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Cerebrospinal-fluid HIV-1 RNA and drug concentrations after treatment with lamivudine plus zidovudine or stavudine.

BACKGROUND: Treatment and prevention of HIV-1-related central-nervous-system disease may be dependent on penetration of antiretroviral drugs into the central nervous system. Few data are available about cerebrospinal-fluid penetration and concomitant changes of HIV-1-RNA concentrations during treatment with antiretroviral agents. We investigated these effects in HIV-1-infected people. METHODS: 28 antiretroviral-naive individuals with CD4 cell counts of 200/microL or more and plasma HIV-1-RNA concentrations of 10,000 or more copies/mL who were free of neurological symptoms were randomly assigned lamivudine plus either stavudine (n = 17) or zidovudine (n = 11). We did lumbar punctures on 28 individuals before and 22 individuals after 12 weeks of treatment to assess HIV-1-RNA and drug concentrations in cerebrospinal fluid. FINDINGS: All 28 individuals had detectable HIV-1-RNA concentrations in the cerebrospinal fluid (median 4.64 log10 copies/mL and 4.20 log10 copies/mL in the lamivudine plus zidovudine and lamivudine plus stavudine groups, respectively). There was no correlation between plasma and cerebrospinal-fluid HIV-1-RNA concentrations (r = 0.18, p = 0.35). After 12 weeks of treatment none of the individuals had detectable HIV-1-RNA concentrations in the cerebrospinal fluid. The highest drug concentration in the cerebrospinal fluid was for lamivudine followed by stavudine and zidovudine. Concentrations were consistent over time, unlike plasma concentrations. Therefore, we found time-dependent cerebrospinal-fluid to plasma drug-penetration ratios, which were highest for zidovudine followed by stavudine and lamivudine. INTERPRETATION: The two drug combinations were equally effective in the decrease of cerebrospinal fluid HIV-1-RNA concentrations. All drugs penetrated the cerebrospinal fluid. Antiretroviral drugs other than zidovudine might be useful in the prevention of AIDS dementia complex.

AIDS Dementia Complex↗

OBSERVATIONS ON VITAMIN B12 IN SERUM AND CEREBROSPINAL FLUID IN MULTIPLE SCLEROSIS.

There are several claims that B(12) concentrations in serum and cerebrospinal fluid are grossly abnormal in multiple sclerosis, but results are conflicting. This paper reports measurements of these concentrations in 40 serum samples and 23 samples of lumbar cerebrospinal fluid from cases of multiple sclerosis, and in appropriate controls, using Euglena gracilis, z strain. The serum concentrations were found to be normal; the mean concentration in cerebrospinal fluid was slightly reduced, but all values were within the control range. In both control samples and samples from cases of multiple sclerosis, the B(12) concentration in lumbar cerebrospinal fluid was correlated with the concentration in serum. There was no correlation between B(12) concentration and total protein in cerebrospinal fluid.A number of estimations of serum B(12) were also made with Lactobacillus leichmannii, after extraction in the presence and absence of cyanide. These showed a difference between cases of multiple sclerosis and controls, one interpretation of which might be that the serum in multiple sclerosis contains an abnormally low concentration of hydroxocobalamin.

Blood↗

Neonatal herpes simplex virus infections: HSV DNA in cerebrospinal fluid and serum.

AIM: To investigate the diagnostic potential of herpes simplex virus (HSV) DNA in cerebrospinal fluid and serum; to correlate the findings with outcome in the child and with type of maternal infection. METHODS: Cerebrospinal fluid and serum specimens from 36 children with verified neonatal HSV infections, diagnosed between 1973 and 1996, were examined using the polymerase chain reaction technique (PCR). RESULTS: In 21 children for whom both cerebrospinal fluid and sera were available, HSV DNA was found in one or both specimens in 19 (90%). Overall, HSV DNA was found in the cerebrospinal fluid of 74% of 27 children, and in the sera of 20 out of 30 children (67%). In two children HSV DNA was not demonstrable in either serum or cerebrospinal fluid. In sequential specimens from four children, the persistence of HSV DNA after the end of intravenous treatment was associated with a poor prognosis. CONCLUSIONS: These findings indicate that HSV DNA detection in CSF and serum is highly sensitive for the diagnosis of neonatal HSV infections but does not replace the detection of virus in other locations using virus isolation and antigen detection.

Acyclovir↗

Effects of proteins, blood cells and glucose on the viscosity of cerebrospinal fluid.

