Growth hormone levels in the blood serum and cerebrospinal fluid of patients with multiple sclerosis

In 1984 the authors determined by radioimmunoassay (ORIPI-RIA kit) the serum growth hormone levels in 35 patients with multiple sclerosis (20 M, 15 F) aged from 20 to 54 years, and in 10 cases the determination was carried out in the cerebrospinal fluid (CSF). The control group comprised 40 patients with ischialgia or neuroses. The normal range of GH values in the serum determined with this kit was from 0 to 80 microIU/ml, and the laboratory normal range was from 0 to 10 microIU/ml. The normal GH value for the CSF is being established (calculations based on mean values). No significant differences were observed in the GH concentrations in the serum between the patients and the control group, and between males and females in either group. No significant differences were found also in the GH level in the CSF of males and females with multiple sclerosis. Treatment with corticosteroids received by over 80% of the patients (at least 6 months before the study) caused no significant rise in GH concentration. However, an increasing tendency was observed of GH concentration in patients which requires confirmation in a greater number of cases.     

Prolactin in the blood serum of patients with multiple sclerosis

The authors determined in 1984 by radioimmunoassay (INEP kit) the serum prolactin concentration in 76 multiple sclerosis patients (33 males and 34 females) aged from 21 to 53 years, with disease duration from 2 to 30 years. The control group comprised 110 healthy subjects. Normal prolactin values were 150-750 mIU/ml in females and 150-500 mIU/ml in males. In about one-third of the patients raised prolactin level was found which failed to correlate with the age of the patients and with increased beta-endorphin level in them. The authors suppose that hyperprolactinaemia may be of importance in certain clinical signs of multiple sclerosis. Further investigations on prolactin are conducted with reference to the circadian rhythm of prolactin secretion and dynamic tests.     

Elevated soluble interleukin-2 receptor levels in patients with active multiple sclerosis

The level of soluble interleukin-2 receptor (sIL-2R) was quantitated with enzyme-linked immunosorbent assay in serum and cerebrospinal fluid obtained from 24 patients with multiple sclerosis and 10 patients with other neurological disorders in whom immunological mechanisms are unlikely to participate. The sIL-2R level in the serum and cerebrospinal fluid of patients with multiple sclerosis in relapse was significantly higher compared with patients with multiple sclerosis in remission and with controls. The sIL-2R level, especially in the cerebrospinal fluid, showed higher sensitivity and specificity than other clinical parameters including the cerebrospinal fluid IgG ratio, peripheral lymphocyte CD4/CD8 ratio, cerebrospinal fluid myelin basic protein and oligoclonal bands. Our data suggest that measurement of the sIL-2R level may be useful in evaluating disease activity in patients with multiple sclerosis.     

多发性硬化患者病情演变与血浆和脑脊液趋化因子CXCL10水平的相关性

目的 观察急性期多发性硬化(MS)患者血浆和脑脊液中趋化因子CXCL10水平的动态变化规律及其与临床神经功能障碍的相关性,探讨其对疾病活动性的判定价值.方法 收集急性期MS患者、缓解期MS患者及健康对照各53例,神经系统非炎性疾病(NIND)32例,采用酶联免疫吸附试验法检测血浆和脑脊液中CXCL10水平,并进行扩展残疾状况评分量表(EDSS)评分.结果 (1)与急性期初期相比,急性期MS组患者第2、4周血浆CXCL10水平[(601±365)、(575±297)pg/ml]明显升高(t=-2.898、-2.651,P=0.001、0.003);第4周脑脊液中CXCL10水平[(1807±803)pg/ml]与急性期初期比较差异无统计学意义.(2)急性期初期MS组血浆CXCL10水平明显高于缓解期MS组[(287±118)pg/ml,t=3.555,P=0.001]和健康对照组[(248±130)pg/ml,t=4.895,P=0.000].(3)急性期MS组脑脊液CXCL10水平[(1774±604)pg/ml]明显高于NIND组[(122±114)pg/ml,t=15.192,P=0.000].(4)急性期MS组患者血浆与脑脊液中CXCL10水平间存在相关性(r=0.792,P=0.001);脑脊液CXCL10水平与同期EDSS评分之间存在相关性(r=0.526,P=0.002).结论 (1)MS患者血浆中CXCL10水平对判断疾病活动性有一定的参考价值.(2)急性期MS患者血浆CXCL10水平能在一定程度上反映其在脑脊液中的水平.(3)检测急性期MS患者脑脊液CXCL10水平对判断临床功能障碍程度有一定的参考价值.

