精神分裂症脑脊液细胞产生IL—6的研究

本研究在精神分裂症脑脊液细胞微量培养技术的基础上，应用ＥＬＩＳＡ双抗体夹心法检测了患者脑脊液中及培养的脑脊液细胞细胞产生ＩＬ－６的情况，实验结果表明，精神分裂症患者脑脊液细胞在ＰＨＡ刺激下，产生ＩＬ－６的能力明显增强，且与脑脊液细胞产生ＩｇＧ的功能密切相关。提示增高的ＩＬ－６引起的免疫调节紊乱和促发免疫损伤可能是精神分裂症致病因素之一。     

IL-15 is elevated in serum and cerebrospinal fluid of patients with multiple sclerosis

Interleukin-15 (IL-15) is a novel proinflammatory cytokine having similar biological activities to IL-2 which is implicated in the pathogenesis of multiple sclerosis. It is produced by activated blood monocytes, macrophages and glial cells. There is little information about the involvement of IL-15 in the development of multiple sclerosis (MS). The objective of our study was to measure IL-15 serum and cerebrospinal fluid (CSF) levels in MS patients and to correlate serum and CSF IL-15 concentrations with clinical parameters of the disease. CSF IL-15/Serum IL-15 ratio (c/s IL-15 ratio) was introduced to assess the origin of elevated IL-15 levels. MATERIALS AND METHODS: We measured serum and CSF IL-15 levels in 52 patients with MS and 36 age and gender matched patients with inflammatory (IND) and non-inflammatory neurological diseases (NIND) studied as control groups. IL-15 levels were correlated with clinical parameters as duration, disability, MRI activity and clinical subtypes of the disease. RESULTS: MS patients were found to have significantly higher serum IL-15 levels compared with IND (p=0.00016) and NIND patients (p=0.00045). Elevated levels of IL-15 were also found in CSF samples from MS patients compared with patients with IND (p=0.00034) and NIND (p=0.0003). Among MS subgroups there were no statistically different IL-15 serum and CSF concentrations. No significant correlation of serum and CSF IL-15 concentrations with MRI activity, disability assessed by EDSS score and duration of the disease were also found. C/S IL-15 ratio was found lower in MS patients compared with IND (p=0.01) and not significantly different compared with NIND patients (p=0.14) suggesting that systemic activation might be the source of high CSF IL-15 levels in MS patients. CONCLUSIONS: Our findings suggest a possible role of IL-15 in the immunopathogenetic mechanisms of MS.     

Distribution of growth hormone and thyroid-stimulating hormone in cerebrospinal fluid and pathological compartments of the central nervous system

Human growth hormone (HGH) radio-immunoassay (RIA) was adapted for an accurate measurement of immunoreactive HGH concentrations in the CSF in different cases of hypothalamic-somatotropin dysfunctions.In control subjects (n = 43) mean HGH levels were 0.35 ± 0.03 ng/ml in CSF and 1.95 ± 0.2 ng/ml in plasma with a $\text{CSF}\text{plasma}$ ratio of 17%. The thyroid-stimulating hormone (TSH) RIA gave in controls mean basal levels of 2.65 ± 0.2 μU/ml in CSF and 5.95 ± 0.3 μU/ml in plasma with a $\text{CSF}\text{plasma}$ ratio of 44%. HGH and TSH concentrations in CSF and plasma show a very good correlation; but the regression curves for both hormones are distinctly different and appear specific for each polypeptide hormone.Hypothalamic-somatotropin hyperreactivity was reported in diabetic retinopathy (DR). CSF and plasma HGH concentrations in a group of diabetic patients with progressing retinopathy (n = 27) were not different from those in normal subjects (respectively 0.35 ± 0.05 in CSF and 2.10 ± 0.25 ng/ml in plasma with a $\text{CSF}\text{plasma}$ ratio of 16%). The HGH regression curve obtained in diabetics is similar to that of controls. These data do not substantiate the hypothesis of an HGH hyperreactivity in diabetic retinopathy.In somatotropin hypersecretion (acromegaly) without adenoma suprasellar extension, higher HGH concentrations recorded in CSF than in plasma cannot be attributed to an anatomical break-down of the CSF blood-brain barrier and suggest an active transport process of pituitary hormones to the CNS.HGH and TSH concentrations were measured in the cystic fluid of CNS tumors. In 1 case of a cystic dysembryoma, the HGH and TSH of CF were considerably increased. In gliomas (n = 8) the HGH and TSH cystic fluid concentrations were more elevated (respectively 0.72 ± 0.2 ng/ml and 3.6 ± 0.7 μU/ml) than in the CSF of controls.     