It has long been assumed that cerebrospinal fluid (CSF) is a newtonian fluid with viscosity similar to water, yet high protein content, has been postulated to increase the viscosity of CSF in vivo. Such an increase in viscosity may have serious implications for the effectiveness of surgical shunts implanted to re-establish the CSF flow in cases of abnormal CSF circulation. In this study, glucose content, total protein content and blood cell count in the CSF of 23 patients undergoing brain surgery were measured. Viscosity measurements were performed on duplicate CSF samples over a range of shear strain rates of 25-1,460 s-1. The results indicated that high protein or high cell concentration in CSF does not significantly affect the viscosity of the cerebral fluid at those shear rates. CSF is clearly newtonian, and its viscosity at 37 degreesC is in the range of 0.7-1 mPa.s.

Adolescent↗

Cerebrospinal fluid beta-endorphin and cortisol study in Rett syndrome.

An evaluation of cerebrospinal fluid and plasma beta-endorphin and cortisol levels was performed in 15 girls affected with classic Rett syndrome. There were no differences between the patient group and the control group in plasma cortisol and beta-endorphin levels. But in Rett syndrome, a significant increase in beta-endorphin was noted in the cerebrospinal fluid, with an elevation of the cerebrospinal fluid/plasma beta-endorphin ratio and a decrease in cerebrospinal fluid cortisol. A substantial overlap between patients and control group diminishes the diagnostic value of cerebrospinal fluid beta-endorphin assay in girls suspected of having Rett syndrome.

Adolescent↗

Analysis of cartilage-derived retinoic acid-sensitive protein in cerebrospinal fluid From patients With spinal diseases.

STUDY DESIGN: The expression of cartilage-derived retinoic acid-sensitive protein (CD-RAP) was measured in cerebrospinal fluid from patients with spinal diseases. OBJECTIVES: To quantify the levels of CD-RAP in human cerebrospinal fluid and to clarify its character. SUMMARY OF BACKGROUND DATA: Cartilage-derived retinoic acid-sensitive protein is a newly discovered, secreted molecule that is expressed during the chondrogenesis phase of endochondral bone formation and in articular cartilage. In recent studies CD-RAP has been detected in the serum of patients with melanoma and breast cancer, and it has been used to monitor tumor activity. However, the function of CD-RAP is unknown, and the expression of CD-RAP in human cerebrospinal fluid has never been reported. METHODS: The concentration of CD-RAP in human cerebrospinal fluid was measured by enzyme-linked immunosorbent assay with antihuman CD-RAP antibodies. Cerebrospinal fluid samples were collected from two groups of patients. Group 1, the control group, consisted of 40 patients: 22 with trauma and 18 with gynecologic diseases. Group 2 consisted of 172 patients with spinal diseases: 5 with meningioma, 5 with neurinoma, 5 with arachnoid cyst, 30 with cervical spondylotic myelopathy, 35 with lumbar disc herniation, 56 with lumbar canal stenosis, and 36 with scoliosis. RESULTS: The concentration of CD-RAP in the control group was 16.5 +/- 8.3 ng/mL. The concentrations of CD-RAP in Group 2 were: 35.3 +/- 14.7 ng/mL in meningioma, 23.5 +/- 7.41 ng/mL in neurinoma, 26.0 +/- 22.2 ng/mL in arachnoid cyst, 41.7 +/- 22.3 ng/mL in cervical myelopathy, 27.8 +/- 14.7 ng/mL in lumbar disc herniation, 36.5 +/- 18.4 ng/mL in lumbar canal stenosis, and 13.4 +/- 7.48 ng/mL in scoliosis. The concentrations of CD-RAP in cervical myelopathy, lumbar canal stenosis, and lumbar disc herniation were significantly higher than in the control group (P < 0.001). CONCLUSIONS: The CD-RAP concentration was low in the control group, whereas it was significantly higher in spinal diseases that cause spinal stenosis. CD-RAP is expressed in cerebrospinal fluid as a result of damage to or stressing of neural structures and could be a marker for spinal diseases.

Adolescent↗

Molecular characterization of immunoreactivities of peptides derived from chromogranin A (GE-25) and from secretogranin II (secretoneurin) in human and bovine cerebrospinal fluid.