Abstract：

Objective To investigate the evolution of CXCL10 in blood plasma and cerebrospinal fluid (CSF) during relapses of multiple sclerosis (MS),and the correlation between these and the clinical neurological dysfunction.Methods Fifty-three patients with definite MS during relapsing state (relapsing MS group) diagnosed by the McDonald criteria;fifty-three patients with definite MS during remitting state ( remitting MS group);thirty-two patients with non-inflammatory neurologic disease ( NIND group) and fiftythree healthy controls (NC group) were enrolled in the study.Each patient clinical status was evaluated with the Expanded Disability Status Scale ( EDSS).Plasma and CSF levels were analyzed by enzyme-linked immunoassay.Results ( 1 ) The CXCL10 level in plasma in relapsing MS group elevated significantly between the 2nd ( (601 ± 365 ) pg/ml,t = - 2.898,P = 0.001) and the 4th ( (575 ± 297 ) pg/ml,t = -2.651,P=0.003) week after relapsing;GXL10 in CSF (n =32) did not changed significantly in the 4th week after relapsing( (1807 ±803) pg/ml).(2) The CXCL10 level in plasma in relapsing MS group were significantly higher than that in the healthy control group ((248±130) pg/ml,(=4.895,P=0.000) and remitting MS group ((287 ±118) pg/ml,t = 3.555,P = 0.001 ).( 3 ) The CXCL10 level in CSF in relapsing MS group (( 1774 ± 604) pg/ml) was significantly higher than that in NIND group ( ( 122 ± 114) pg/ml,t= 15.192,P =0.000).(4) The CXCL10 level in plasma in relapsing MS group had correlation with that in CSF (r=0.792,P=0.001).The CXCL10 level in CSF in relapsing MS group had correlation with EDSS scores (r = 0.526,P = 0.002 ).Conclusions The CXCL10 level in plasma might be implemented as a paraclinical marker of disease activity in MS.The CXCL10 level in plasma of MS may be relevant to that in CSF.The CXCL10 level in CSF of MS may indicate the clinical neurological dysfunction.     

Levels of transforming growth factor alpha (TGF-alpha) in human cerebrospinal fluid.

In this study, we investigated cerebrospinal fluid of patients with various neurological symptoms for the presence of transforming growth factor alpha (TGF-alpha). 41 samples of cerebrospinal fluid were collected by lumbar puncture performed routinely due to the clinical suspicion of neurological disease from 22 females (age 15-80 years, median 42 years) and from 19 males (age 18-82 years, median 48 years). A highly sensitive and specific radioimmunoassay was used to determine the concentration of TGF-alpha in the samples. The detection limit of the assay was about 200 pg TGF-alpha. There was no cross-reactivity to human EGF. We showed CSF indeed does contain TGFalpha. As TGF-alpha was detected in all 41 samples investigated, this growth factor appears to be a constant component of CSF. The mean concentration was 5.5 ng TGF-alpha (S.D. +/- 2.7 pg/ml, range 1.1 to 13.9 pg/ml). There was no significant correlation between TGF-alpha concentration in CSF and age (r = -0.006) and there was no significant difference between females (mean 5.8+/-3.10 pg/ml) and males (mean 5.2+/-1.96 pg/ml). No diagnosis was over represented in patients with TGF-alpha concentrations above or below 1 S.D. off the mean. However, highest concentrations of TGF-alpha were found in the group of patients with peripheral neurological sensory dysfunctions and polyneuropathy. We conclude that TGF-alpha is not only a constant component of human cerebrospinal fluid in adults but could also be significantly involved in the pathophysiology of various neurological diseases. The earlier hypothesis that TGF-alpha could mainly have a role in brain development needs hence to be re-evaluated.     