Regulation of brain interleukin-1β (IL-1β) system mRNAs in response to pathophysiological concentrations of IL-1β in the cerebrospinal fluid

Interleukin-1β (IL-1β) is released during pathophysiological processes. IL-1β induces neurological manifestations when administered into the cerebrospinal fluid (CSF) at pathophysiological concentrations detected during central nervous system (CNS) infections and other neurological disorders. In the present study, we investigated the regulation of the IL-1β system in the CNS in response to the chronic intracerebroventricular (icv) microinfusion of IL-1β at estimated pathophysiological concentrations in the CSF. IL-1 receptor type I (IL-1RI), IL-1 receptor antagonist (IL-1Ra), and IL-1β mRNAs were determined by sensitive RNase protection assays in brain target regions for IL-1β (cerebellum, parieto-frontal cortex, hippocampus, and midbrain). The results show that chronic icv microinfusion of IL-1β induced significant anorexia, increased the cerebellar IL-1RI mRNA content, increased IL-1Ra and IL-1β mRNAs levels in the cerebellum > midbrain > cortex > hippocampus, and induced profiles of IL-1RI mRNA, IL-1Ra mRNA, and IL-1β mRNA that were highly intercorrelated. On the other hand, levels of rat glyceraldehyde 3-phosphate dehydrogenase mRNA and 18S rRNA were fairly constant, and heat-inactivated IL-1β had no effect on food intake or on IL-1RI, IL-1Ra, and IL-1β mRNAs levels in any brain region. The data suggest the operation of an IL-1β feedback system (IL-1β/IL-1Ra/IL-1RI) in brain regions. Dysregulation of the CNS IL-1β feedback system may have pathophysiological significance. This may be reflected, for example, in the pathogenicity and severity of neurological diseases, such as CNS infections.     

Increased levels of IL-23 and osteopontin in serum and cerebrospinal fluid of multiple sclerosis patients

Osteopontin (OPN) and interleukin-23 (IL-23) are pro-inflammatory cytokines proposed to play central roles to the development of multiple sclerosis (MS). The aim of this study was to evaluate levels of OPN, IL-23 and other inflammatory cytokines and investigate their relationships in serum and cerebrospinal fluid (CSF) in patients with MS. Fifty one MS patients and 48 patients with non-inflammatory neurological diseases (NIND) were recruited from clinic. The levels of OPN, IL-23, IL-17, IL-6, and tumor necrosis factor-alpha (TNF-alpha) in serum and CSF were determined in each participant. Compared with NIND group, MS patients had significantly elevated levels of OPN, IL-23, IL-17 and TNF-alpha in CSF, and elevated levels of IL-23, IL-17 and TNF-alpha in serum (All P<0.001). In MS patients, OPN and IL-23 were positively correlated with IL-17 (r=0.302, P=0.019; r=0.417, P=0.001, respectively); and IL-23 was positively correlated with EDSS (r=0.329, P=0.019). Both OPN and IL-23 may play pivotal role in development of MS and might be specific markers and therapeutic targets for MS.     

Nonepileptic seizure outcome varies by type of spell and duration of illness

PURPOSE: To determine whether differences in clinical manifestations of psychogenic nonepileptic events are associated with differences in outcome and whether the length of illness before diagnosis correlates with outcome. METHODS: We reviewed ictal videotapes and EEGs in 85 patients diagnosed with exclusively nonepileptic psychogenic seizures during inpatient CCTV-EEG monitoring at the University of Michigan between June 1994 and December 1996. They were classified into groups of similar ictal behaviors. Fifty-seven of these patients were available to respond to a follow-up telephone survey about their condition 2-4 years after discharge. We examined demographics, baseline EEG abnormalities, and outcome of treatment interventions. We also evaluated whether interventions were more likely to succeed if patients were diagnosed early in the course of the illness. RESULTS: We found that the largest groups consisted of patients with motionless unresponsiveness ("catatonic," n = 19) and asynchronous motor movements with impaired responsiveness ("thrashing," n = 19). Infrequent signs included tremor, automatisms, subjective events with amnesia, and intermittent behaviors. There was a higher incidence of baseline EEG abnormalities in the thrashing group (31%) than in the catatonic group (0%). There was a higher incidence of complete remission of spells in the catatonic group (53%) than in the thrashing group (21%). Patients who had a more recent onset of seizures (most often within 1 year) were much more likely to have remission of spells after diagnosis. CONCLUSIONS: Classification of nonepileptic seizures is useful in predicting outcome and may be valuable in further investigation of this complex set of disorders.     

