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Low leukocyte counts with blast cells in cerebrospinal fluid of children with newly diagnosed acute lymphoblastic leukemia.

BACKGROUND: Treatment of the central nervous system is crucial to the successful treatment of acute lymphoblastic leukemia in children. The intensity and timing of the therapy are based on the presence or predicted risk of central nervous system leukemia as assessed according to criteria that remain controversial. METHODS: The clinical importance of leukemic blast cells detected in cerebrospinal fluid at the time of diagnosis was evaluated in 351 children with acute lymphoblastic leukemia in a randomized trial of intensive chemotherapy. All patients received intrathecal chemotherapy during the first year. Patients considered to be at high risk of relapse because of their clinical and cytogenetic features also received cranial irradiation and intrathecal chemotherapy one year after remission. Patients were considered to have central nervous system leukemia at diagnosis if they had at least 5 leukocytes per microliter of cerebrospinal fluid, with leukemic blast cells apparent in cytocentrifuged preparations, or cranial-nerve palsy; they received additional intrathecal injections of chemotherapeutic agents and cranial irradiation. Patients were retrospectively classified on the basis of cerebrospinal fluid findings: 291 patients had no detectable blast cells, 42 had fewer than 5 leukocytes per microliter and blast cells, and 18 had central nervous system leukemia as defined above. The clinical characteristics and outcomes of treatment in these groups were analyzed. RESULTS: The five-year probability of survival free of relapses confined to the central nervous system in patients with detectable blast cells and fewer than 5 leukocytes per microliter of cerebrospinal fluid was lower than in patients without blast cells (mean [+/- SE], 87 +/- 13 vs. 96 +/- 2 percent), but was not different from the probability in patients with central nervous system leukemia at diagnosis. All such isolated relapses of leukemia in patients with detectable blast cells occurred during the first year of treatment, before scheduled cranial irradiation. In a multivariate analysis, the presence of cerebrospinal fluid blast cells with fewer than 5 leukocytes per microliter was independently related to the risk of relapse confined to the central nervous system. CONCLUSIONS: Patients with leukemic blast cells in their cerebrospinal fluid are at increased risk for central nervous system relapse when cranial irradiation is delayed. Such patients require intensified central nervous system treatment early in the course of therapy.

Adolescent↗

Acid glycosidase and arylsulfatase activities of human cerebrospinal fluid as measured by concanavalin A-sepharose affinity chromatography.

An affinity chromatographic method using concanavalin A-Sepharose is described for the determination of N-acetyl-beta-D-glucosaminidase, arylsulfatase. alpha-L-Fucosidase and alpha-D-mannosidase activities in the human cerebrospinal fluid. By this method (starting with 12 to 20 ml samples of cerebrospinal fluid) the above enzymes could be obtained in a concentrated form and their activities could be determined within incubation periods of 30 min to 1 h under the assay conditions described. The pH optima of the enzymes were in the range of pH 4 to 5. About 80% of the total cerebrospinal fluid N-acetyl-beta-D-glucosaminidase was found to be the A form by DEAE-Sephadex A-50 chromatography. About 60% of the total arylsulfatase was also found to be the A form. Determination of these enzyme activities in a few samples of human cerebrospinal fluid indicated a rough proportionality between the enzyme activities and the protein concentration in the cerebrospinal fluid.

Acetylglucosaminidase↗

[Changes in fatty acids composition in cerebrospinal fluid of patients with myelopathy].

The composition of fatty acids in the cerebrospinal fluid of patients with cervical myelopathy, thoracic myelopathy, cauda equina syndrome, and spinal cord injury were measured by gas chromatography. The relationship between the change in fatty acids composition and the improvement of symptoms and pathology were studied. The percent distribution of eicosadienoic acid (C20: 2) in fatty acids composition was found to be significantly increased in the cerebrospinal fluid of patients with cervical and thoracic myelopathies (p less than 0.05), and with incomplete spinal cord injury (p less than 0.01) against control group. Although the high percent distribution, especially over 10%, of C20: 2 in the cerebrospinal fluid of the patients with cervical or thoracic myelopathy before operation decreased after operation, no correlation was found between the decrease of percent distribution of C20: 2 and improvement of symptoms. A positive relationship was found between the decrease of percent distribution of C20: 2 and the improvement in symptom of patients with central spinal cord injury.