情感性精神障碍病人ACTH增高对睾酮的作用

目的本研究通过观察情感性精神障碍发作入院病人血清总睾酮（TES）,皮质醇（COR）,与血浆促肾上腺皮质激素（ACTH）升高的关系,探讨情感性精神障碍患者HPA轴的改变对性腺激素水平的作用。方法应用化学发光免疫分析法,检测急性发作入院的男性情感性精神障碍病人（80例）和精神分裂症患者（75例）血浆ACTH及血清TES、COR水平。结果情感性精神障碍病人和精神分裂症病人血浆ACTH水平均显著高于正常对照组（47士29）pg／mlvs（19±11）pg／ml（P〈0．01）,（54±33）pg／mlvs（19±11）pg／ml,P〈0．01,而血清TES和COR与对照组比较无统计学意义;以ACTH≥50pg／ml为增高组,以ACTH（50pg／ml为正常组分组,ACTH异常的情感性精神障碍病人血清TES浓度均显著高于ACTH正常的情感性精神障碍患者和对照组（623±233）mg／dlvs（412±274）mg／dl,P〈0．01,（623±233）mg／dlvs（469±171）mg／dl,（P〈0．01）,血清COR浓度亦高于ACTH正常的情感性障碍患者和对照组（19．8±5．]）μg／dlvs（16．2±6．5）μg／dl,P〈0．01,（19．8±5．1）pg／dlvs（17．4±5．2）μg／dl vs,P〈0．05）,ACTH的升高与TES、COR呈正相关（r=0．495,P〈0．01,r=0．345,P〈0．01）。结论情感性精神障碍病人ACTH增加,导致COR、TES的异常分泌,HPA轴的激活,可以引起性腺激素的分泌增加。进一步研究ACTH变化的内在规律,将对揭示情感障碍的发病机制有重要作用。     

Cerebrospinal fluid atrial natriuretic factor in intracranial disease

We tested the hypothesis that the concentration of atrial natriuretic factor in the cerebrospinal fluid is an indicator of brain injury in patients with intracranial disease. Atrial natriuretic factor concentration was measured in 72 samples of cerebrospinal fluid from 28 patients with intraventricular drains and in nine samples from outpatient controls undergoing diagnostic lumbar puncture. Levels were correlated with diagnosis; systemic fluid administration; concentration of atrial natriuretic factor in the plasma; intracranial pressure; sodium, glucose, and protein concentrations, osmolality, and cell count in the cerebrospinal fluid; sodium concentration in the serum; and hemodynamics. Atrial natriuretic factor concentration was highest in cerebrospinal fluid from patients with intracerebral hematoma, followed by those with obstructive hydrocephalus and subarachnoid hemorrhage (19 +/- 2, 13 +/- 3, and 8 +/- 2 pg/ml, respectively); atrial natriuretic factor concentration was less than 4 pg/ml in the controls. Patients treated with fluid restriction had significantly higher atrial natriuretic factor levels than those receiving maintenance or high-volume fluids (16 +/- 3, 8 +/- 2, 10 +/- 1 pg/ml, respectively). The concentration of atrial natriuretic factor in the plasma was significantly elevated in patients with intracerebral hematoma and subarachnoid hemorrhage (155 +/- 38 and 92 +/- 20 pg/ml, respectively) and did not correlate with fluid administration or the concentration of atrial natriuretic factor in the cerebrospinal fluid. Neither cerebrospinal fluid nor plasma concentrations of atrial natriuretic factor correlated with intracranial pressure; cerebrospinal fluid sodium, glucose, or protein concentrations, osmolality, or cell count; serum sodium concentration; or hemodynamics. We conclude that the concentration of atrial natriuretic factor in the cerebrospinal fluid is a nonspecific indicator of brain injury.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cerebrospinal fluid vasopressin and increased intracranial pressure