Studies on cyclic AMP in different compartments of cerebrospinal fluid.

Adenosine 3', 5'-monophosphate (cAMP) was measured in the CSF of 42 patients undergoing radiological investigation, neurosurgical procedures, or investigation of hepatic coma. The concentration of cAMP was significantly higher in ventricular CSF than in lumbar CSF. Premedication with pentobarbitone plus promethazine increased cAMP in lumbar CSF. There was no difference in cAMP concentration in lumbar CSF obtained before or after injection of air or after the administration of diazepam during lumbar pneumoencephalography. Lumbar CSF cAMP concentration was significantly increased in patients in hepatic coma. The concentration of cAMP in the lateral ventricle was not affected by general anaesthesia or by the presence of a complete block of the aqueduct of Sylvius. There was no decrease in lumbar CSF cAMP in patients with a complete stenosis of the aqueduct of Sylvius, partial blocks of CSF flow at the cervical level, or a complete block at the lower thoracic level. The concentration of cisternal CSF cAMP was similar to that of lumbar CSF. These results suggest that (1) there is a ventriculolumbar gradient in the concentration of cAMP but of insufficient magnitude to be detected by mixing of lumbar and ventricular CSF during pneumoencephalography, (2) lumbar CSF cAMP concentration is not dependent on brain as a source of this nucleotide; the source of this nucleotide may be largely derived from the spinal cord, (3) premedication may affect the concentration of cAMP in lumbar CSF cAMP, (4) the formation of cAMP is unimpaired in hepatic coma.     

Evaluation of proinflammatory cytokine (TNF-alpha, IL-1beta, IL-6, IFN-gamma) concentrations in serum and cerebrospinal fluid of patients with neuroborreliosis

BACKGROUND AND PURPOSE: Neuroborreliosis is a tick transmitted disease which becomes an increasingly frequent diagnostic and therapeutic problem in physician practice. The purpose of this work was to evaluate the concentration of proinflammatory cytokines: IL-1beta, IL-6, TNF-alpha, IFN-gamma in serum and cerebrospinal fluid of patients with neuroborreliosis. MATERIAL AND METHODS: 20 persons with diagnosed neuroborreliosis and 10 persons as a control group were examined in this study. The examination of serum and cerebrospinal fluid was performed twice, before and after 4-week therapy with antibiotics. The concentration of cytokines was measured by the ELISA method using kits of Bender Medical System and Quantikine RD Systems. RESULTS: The concentration of measured cytokines IL-1beta, IL-6, TNF-alpha and IFN-gamma in serum and cerebrospinal fluid was significantly higher before therapy. After 4-week therapy with antibiotics the concentration of cytokines in cerebrospinal fluid decreased but was still higher than in the control group except for IL-1beta. CONCLUSIONS: The detection of proinflammatory cytokine concentration in serum and cerebrospinal fluid might be helpful as another parameter monitoring the inflammation course and therapy efficacy.     

Detection of interferon-gamma and IL-6 producing cells in cerebrospinal fluid cells in the central nervous system infectious diseases using immunocytochemistry]