Adult↗

Interleukin 4 and interleukin 10 levels are elevated in the cerebrospinal fluid of patients with Creutzfeldt-Jakob disease.

BACKGROUND: In neurodegenerative diseases, increasing attention has been focused on inflammatory mediators such as pro-inflammatory and anti-inflammatory cytokines and their potential influence in the process of neurodegeneration. In prion diseases, much data has been gained on the cell culture and animal disease models level, but only limited information is available on humans affected by Creutzfeldt-Jakob disease (CJD). OBJECTIVE: To obtain data on anti-inflammatory cytokines interleukin 4 and interleukin 10 in the cerebrospinal fluid of patients with CJD, patients with other dementia, and nondemented neurological patients and controls. DESIGN: Cerebrospinal fluid samples were collected from CJD patients and control subjects, and concentrations of the anti-inflammatory cytokines interleukin 4 and interleukin 10 were determined using an enzyme-linked immunosorbent assay. PATIENTS: Cerebrospinal fluid samples from 61 patients were analyzed. The group was composed of patients with CJD (n = 20), patients with other forms of dementia (n = 10), patients with motoneuron disease (n = 6), patients with normal pressure hydrocephalus (n = 5), and control subjects (n = 20). RESULTS: Interleukin 10 levels were significantly elevated in the cerebrospinal fluid of CJD patients (median, 9.8 pg/mL). The elevation was significant to other dementia (median, 7.9 pg/mL, P<.05), motoneuron disease (median, 7.9 pg/mL, P<.05), normal pressure hydrocephalus (median, 7.0 pg/mL, P<.05), and controls (median, 1.3 pg/mL, P<.001). Levels of interleukin 4 were significantly elevated in cerebrospinal fluid of patients with CJD (median, 26.4 pg/mL) compared with control subjects (median, 6.2 pg/mL, P<.001) and patients with a motoneuron disease (median, 10.5 pg/mL, P<.001) CONCLUSIONS: Elevated levels of the anti-inflammatory cytokines interleukin 4 and interleukin 10 in cerebrospinal fluid of patients with CJD are new findings. The data of the present study provide a clue toward the possible role of cytokines as immunological modifiers in the neurodegenerative process of CJD.

Adult↗

Neurologic abnormalities and recovery of human immunodeficiency virus from cerebrospinal fluid.

Infectious human immunodeficiency virus (HIV) was recovered from 30 of 48 cerebrospinal fluid specimens from seropositive persons with and without neurologic symptoms or disease. Of 16 patients with only neurologic problems or other HIV-related conditions, but not the acquired immunodeficiency syndrome (AIDS), 11 had virus recovered; over half of those with AIDS also had virus isolated. Patients with headache or altered mental status had the highest recovery rate of HIV from cerebrospinal fluid. Although virus was primarily found in patients with detectable neurologic disease, it was also isolated from 5 of 8 patients with normal neurologic examinations. Two of these patients had fever alone. The presence of virus in cerebrospinal fluid did not necessarily correlate with isolation of virus from the serum. These findings suggest that HIV may at times replicate preferentially in the brain and that its presence may not immediately cause neurologic signs or symptoms.

Acquired Immunodeficiency Syndrome↗

Elevated biopterin and homovanillic acid levels in cerebrospinal fluid from children with aseptic meningitis.