Cerebrospinal fluid and plasma vasopressin were measured in patients with cerebral disorders associated with varying levels of elevated intracranial pressure. The mean cerebrospinal fluid vasopressin concentration was significantly increased in patients with pseudotumor cerebri (2.0 +/- 0.2 [SEM] pg/ml), intracranial tumor (2.3 +/- 0.4 pg/ml), and intracranial hemorrhage (1.9 +/- 0.3 pg/ml) compared with control patients (1.2 +/- 0.1 pg/ml). A significant relationship was found between intracranial pressure and the cerebrospinal fluid vasopressin concentration within all groups of patients and in the whole sample as well (r = 0.79; p less than 0.001). In the groups of patients with intracranial tumor, hydrocephalus, and intracranial hemorrhage, some individuals showed plasma vasopressin concentrations inappropriate to the corresponding plasma osmolality, but no relationship was found between intracranial pressure and plasma vasopressin concentration. It is suggested that increased intracranial pressure is a stimulus to centrally released vasopressin. The clinical importance of increased cerebrospinal fluid vasopressin concentrations is still not known.     

Reduced lumbar cerebrospinal fluid corticotropin releasing factor (CRF) levels in amyotrophic lateral sclerosis

Corticotropin-releasing factor (CRF) is widely distributed within the brain and spinal cord and may have direct extrahypophysiotrophic effects, independent of its pituitary action. The CRF level was measured using, the RIA method in cerebrospinal fluid (CSF) from 5 patients with amyotrophic lateral sclerosis (ALS), and in CSF from 10 patients with discopathy, treated as a controlled group. The median values of CRF level in the patients with ALS was 27.5 pg/ml, and this value was significantly lower than in controls, 53.5 pg/ml (P less than 0.05). These results suggests that CRF may be related in the pathophysiology of ALS.     

Levels of transforming growth factor alpha (TGF-a)in human cerebrospinal fluid

In this study, we investigated cerebrospinal fluid of patients with various neurologicalsymptoms for the presence of transforming growth factor alpha (TGF-a). 41 samples ofcerebrospinal fluid were collected by lumbar puncture performed routinely due to the clinicalsuspicion of neurological disease from 22 females (age 15–80 years, median 42 years) and from19 males (age 18–82 years, median 48 years). A highly sensitive and specific radioimmunoassaywas used to determine the concentration of TGF-a in the samples. The detection limit of the assaywas about 200 pg TGF-a. There was no cross-reactivity to human EGF. We showed CSF indeeddoes contain TGFa. As TGF-a was detected in all 41 samples investigated, this growth factorappears to be a constant component of CSF. The mean concentration was 5.5 ng TGF-a (S.D.±2.7 pg/ml, range 1.1 to 13.9 pg/ml). There was no significant correlation between TGF-aconcentration in CSF and age (r=−0.006) and there was no significant differencebetween females (mean 5.8±3.10 pg/ml) and males (mean 5.2±1.96 pg/ml). No diagnosis wasover represented in patients with TGF-a concentrations above or below 1 S. D. off the mean.However, highest concentrations of TGF-a were found in the group of patients with peripheralneurological sensory dysfunctions and polyneuropathy. We conclude that TGF-a is not only aconstant component of human cerebrospinal fluid in adults but could also be significantly involvedin the pathophysiology of various neurological diseases. The earlier hypothesis that TGF-a couldmainly have a role in brain development needs hence to be re-evaluated.     

Concentration of epidermal growth factor in the cerebrospinal fluid of patients with amyotrophic lateral sclerosis

In 15 patients with SLA and 15 with discopathy regarded as a control group the level of epidermal growth factor (EGF) was determined by radioreceptor assay in the serum and cerebrospinal fluid. The EFG level in the serum could not be determined by this method. In the CSF of SLA patients this level was 587.6 +/- 257.7 pg/ml and was significantly lower in relation to the control group in which it was 990.9 +/- 297.5 pg/ml. The authors discuss in this connection the role of EGF in SLA pathogenesis.     