Chromogranin A and secretogranin II are members of the so-called chromogranins, the acidic proteins stored in neuroendocrine large dense-core vesicles. We characterized chromogranin A and secretogranin II immunoreactivities in cerebrospinal fluid by radioimmunoassays using synthetic peptides derived from these components (GE-25 for chromogranin A and secretoneurin for secretogranin II). In lumbar cerebrospinal fluid, high levels (more than 1000 fmol/ml) of these two components were found, whereas in ventricular cerebrospinal fluid the secretoneurin levels were relatively low. The cerebrospinal fluid/serum ratio for secretoneurin was close to 170. High-performance liquid chromatography revealed that in both cerebrospinal fluid and extracts from human brain secretoneurin was the predominant immunoreactive component. In cerebrospinal fluid chromogranin A immunoreactivity was present as intermediate-sized peptides with little intact chromogranin A and free GE-25 peptide. In human brain samples smaller peptides including GE-25 were more predominant. Analogous findings for secretoneurin and chromogranin A were obtained for bovine brain samples. We can conclude that chromogranins are present in cerebrospinal fluid in concentrations much higher than those of classical neuropeptides also stored in large dense-core vesicles. Therefore, their degree of proteolytic processing can be analysed with small samples of cerebrospinal fluid. A possible disturbance of proteolytic processing in large dense-core vesicles in various pathological conditions can now be discovered.

Adult↗

Radiology of cerebrospinal fluid rhinorrhea.

Fifty-one patients with cerebrospinal fluid rhinorrhea were evaluated at the Mayo Clinic from 1974 to 1977. The causes of the leak were fairly even distributed among postoperative, traumatic unrelated to previous surgery, and nontraumatic. The slightly fewer patients with a traumatic cause compared with those reported in most series reflects the referral patterns and surgical nature of the practice at the institution. Three-fourths of the patients had plain films of the skull, although the site of the leak was identified in only 21% of them. Two-thirds of the patients had tomography, which was helpful in 53%, especially in 10 of the 13 patients with traumatic nonpostoperative cerebrospinal fluid rhinorrhea. Posteroanterior tomography generally was more helpful than lateral tomography, except in leaks around the frontal sinuses. Radioisotope cisternography with intranasal pledgets helped localize the site of leak in 50% of patients and suggested the site of the leak in 25%. Radioisotope cisternography with pledgets often gave helpful positive results when the plain films and tomography were not helpful.

Adolescent↗

The 14-3-3 cerebrospinal fluid immunoassay lacks utility in the diagnosis of clinical scrapie.

This study determined whether the immunoassay for cerebrospinal fluid 14-3-3 protein concentration was sensitive and specific in the diagnosis of naturally occurring clinical scrapie in sheep. Cerebrospinal fluid was collected from 9 sheep with the confirmed diagnosis of scrapie. Additionally, cerebrospinal fluid was collected from 13 clinically normal sheep, which originated from a closely monitored flock with no history of scrapie. Sensitivity and specificity were calculated using standard epidemiological methods. Cerebrospinal fluid immunoassay results did not differ significantly between positive and negative sheep. Test sensitivity varied from 0.55 to 0.66, depending on the choice of test endpoint. Test specificity varied from 0.30 to 0.77, depending on the choice of test endpoint. The 14-3-3 cerebrospinal fluid immunoassay appears to have no value in the diagnosis of clinical scrapie in sheep.

14-3-3 Proteins↗

Cerebrospinal fluid analysis in human immunodeficiency virus infection.

Cerebrospinal fluid (CSF) analytes were evaluated in 59 human immunodeficiency virus (HIV+) individuals to assess neurological involvement. Glucose, total protein, cell counts, p24 antigen, CSF: serum albumin/IgG ratios, and oligoclonal bands were measured. Eighty percent of samples showed abnormalities in one or more analyte. In some patients samples, these abnormalities could mimic those of secondary opportunistic infection when none was present. The presence of oligoclonal banding in CSF (31 percent) and disturbances in CSF: serum albumin/IgG ratio (30 percent) were related to decreases in serum CD4+ lymphocytes. Disturbances in CSF: Serum albumin/IgG ratio were also related to severity of non-neurological HIV disease staging. Cerebrospinal fluid oligoclonal bands were distinct from that found in serum in the same subjects. Since immune complexes between immunoglobulins and enzymes are observed in these same patients, these oligoclonal bands may result in artifactually elevated enzyme results secondary to decreased clearance leading to erroneous clinical decisions. There was no significant relationship between any abnormalities and the presence of neurologic disease as established by a wide variety of other studies. It is important to recognize the limits of CSF interpretation in this patient group.