To examine biopterin fractions and biogenic amine metabolites in cerebrospinal fluid in aseptic meningitis, the concentrations of homovanillic acid, 5-hydroxyindoleacetic acid, and the total, the oxidized form, and the reduced form of biopterin were determined in cerebrospinal fluid specimens from 15 children with aseptic meningitis in the acute phase, 15 children with aseptic meningitis in the recovery phase, and six other children as controls. The concentration of each substance was significantly higher in the acute phase than in the recovery phase. Homovanillic acid in the acute phase was significantly increased compared to that in the control group. The concentrations of the total, the oxidized form, and the reduced form of biopterin, and 5-hydroxyindoleacetic acid were higher in the acute phase than those in the controls; however, the differences were not significant. The concentration of each substance in the recovery phase was not significantly different from that in the controls. There was no difference in the 5-hydroxyindoleacetic acid/homovanillic acid ratio or in the reduced form/total biopterin ratio among the patients in acute and recovery phases and the controls. These results suggested that levels of biopterin and biogenic amine metabolites in cerebrospinal fluid are increased in the acute phase of aseptic meningitis and return to normal during the recovery phase. This is the first report of increased concentrations of biopterin fractions and biogenic amine metabolites in aseptic meningitis.

Biopterins↗

Diffusion of a new beta-lactam (LY 127935) into cerebrospinal fluid. Implications for therapy of gram-negative bacillary meningitis.

LY 127935, a new oxa beta-lactam with an expanded gram-negative spectrum, was administered intravenously to seven patients, including two patients with documented gram-negative bacillary meningitis. In the patients receiving continuous therapy (2 g intravenously every 8 hours) cerebrospinal fluid trough levels of LY were never less than 6 micrograms/ml. Peak cerebrospinal fluid levels of LY ranged from 25 to 39 micrograms/ml and occurred approximately 2.5 hours after the intravenous administration of the drug. Cerebrospinal fluid levels of LY were 19 per cent to greater than 100 per cent of simultaneous serum levels. Cerebrospinal fluid bactericidal activity was 1:4 to 1:256. Intravenous LY, because of its expanded gram-negative spectrum and excellent cerebrospinal fluid penetration, is a potentially useful antibiotic in the treatment of gram-negative bacillary meningitis.

Aged↗

An in vitro bioassay for quantification of melarsoprol in serum and cerebrospinal fluid.

A biological assay was developed for measuring melarsoprol in serum and cerebrospinal fluid of patients with human African trypanosomiasis. Trypanosomes were cultivated in microtiter plates for 72 hours with melarsoprol (Mel B) in concentrations of 1.25 micrograms/ml to 2.2 ng/ml. The minimum inhibitory concentration of Mel B for a reference Trypanosoma brucei rhodesiense clone was determined by microscopical examination. Samples of serum or cerebrospinal fluid were incubated under the same conditions and the highest dilution determined which caused death of all trypanosomes. The melarsoprol concentration of the sample was then calculated using the sample dilution and the determined minimal inhibitory concentration of the trypanosome population used for the assay. The test was validated using a number of reference samples and it was used for melarsoprol determination in serum- and cerebrospinal fluid samples taken from two treated patients. A sample size of 100 microliters was sufficient to perform the assay. The lower detection limit was 9 ng/ml (22.6 nmol/ml). The assay has potential for measuring other trypanocidal drugs in body fluids.

Animals↗

Guanidino compounds in serum and cerebrospinal fluid of non-dialyzed patients with renal insufficiency.

Twelve guanidino compounds were determined in simultaneously sampled serum and cerebrospinal fluid of eight non-dialyzed patients with renal insufficiency. Liquid cation exchange chromatography with a highly sensitive fluorescence detection method was used. In patients with serum urea levels about 10 times higher than in controls, the levels of guanidinosuccinic acid, creatinine, guanidine and methylguanidine, in serum as well as in cerebrospinal fluid, are at least 10 times higher than in control subjects. The levels of argininic acid and N-alpha-acetylarginine (in serum) and gamma-guanidinobutyric acid (in cerebrospinal fluid) are slightly increased (less than 10 X). The levels of the other guanidino compounds are close to normal values. A significant positive correlation exists between the guanidinosuccinic acid, creatinine and guanidine levels in serum and cerebrospinal fluid. The accumulation of several experimentally proven toxic guanidino compounds could contribute to the complex nervous system symptomatology and the hematological complications seen in renal insufficiency.

