Cationic liposome-mediated DNA transfection in organotypic explant cultures of the ventral mesencephalon.
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We have examined the potential of cationic liposomes as a tool for approaches to gene therapy in the CNS. Our previous work has shown that cationic liposomes formulated from 3 beta-[N-(N',N'-dimethylaminoethane)carbamoyl] cholesterol (DC-Chol) and dioleoyl-L-alpha-phosphatidylethanolamine (DOPE) could achieve high transfection levels in a neuronal cell line (McQuillin et al. Neuroreport 1997; 8: 1481-1484). We therefore wished to assess transfection efficiencies in organotypic cultures from the brain with a reporter plasmid expressing E. coli beta-galactosidase in order to mimic an in vivo model. Explant cultures were generated according to the method of Stoppini et al (J Neurosci Meth 1991; 37: 173-182) with slight modifications. Brain slices were maintained on transparent porous membranes and were observed to maintain their intrinsic connectivity and cytoarchitecture to a large degree over periods of up to 6 weeks in culture. CNS tissue was obtained from rats at birth or 5 days after birth. After transfection beta-galactosidase expression was detected in cells of both neuronal and non-neuronal morphology. Control cultures were exposed to liposome alone and a plasmid that had the beta-galactosidase gene insert removed. Only low levels of endogenous beta-galactosidase reactivity were seen in these control cultures. DC-Chol/DOPE-mediated transfection was confirmed using a RT-PCR protocol capable of differentiating between untranscribed plasmid DNA and RNA generated from the transfected vector. These results suggest that cationic liposomes, particularly DC-Chol/DOPE liposomes, will be useful as delivery agents for gene transfer to CNS cells in vitro and possibly in vivo. (+info)
A comparison of standard cardiopulmonary resuscitation and active compression-decompression resuscitation for out-of-hospital cardiac arrest. French Active Compression-Decompression Cardiopulmonary Resuscitation Study Group.
(18/1158)
BACKGROUND: We previously observed that short-term survival after out-of-hospital cardiac arrest was greater with active compression-decompression cardiopulmonary resuscitation (CPR) than with standard CPR. In the current study, we assessed the effects of the active compression-decompression method on one-year survival. METHODS: Patients who had cardiac arrest in the Paris metropolitan area or in Thionville, France, more than 80 percent of whom had asystole, were assigned to receive either standard CPR (377 patients) or active compression-decompression CPR (373 patients) according to whether their arrest occurred on an even or odd day of the month, respectively. The primary end point was survival at one year. The rate of survival to hospital discharge without neurologic impairment and the neurologic outcome were secondary end points. RESULTS: Both the rate of hospital discharge without neurologic impairment (6 percent vs. 2 percent, P=0.01) and the one-year survival rate (5 percent vs. 2 percent, P=0.03) were significantly higher among patients who received active compression-decompression CPR than among those who received standard CPR. All patients who survived to one year had cardiac arrests that were witnessed. Nine of 17 one-year survivors in the active compression-decompression group and 2 of 7 in the standard group, respectively, initially had asystole or pulseless electrical activity. In 12 of the 17 survivors who had received active compression-decompression CPR, neurologic status returned to base line, as compared with 3 of 7 survivors who had received standard CPR (P=0.34). CONCLUSIONS: Active compression-decompression CPR performed during advanced life support significantly improved long-term survival rates among patients who had cardiac arrest outside the hospital. (+info)
Value of magnetization transfer contrast as a sensitive technique to reflect histopathological changes in the white matter adjacent to the frontal horns of lateral ventricles.