AIDS-Related Complex↗

Vasopressin enhances the clearance of beta-endorphin immunoreactivity from rat cerebrospinal fluid.

The effect of intracerebroventricular (lateral ventricle) administration of arginine8-vasopressin (AVP) on the concentration of beta-endorphin immunoreactivity in the cerebrospinal fluid obtained from the cisterna magna was studied in rats. A decrease was observed 5 min following injection of 0.9 fmol AVP. No statistically significant changes were found 5 min after intracerebroventricular treatment of rats with 0.09 or 9 fmol. The decrease induced by 0.9 fmol AVP was of short duration and was found 5 min after treatment but not 10 and 20 min. Desglycinamide9-AVP (0.97 fmol), [pGlu4, Cyt6]-AVP-(4-9) (1.44 fmol), N alpha-acetyl-AVP (0.88 fmol), lysine8-vasopressin (0.94 fmol) and oxytocin (1 fmol) when intracerebroventricularly injected did not affect the levels of beta-endorphin immunoreactivity in the cerebrospinal fluid 5 min later. This suggests that the intact AVP-(1-9) molecule is required for this effect. Intracerebroventricular pretreatment of rats with the vasopressin V1-receptor antagonist d(CH2)5Tyr(Me)AVP (8.63 fmol) completely blocked the effect of AVP (0.9 fmol). In order to investigate further the underlying mechanism, the effect of AVP on the disappearance from the cerebrospinal fluid of exogenously applied beta-endorphin was determined. Following intracerebroventricular injection of 1.46 pmol camel beta-endorphin-(1-31), the beta-endorphin immunoreactivity levels in the cisternal cerebrospinal fluid increased rapidly, and reached peak values at 10 min. The disappearance of beta-endorphin immunoreactivity from the cerebrospinal fluid then followed a biphasic pattern with calculated half-lives of 28 and 131 min for the initial and the terminal phase, respectively. Treatment of rats with AVP (0.9 fmol; icv) during either phase (10, 30, 55 min following intracerebroventricular administration of 1.46 pmol beta-endorphin-(1-31)) significantly enhanced the disappearance of beta-endorphin immunoreactivity from the cerebrospinal fluid. The data suggest that vasopressin plays a role in the regulation of beta-endorphin levels in the cerebrospinal fluid by modulating clearance mechanisms via V1-receptors in the brain.

Animals↗

Relationship of senescence of cerebrospinal fluid circulatory system to dementias of the aged.

In common with other organ systems, the cerebrospinal fluid circulatory system is subject to senescence. Cerebrospinal fluid production and turnover rates decline. The choroid plexus calcifies and its blood supply falters. Microvascular disease violates the integrity of the blood-brain barrier. The arachnoid membranes thicken. Arachnoid villi occlude and degenerate. The consequent functional losses are exacerbated by the deterioration of other interacting organ systems. Eventually, the cerebrospinal fluid circulatory system may fail, resulting in stagnation, contamination, compositional deficiencies, and impaired clearance of noxious substances. The hypothesis is that senescence of the cerebrospinal fluid circulatory system plays a part in some dementias of the aged.

Aged↗

An enzyme immunoassay for the quantitation of IgG in serum and cerebrospinal fluid.

An enzyme immunoassay for the determination of IgG in serum and cerebrospinal fluid was devised and evaluated to see if it performed to clinically acceptable standards. For normal levels of IgG in serum and cerebrospinal fluid the between day coefficient of variation was less than 13%. Using patient material, this new assay was compared with radial immunodiffusion; in 68 sera there was a correlation coefficient of 0.939 and in 49 cerebrospinal fluid specimens, it was 0.825. The assay range for the enzyme immunoassay was wider than that in radial immunodiffusion; the enzyme immunoassay showed greater sensitivity in that the lowest IgG value determined was 1.0 mg/l in a cerebrospinal fluid sample. No linearity aberration or matrix effects were observed. There was no appreciable interference, under the assay conditions, from immunoglobulins A or M, kappa or lambda light chains, or human serum albumin. Recoveries were about 100% over the whole assay range. The procedure has proven to be simple and relatively rapid. Assay results are available within 5 h. The reagents are stable for more than 6 months.

Horseradish Peroxidase↗

Apolipoproteins in human cerebrospinal fluid.