Aged↗

Effects of ventricular drainage and dural closure on cerebrospinal fluid leaks after posterior fossa tumor surgery.

In a retrospective study of 50 consecutive children with posterior fossa tumors treated at Texas Children's Hospital, Houston, Tex., in 1989-1992, we evaluated perioperative factors which might influence the development of postoperative cerebrospinal fluid leaks. Factors analyzed included the presence of preoperative hydrocephalus, the institution of cerebrospinal fluid diversion, and the method of dural closure. No statistically significant impact on subsequent cerebrospinal fluid leakage was demonstrated.

Adolescent↗

[Erythromycin penetration into the cerebrospinal fluid of patients].

Permeability of erythromycin through the barrier of blood-cerebrospinal fluid in neurosurgical patients after its oral administration in a dose of 300-500 mg and intravenous administration in a dose of 200 mg was studied. The erythromycin was determined after the antibiotic single administration at intervals of 40 minutes to 6 hours. A total of 31 observations were performed. Low penetration of erythromycin into the cerebrospinal fluid of the patients was shown. The administration route (oral or intravenous) practically had no effect on the antibiotic penetration level into the subarachnoidal spaces. The highest liquor levels were observed within the period of 3 to 6 hours after the drug administration. The maximum index of penetration from the blood into the cerebrospinal fluid was about 10 per cent. The erythromycin penetration increased in cases with inflammatory changes in the meninges.

Administration, Oral↗

Cerebrospinal fluid monoamine and adrenal correlates of aggression in free-ranging rhesus monkeys.

Clinical and preclinical studies involving several different mammalian species and research paradigms suggest a negative correlation between aggression and central serotonin activity. To test the generalizability of laboratory findings in rhesus monkeys that show a negative correlation between cerebrospinal fluid 5-hydroxyindoleacetic acid concentrations and aggression, we obtained cisternal cerebrospinal fluid and blood plasma samples from monkeys living in naturalistic conditions. During a semiannual trapping, 28 juvenile and adolescent male rhesus monkeys were chosen from a population of 4200 provisioned, free-ranging rhesus monkeys living on Morgan Island, a sea island located off the coast of South Carolina. Based on direct observations of participation or avoidance of aggressive behavior and examinations of apparent fight wounds, 18 monkeys were selected for cerebrospinal fluid taps and blood samples. The remaining 10 monkeys were selected at random. Descriptions of aggressive behavior and the number of old scars and recent wounds were carefully transcribed, and a photograph showing wounds and scars was obtained for each animal. Using the transcriptions and photographs, researchers experienced in rhesus monkey behavior, but blind to the subjects' monoamine and hormone concentrations, were asked to rank the monkeys from the most to the least aggressive. The results showed a significant negative correlation between high rankings for aggression and cerebrospinal fluid 5-hydroxyindoleacetic acid concentrations. There was evidence that aggression was associated with stress, in that cerebrospinal fluid, norepinephrine, and plasma corticotropin and cortisol concentrations were positively correlated with high rankings of aggression.

Adrenocorticotropic Hormone↗

Usefulness of adding multiplex nested-polymerase chain reaction assay of cerebrospinal fluid samples to routine diagnostic testing for herpesvirus encephalitis.