To evaluate the relationship between cytokines and cerebrospinal fluid (CSF) cells, we detected interferon (IFN)-gamma and interleukin (IL)-6 producing cells in CSF from the patients with central nervous system (CNS) infectious diseases by immunocytochemistry. Five CSF cell smears from three herpes encephalitis patients, three from a patient with EB virus radiculoneuritis, four from the three patients with purulent meningitis, five from five patients with viral meningitis were obtained during early or subacute stages of diseases. Control CSF cell smears were taken from twenty seven patients with motor neuron disease, Parkinson's disease and spinocerebellar degeneration. Immunocytochemistry using specific polyclonal anti-IFN-gamma and IL-6 sera were used to detect each producing cell. Simultaneously, individual positively immuno-reactive cells were morphologically classified macrophage or lymphocyte. The IFN-gamma positive cells immunostained with specific antibody showed brown-colored deposits within the cytoplasm whereas no deposit was in the nucleus (Fig. 1). These phenotype of IFN-gamma positive cells were considered to be lymphocytes or macrophages. However, IFN-gamma-positive macrophages were predominantly seen at the early stages of herpes simplex encephalitis and purulent meningitis. The percent of IFN-gamma positive cells in total CSF cells obtained from the patients with the CNS infectious diseases was 2.3-38.7 as shown in Table 1. The IL-6 positive cells (Fig. 2) were also found early in the course and in subacute stages in the CNS infectious diseases and ranged from 2.5-50 percent in total CSF cells (Table 1). In contrast neither IFN-gamma- nor IL-6-positive cells were detected in non-inflammatory diseases (Table 1).(ABSTRACT TRUNCATED AT 250 WORDS)     

Interleukin-6 and interleukin-1 receptor antagonist in cerebrospinal fluid from patients with recent tonic-clonic seizures

We have previously reported increased concentrations of interleukin (1L)-6 in CSF from patients with tonic-clonic seizures, where increased cytokine production most likely is a consequence of neuronal epileptic activity associated with seizures. The biological effects of IL-6 are mediated by other cytokines, which are studied here in addition to IL-6. The purpose of this study was to analyze levels of soluble cytokines from plasma and CSF from patients with newly developed tonic-clonic seizures. The concentrations of IL-6, IL-1 receptor antagonist (IL-1RA), IL-1beta, tumor necrosis factor (TNFalpha) and nerve growth factor (NGF) were measured from plasma and CSF from 22 patients with newly developed tonic-clonic seizures within 24 h from the seizure and 18 controls. The mean concentrations of IL-6 were significantly increased in CSF (P<0.001) and plasma (P<0.01) after tonic-clonic seizures, there was some indication of increased concentrations of IL-1RA and no significant change in NGF, IL-1beta or TNFalpha. Our study shows that cytokine network is activated in patients after recent tonic-clonic seizures. We provide evidence of intrathecal production of IL-6 associated with electrical seizure activity.     

IL-10 levels in cerebrospinal fluid and serum of patients with severe traumatic brain injury: relationship to IL-6, TNF-alpha, TGF-beta1 and blood-brain barrier function

Controlling the extent of inflammatory responses following brain injury may be beneficial since posttraumatic intracranial inflammation has been associated with adverse outcome. In order to elucidate the potential role of anti-inflammatory mediators, the production of interleukin-10 (IL-10) was monitored in paired cerebrospinal fluid (CSF) and serum of 28 patients with severe traumatic brain injury (TBI) and compared to control samples. The pattern of IL-10 was analyzed with respect to the patterns of IL-6, tumor necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta1 (TGF-beta1) in both fluids during a time period of up to 22 days. In parallel, the function/dysfunction of the blood-brain barrier (BBB) was monitored using the CSF-/serum-albumin quotient (Q(A)) and compared to intrathecal cytokine levels. Mean IL-10 concentration in CSF was elevated in 26 out of 28 TBI patients (range: 1.3-41.7 pg/ml) compared to controls (cut-off: 1.06 pg/ml), whereas only seven patients had elevated mean IL-10 concentration in serum (range: 5.4-23 pg/ml; cut-off: 5.14 pg/ml). The time course of IL-10 was similar in both fluids, showing a peak during the first days and a second, lower rise in the second week. Intrathecal IL-10 synthesis is hypothesized since CSF-IL-10 levels exceeded serum-IL-10 levels in most of the patients, IL-10-index (CSF/serum-IL-10/QA) was elevated in 23 individuals, and elevation of CSF-IL-10 showed to be independent from severe BBB dysfunction. Neither CSF nor serum IL-10 values correlated with the dysfunction of the BBB. IL-10, IL-6 and TGF-beta1 showed similar patterns in CSF over time, whereas rises of TNF-alpha corresponded to declines of IL-10 levels. Our results suggest that IL-10 is predominantly induced intrathecally after severe TBI where it may downregulate inflammatory events following traumatic brain damage.     