The presence of apolipoproteins A-I, E, C-II, and C-III and the absence of apolipoprotein B was demonstrated in human cerebrospinal fluid. The concentration of apolipoproteins was measured by electroimmunoassay. Apolipoproteins E, C-II, and C-III were present in cerebrospinal fluid at 3--5% of their concentration in plasma; the cerebrospinal fluid level of apolipoprotein A-I was 0.4%. Most of the cerebrospinal fluid apolipoproteins were present in the rho less than 1.21 g/ml lipoprotein fraction. The major apolipoporteins of cerebrospinal fluid are E and A-I. The possible mechanism of transfer and the physiological and pathophysiological role of apolipoproteins in cerebrospinal fluid are postulated.

Apolipoproteins↗

Cerebrospinal fluid alterations in bacterial meningitis.

239 matched cerebrospinal fluid and serum samples of 50 patients with bacterial meningitis were investigated during the course of the disease. Special attention was drawn to thecal immunoglobulin (Ig) production, which was determined by Link's index and by Reiber's formula with a modification for IgM and IgA being more sensitive for these two Igs than Link's index. A correlation was found between the duration of local IgM production and the outcome of the disease.

Bacterial Infections↗

Pharmacokinetics and cerebrospinal fluid (CSF) concentrations of vancomycin in pediatric patients undergoing CSF shunt placement.

Staphylococcus epidermidis has been established as the common pathogen causing cerebrospinal fluid shunt infections. In addition, clinical isolates of S. epidermidis from infected shunts are typically resistant to methicillin. Vancomycin is often used for neurosurgical prophylaxis due to its excellent in vitro activity against methicillin-resistant staphylococci. Limited data are available about the pharmacokinetics and cerebrospinal fluid concentrations of vancomycin in pediatric patients intraoperatively. The objectives of this study were to characterize the pharmacokinetics and determine the cerebrospinal fluid concentrations of vancomycin. Eight patients (mean age 8.3 +/- 7.0 years) received three doses of intravenous vancomycin, 15 mg/kg every 6 h. The first dose was administered 1 h prior to surgery. Blood samples were collected at 0, 0.5, 1, 2, 4, and 5 h after the end of the infusion. A cerebrospinal fluid sample was collected at the time of shunt insertion. Urine samples were collected over a 24-hour period. Vancomycin was measured with a fluorescence polarization immunoassay. The peak serum concentrations ranged from 15.6 to 33.7 micrograms/ml; cerebrospinal fluid concentrations ranged from less than 0.6 to 0.8 microgram/ml. The mean total clearance, renal clearance, apparent volume of distribution, and elimination half-life were 0.11 +/- 0.05 l/h/kg, 0.07 +/- 0.02 l/h/kg, 0.54 +/- 0.15 l/kg, and 4.8 +/- 4.0 h, respectively. Approximately 70% of total vancomycin dose was excreted in the urine. A 2- to 5-fold variation in total clearance and a 2.5-fold variability in renal clearance were observed. Low cerebrospinal fluid concentrations of vancomycin were present at the time of shunt insertion in these pediatric patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

Oxytocin, vasopressin, and estrogen-stimulated neurophysin: daily patterns of concentration in cerebrospinal fluid.

The concentrations of oxytocin, arginine vasopressin, and estrogen stimulated neurophysin in cerebrospinal fluid of monkeys showed a daily fluctuation with high concentrations occurring during the light period. The patterns of oxytocin and estrogen-stimulated neurophysin in the cerebrospinal fluid were not observed in the plasma nor were they altered after the administration of a dose of estradiol that increased concentrations of estrogen-stimulated neurophysin in plasma. The disassociation between these cerebrospinal fluid and plasma patterns and values suggests that the secretory activity of neurons that release estrogen-stimulated neurophysin and oxytocin into the cerebrospinal fluid is controlled by mechanisms different from those that control their release into the plasma.

Animals↗

Cerebrospinal fluid circulation, cerebral edema, and intracranial pressure.

Cerebrospinal fluid (CSF) circulation plays an important role in acute and chronic disorders of the central nervous system. Correction of impaired CSF circulation by medical or surgical means carries important risks as well as lifesaving benefits. CSF circulation is intimately associated with intracranial pressure, cerebral edema, cerebral perfusion pressure, and cerebral blood flow. Clinical and experimental aspects of the CSF circulation are examined to provide insight into the often subtle physiological interactions that must be considered when treating patients with altered CSF circulation.

Animals↗