(19/1158)
The purpose of this study is to evaluate the usefulness of magnetization transfer contrast (MTC) as a technique to reflect histopathological changes in the white matter adjacent to the frontal horns of the lateral ventricles. Radiological-pathological correlation was performed in six patients who underwent Magnetic Resonance (MR) examination prior to death and in whom postmortem examinations of the brain were obtained. The extent and the severity of degeneration in the white matter adjacent to the frontal horns were evaluated histopathologically, and compared with those observed on the conventional proton density (PD) weighted MR images (Group 1). Changes in the white matter of another 35 patients were classified into three types according to the pattern of high signals adjacent to the frontal horns on conventional PD weighted MR images, and magnetization transfer ratio (MTR) in the white matter adjacent to the frontal horns was calculated from multi-slice and single-slice FSE images (Group 2). The relationship between signal intensities and MTR in the white matter adjacent to the frontal horns was evaluated. The extent of degeneration in the white matter adjacent to the frontal horns was classified into mild, moderate and severe types on the basis of stainin for myelins, axons and astrocytes. In Group 1, histopathological findings indicated a difference in severity of degeneration in the white matter adjacent to the frontal horns among the three types, while no significant differences were noted in the signals on PD weighted MR images. In Group 2, MTR showed significant differences in the signal intensities in the white matter adjacent to the frontal horns (p < 0.01) between the three types, while conventional PD weighted MR images failed to differentiate between them. In conclusion, MT imaging is a sensitive technique to evaluate the histopathological changes in the white matter adjacent to the frontal horns that cannot be detected by conventional MR imaging. (+info)
Remacemide hydrochloride: a double-blind, placebo-controlled, safety and tolerability study in patients with acute ischemic stroke.
(20/1158)
BACKGROUND AND PURPOSE: Remacemide hydrochloride and its principal active desglycinyl metabolite are low-affinity noncompetitive N-methyl-D-aspartate (NMDA)-receptor channel blockers. Remacemide hydrochloride has demonstrated neuroprotection in animal models of hypoxia and ischemic stroke. This study assessed the safety, tolerability, and pharmacokinetics of ascending doses of remacemide hydrochloride in patients with recent onset (within 12 hours) ischemic stroke. METHODS: This was a placebo-controlled, dose escalating, parallel group study. Groups of 8 patients (6 active, 2 placebo) were planned to receive twice-daily treatment, with l00 mg, 200 mg, 300 mg, 400 mg, 500 mg, or 600 mg remacemide hydrochloride given as 2 intravenous infusions followed by 6 days' oral treatment. Patients who were unable to swallow discontinued study medication but continued to be monitored for safety; these patients were replaced. A CT or MRI scan was performed within 48 hours of admission to establish the cause of focal neurological deficit. Patients with ischemic stroke continued in the study. Patients with other causes of focal neurological deficit were withdrawn and replaced. Because the frequency of dysphagia after stroke in the first dose group (100 mg BID) was higher than had been anticipated, the protocol was amended so that subsequent dose groups received 6 intravenous infusions (2 doses per day for 3 days). Neurological and functional outcome data were collected, but the study was not powered to demonstrate drug efficacy. Patient safety was assessed by clinical observation, laboratory tests, and ECGs, while tolerability was assessed by recording adverse events. Blood sampling was included to determine plasma concentrations of remacemide and the desglycinyl metabolite at fixed points during the dosing period. RESULTS: The most common adverse events considered by the investigator to be possibly treatment related were related to the central nervous system (CNS), and these events appeared to increase with dose. Four patients were withdrawn from the study because of CNS-related events: 1 in the placebo group, 1 in the 500 mg BID group, and 2 in the 600 mg BID group. Infusion site reactions and gastrointestinal upset were also reported and considered to be treatment related. One patient in the placebo group and 4 patients in the 600 mg BID dose group experienced vomiting, whereas this event was not reported by patients in the other dose groups. CONCLUSIONS: On the evidence of this study, the maximum well-tolerated dose for remacemide hydrochloride in acute stroke is 400 mg BID. Doses of 200 mg BID or higher attained the putative neuroprotective plasma concentrations of remacemide predicted from animal models (250 to 600 ng/mL). The expected gradual accumulation of active metabolite might suggest that optimal neuroprotective concentrations are unlikely to be achieved within the early hours of treatment at this dose. However, plasma concentrations do not directly reflect brain concentrations, because studies in rats show that remacemide and the desglycinyl metabolite rapidly reach comparable brain concentrations within 1 hour, despite a lower plasma concentration of the metabolite. (+info)
Incidence of childhood brain and other non-haematopoietic neoplasms near nuclear sites in Scotland, 1975-94.