Behavior of children with seizures. Comparison with norms and effect of seizure type.

Scores for 112 children aged 6 to 12 years, with well-controlled seizures and of average or higher IQ, were compared for problem behavior with established norms. As assessed on the Conners' Teacher Rating Scale, the group with seizures was comparable to the normative group on two subscales and superior on two others. In contrast, parents of children in the seizure group rated them as significantly worse on all six subscales of the Revised Behavior Problem Checklist. In a larger group of 133 children with seizures, from which this sample was selected, the relationship of age, sex, and seizure type to behavior problems was examined. Subjects with partial seizures were rated as slightly more aggressive and antisocial than those with generalized seizures. Findings were discussed in regard to differences in perception of behavior by parents and teachers and the possible relevance of seizure type to the expression of behavior problems.     

Substance P in serum and cerebrospinal fluid of depressed patients: no effect of antidepressant treatment

The neuropeptide substance P (SP) and its receptor, the neurokinin receptor-1 (NK-1), have been associated with some aspects of the pathophysiology of depression. There is limited information available about the effects of antidepressant treatment on serum and cerebrospinal fluid (CSF) concentrations of SP. We measured serum levels of SP in 78 depressed patients after a 6-day medication washout period, as well as after 14 and 35 days of antidepressant treatment with either paroxetine or amitriptyline. In 11 patients, SP was determined in CSF both before and after treatment. Eleven healthy male subjects served as controls. Baseline SP concentrations were independent of age, gender and severity of depression. Neither the total group nor subgroups showed significant differences in SP serum concentrations. SP concentrations in CSF did not change significantly in the patients during treatment, but there was a trend for an increase in paroxetine-treated patients. Serum SP concentrations were not related to treatment response or the class of antidepressant administered. Our data do not support the hypothesis that changes in SP levels in serum or CSF are related to antidepressant response.     

Interleukin-6 and its soluble receptor in serum and cerebrospinal fluid after cerebral trauma

Interleukin-6 (IL-6) and its soluble receptor (sIL-6-R) were measured in cerebrospinal fluid (CSF) and serum of 11 severely head injured patients for up to 3 weeks following trauma. IL-6 increased immediately after injury displaying much higher concentrations in CSF than in serum (n = 11). Differently, median levels of sIL-6-R remained in the normal ranges being 10 times higher in serum than in CSF. However, increased amounts over control levels were found in CSF (n = 7) and intrathecal release of sIL-6-R was also suggested (n = 7). Although no correlation with the extent of cerebral lesion or with clinical outcome was evident, elevation of sIL-6-R in CSF supports a pivotal role for IL-6/sIL-6-R complex in the injured brain.     

Vasopressin in the cerebrospinal fluid of febrile children with or without seizures

Immaturity in water and electrolyte balance in the brain has been considered to increase the susceptibility of young animals and children to febrile convulsions (FCs). Arginine-vasopressin (AVP) is involved in the regulation of several centrally mediated events such as modulation of fever and the ease with which water permeates into and out of the brain. To evaluate the possible role of AVP in the control of water balance and susceptibility to convulsions during fever we measured the AVP concentration in the cerebrospinal fluid (CSF) and plasma of febrile children with or without convulsions. The febrile population consisted of 47 children, of whom 29 experienced seizures during fever. Seven children with epileptic symptoms and 18 children without seizures were included as nonfebrile controls. The CSF AVP concentration in febrile children without seizures and in nonfebrile convulsive children was significantly lower (0.60 ± 0.07 pmol / 1, mean ± SEM,P < 0.01 and 0.65 ± 0.19 pmol/l,P < 0.05, respectively) than in nonfebrile children without convulsions (0.83 ± 0.06 pmol/1). However, the levels of CSF AVP were not significantly different in children with FCs (0.71 ± 0.06 pmol/1) compared with other groups. CSF AVP correlated with the CSF osmolality (r = 0.33, P = 0.02). No statistical differences in plasma AVP levels between the groups could be found. The present data provide support for the hypothesis of synchronous regulation of osmolality and AVP concentration in CSF. During fever the concentration of CSF AVP was lower in nonconvulsive children compared with nonfebrile nonconvulsive children. CSF AVP levels were not affected in febrile children by convulsions.