treatment with statins reduces cardiovascular end-points in diabetic patients with previous MI (secondary prevention). Large studies in diabetic patients without existing heart disease have shown statistically insignificant reductions in heart disease and MI with improved glycaemic control of the diabetes (primary prevention). The treatment of hypertension in people with diabetes prevents cardiovascular end-points, and studies on whether the treatment of hyperlipidaemia reduces heart disease and MI are proceeding.
Adrenergic beta-Antagonists↗