(21/1158)
OBJECTIVES: To examine the risk of cancers other than leukaemia and non-Hodgkin's lymphoma in children resident in the vicinity of nuclear sites in Scotland. METHODS: The study dataset comprised registrations of cancer other than leukaemia and non-Hodgkin's lymphoma diagnosed in children aged under 15 in the period 1975-94. These were validated for completeness and accuracy and analysed in two groups: (a) tumours of the central nervous system and (b) other malignant tumours (excluding leukaemia and non-Hodgkin's lymphoma). Around each nuclear site observed cases (O) were enumerated and expected numbers (E) calculated with adjustment for age, sex, deprivation, and an urban-rural category. Stone's maximum likelihood ratio test (MLR) was used to determine whether there was any evidence of increased risk of these neoplasms among children living within 25 km of one of the nuclear sites investigated. The significance level of each MLR statistic was estimated by simulation. RESULTS: More tumours of the central nervous system were observed than expected within 25 km of Dounreay (O/E = 1.14), Hunterston (1.14), and Rosyth (1.22). These results were based on 2, 26, and 136 observed cases, respectively. The unconditional MLR was significant only for Rosyth (p = 0.006). The conditional application of the MLR test for Rosyth was not significant (p = 0.771). For the group of other malignant neoplasms, the unconditional MLR test was not significant for any of the seven sites. CONCLUSIONS: There was no evidence for generally increased risk of either tumours of the central nervous system or other malignant tumours in children living near nuclear sites. The significant excess of tumours of the central nervous system around Rosyth is likely to be due to the high incidence of these tumours in east central Scotland. Further investigations in this area are warranted. (+info)
Superficial siderosis of the CNS associated with multiple cavernous malformations.
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Superficial siderosis of the CNS due to chronic, recurrent subarachnoid hemorrhage is an uncommon and potentially debilitating disorder. The classic clinical manifestation is progressive bilateral sensorineural hearing loss (SNHL), although ataxia and pyramidal signs also are observed frequently. Cavernous malformations rarely present with subarachnoid hemorrhage. We describe an unusual case of a young patient who presented with progressive, bilateral SNHL who was found to have superficial CNS siderosis associated with multiple cavernous malformations. (+info)
HIV infection and seizures.
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New-onset seizures are frequent manifestations of central nervous system disorders in patients infected with human immunodeficiency virus (HIV). Seizures are more common in advanced stages of the disease, although they may occur early in the course of illness. In the majority of patients, seizures are of the generalised type. Status epilepticus is also frequent. Associated metabolic abnormalities increase the risk for status epilepticus. Cerebral mass lesions, cryptococcal meningitis, and HIV-encephalopathy are common causes of seizures. Phenytoin is the most commonly prescribed anticonvulsant in this situation, although several patients may experience hypersensitivity reactions. The prognosis of seizure disorders in HIV-infected patients depends upon the underlying cause. (+info)
Rhodesian trypanosomiasis in a splenectomized patient.
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We report the first apparent case of a splenectomized individual who developed severe trypanosomiasis with central nervous system involvement. The patient was a 41-year-old man who participated in an east African safari. Upon his return to the United States, the patient presented with an infection with Trypanosoma brucei rhodesiense that was treated successfully with suramin and melarsoprol. The onset of symptoms, laboratory studies, and disease progression did not differ from previously reported cases in the literature. The role of the spleen in trypanosomiasis is not well understood and the few reports available describe only animal models. This report suggests that asplenia had no apparent effect on the onset of symptoms and overall severity of illness. Further studies are necessary to ultimately define the role of the spleen in trypanosomiasis. (+info)