The present study was conducted to assess the usefulness of adding the multiplex nested-polymerase chain reaction assay of cerebrospinal fluid samples to routine diagnostic testing for herpesvirus encephalitis and to monitor the efficacy of therapy. Cerebrospinal fluid samples from 45 patients with presumed herpesvirus encephalitis were tested for herpes simplex virus, varicella-zoster virus, cytomegalovirus, human herpesvirus 6, and Epstein-Barr virus. Ten of the 45 patients were positive for a virus using the polymerase chain reaction assay: herpes simplex virus (n=5), Epstein-Barr virus (n=3), and herpes simplex virus plus the Epstein-Barr virus (n=2). Cerebrospinal fluid from two patients who had undergone acyclovir therapy gave negative results. Analysis of cerebrospinal fluid by multiplex polymerase chain reaction can be useful for establishing an accurate diagnosis and as a marker of the efficacy of therapy.

Adult↗

Increase in cerebrospinal fluid and plasma levels of 3-methoxy-4-hydroxyphenylglycol in acute stroke.

BACKGROUND AND PURPOSE: 3-Methoxy-4-hydroxyphenylglycol is known to be a principal metabolite of brain norepinephrine and to be released into the blood and cerebrospinal fluid in association with activation of the central noradrenergic system. We examined changes in plasma and cerebrospinal fluid levels of 3-methoxy-4-hydroxyphenylglycol during acute stroke to see if there might be a correlation between these and the patient's clinical state. METHODS: We measured plasma levels of 3-methoxy-4-hydroxyphenylglycol in 32 control subjects and in 50 patients with brain hemorrhage and 57 patients with brain infarction who were admitted to the hospital within 72 hours after onset. In addition, we estimated 3-methoxy-4-hydroxyphenylglycol concentrations in the cerebrospinal fluid of 37 patients with brain infarction and eight control patients. RESULTS: Mean +/- SEM values for plasma 3-methoxy-4-hydroxyphenylglycol in the patients with brain hemorrhage and those with brain infarction were 7.3 +/- 0.5 and 6.6 +/- 0.5 ng/ml, respectively. Both values were significantly higher than that obtained in the 32 control subjects (4.6 +/- 0.3 ng/ml, p less than 0.01). Plasma levels of 3-methoxy-4-hydroxyphenylglycol correlated well with state of consciousness and prognosis. The mean +/- SEM level of 3-methoxy-4-hydroxyphenylglycol in the cerebrospinal fluid of the 37 patients with brain infarction (10.9 +/- 0.6 ng/ml) was also significantly higher than that in the eight control patients (7.9 +/- 0.6 ng/ml, p less than 0.01). CONCLUSIONS: The observed increase in plasma and cerebrospinal fluid levels of 3-methoxy-4-hydroxyphenylglycol implies that the activity of the central noradrenergic neurons may be enhanced at the onset of stroke, and these levels may be related to some extent to the clinical state and prognosis of stroke patients.

Aged↗

A bioluminescent assay for enolase (EC 4.2.1.11) activity in human serum and cerebrospinal fluid.

A simple method is described for the measurement of enolase enzyme activity in human serum and in unconcentrated cerebrospinal fluid. The enzyme is measured by a bioluminescent assay, making use of the luciferine/luciferase system. The method is very suitable for use in clinical chemical laboratories. The Michaelis-Menten constants of three enolase isozyme forms have been measured. Data concerning the in vitro stability at 37 degrees C of alfa-alfa, alfa-gamma and gamma-gamma enolase in cerebrospinal fluid are presented. The gamma-gamma form is the most stable enolase form under these conditions. Preliminary data from a clinical study about the diagnostic significance of the enzyme indicate that evident elevations in cerebrospinal fluid enolase levels can be seen in patients from neurological wards. There is a poor correlation between total creatine kinase and enolase cerebrospinal fluid levels.

Electrophoresis, Agar Gel↗

Clinical evaluation of piperacillin with observations on penetrability into cerebrospinal fluid.

Piperacillin, a new semisynthetic penicillin, was evaluated for efficacy and safety in 26 patients, most of whom had pneumonia. Included were four patients with gram-negative meningitis in whom the penetration of piperacillin into cerebrospinal fluid was determined. Cure was achieved in 11 of 17 patients with pneumonia; another 4 were improved. One relapse and one failure occurred among nine patients with gram-negative pneumonia. Cure or improvement occurred in seven of nine patients with gram-negative infection in various extrapulmonary sites. Piperacillin given by continuous infusion in a dosage ranging from 324 to 436 mg/kg of body weight per day to four patients with meningitis resulted in a mean cerebrospinal fluid level of 23 micrograms/ml at 24 h; the mean penetration of piperacillin into the cerebrospinal fluid was 32% at this interval. Levels of piperacillin in cerebrospinal fluid collected later during the course of therapy were also adequate. Adverse effects were noted in six patients, but only one episode of granulocytopenia was serious. Emergence of resistance to piperacillin did not occur, and only one superinfection was noted. Piperacillin appeared to be efficacious in the treatment of pneumonia. It penetrated well into the cerebrospinal fluid of patients with meningitis and may be useful for treatment of selected gram-negative infections in extrapulmonary sites.

Haemophilus Infections↗

Liquid chromatographic-tandem mass spectrometric assay for the simultaneous determination of didanosine and stavudine in human plasma, bronchoalveolar lavage fluid, alveolar cells, peripheral blood mononuclear cells, seminal plasma, cerebrospinal fluid and tonsil tissue.

We have developed a sensitive, high-pressure liquid chromatographic-tandem mass spectrometric (LC/MS/MS) method for the simultaneous determination of didanosine (ddI) and stavudine (d4T) in human plasma, bronchoalveolar lavage fluid (BALF), alveolar cells (AC), peripheral blood mononuclear cells (PBMC), seminal plasma, cerebrospinal fluid (CSF), and tonsil tissue. Plasma, AC, PBMC and CSF were run with an isocratic HPLC method, while BALF supernatant, semen, and tonsil tissue utilized a gradient elution. Samples were prepared by solid phase extraction. Detection was by electrospray positive ionization with multiple reaction monitoring mode. The lower limits of quantitation for both ddI and d4T were 2.0 ng/ml in plasma; 0.5 ng/ml in CSF; 0.4 ng/ml in AC, PBMC, and BALF; 1.0 ng/ml in seminal plasma; and 0.01 ng/mg in tonsil tissue.

Bronchoalveolar Lavage Fluid↗

Protein fractions of lumbar, cisternal, and ventricular cerebrospinal fluid. Separate areas of reference.

Ventricular (n=27), cisternal (n=33) and lumbar (n=127) cerebrospinal fluid of "non-diseased" reference persons was investigated. The following measurements were taken: (1) Total protein, albumin, immunoglobulin A,G, M (IgA,G,M) in unconcentrated cerebrospinal fluid (CSF). (2) Protein fractions in the microzone electrophoresis of concentrated CSF. Albumin and IgG concentrations were highly correlated in all the samples, regardless of their origin. Therefore, bivariate areas of reference as well as interdependent regression coefficients were computed for the paired data. The regression lines of the 3 different areas of reference (ventricular, cisternal, lumbar) ran parallel to each other, displaced along the axis of the IgG concentration: approximately 10% of the lumbar IgG does not originate directly from serum. Although the albumin concentration increased 2.2 times, and the IgG 2.6 times, from ventricular to lumbar region, the concentration of pre-albumin decreased by a factor of 0.7. The concentration of IgA never surpassed the limits of detection set by this method (8 mg/I), in spite of its similarity to IgG regarding molecular weight and size. The observations strengthen the assumption that selective functions are present at the blood-CSF barrier. In 4 illustrative cases with a chronic inflammatory process, the discriminating power of the different reference areas was demonstrated. The findings should be evaluated in a multivariate manner, considering the location from which the sample was obtained.

Cerebral Ventricles↗