Immunoreactive leukotriene C4 levels in CSF of MS patients

Using a sensitive and specific radioimmunoassay levels of leukotriene (LT)C4-like material were estimated in lumbar cerebrospinal fluid (CSF) samples from patients with multiple sclerosis (MS) in comparison to control patients with or without inflammatory processes in the central nervous system (CNS). Levels of LTC4-like material were significantly elevated (p less than 0.01) in CSF from patients with inflammatory diseases such as meningitis, polyradiculitis or meningoencephalitis (57 +/- 53 pg/ml, n = 16) as compared to those from control patients without inflammatory or immunological CNS diseases (21 +/- 16 pg/ml, n = 42). By contrast, LTC4-like material was 16 +/- 7 pg/ml in first manifestations of MS (n = 7). 21 +/- 16 pg/ml in remitting-relapsing MS (n = 15) and 10 +/- 6 pg/ml in chronic progressive MS (n = 8). These results argue against a significant pathophysiological role of cysteinyl-LT in MS.     

Low somatostatin content in cerebrospinal fluid in multiple sclerosis

In 27 patients with multiple sclerosis (MS), and in 10 control subjects of comparable age, percent ideal body weight and sex ratio, the cerebrospinal fluid (CSF) content of somatostatin was measured by radioimmunoassay.
The results showed that the group of patients in relapse (n = 16) had significantly lower somatostatin content in CSF (95 ± 4.1 (SEM) pg/ml) than both the control group (142 ± 8.4 pg/ml) and the group of MS patients (n =11), who had been in a clinical stable phase for more than 6 months (131 ± 3.2 pg/ml). Duration of the disease and degree of neurological impairment were apparently without relation to the reduction of somatostatin content in the CSF. There was no relationship between CSF content of somatostatin and the content of total protein or IgG, neither of which showed any relationship to the activity of the disease.     

Human cerebrospinal fluid somatostatin in neurologic disease

Concentrations of somatostatin-like immunoreactivity (SLI) were examined in human cerebrospinal fluid (CSF). To validate the assay it was shown that CSF which had been run over a somatostatin immunoaffinity column showed no interference with binding of synthetic standards. Reversed phase HPLC showed that the immunoreactive material coeluted with SS14 and SS28 as well as a higher molecular weight precursor. Concentrations of human CSF SLI were stable at both room temperature and 4 degrees C for up to 72 h while repeated freezing and thawing resulted in a significant loss of immunoreactive material after the 3rd repetition. In normal control patients less than 55 years of age, CSF SLI was 54.7 +/- 1.9 pg/ml, while in those older than 55 CSF SLI was 56.2 +/- 2.2 pg/ml. Febrile infants had significantly higher levels (75.4 +/- 7.3) pg/ml. CSF SLI was normal in patients with aseptic meningitis (54.4 +/- 3.4 pg/ml), suggesting that increased CSF protein and white cell counts do not affect concentrations. Concentrations of CSF SLI were significantly increased in intervertebral disc disease (65.1 +/- 5.6 pg/ml), intrinsic spinal cord pathology (101.0 +/- 23.9 pg/ml), central nervous system tumors (78.0 +/- 7.8 pg/ml) and acute cortical damage of varied etiology (277.8 +/- 81.6 pg/ml). Patients with pseudotumor cerebri had concentrations of 43.2 +/- 2.5 pg/ml. Concentrations of CSF SLI were significantly reduced (P less than 0.01) in multiple sclerosis (38.8 +/- 5.5 pg/ml) and old cortical pathology (23.2 +/- 3.9 pg/ml). Serial CSF analysis in patients with acute CNS lesions, suggest that CSF SLI may be a neurochemical marker of acute pathology, as the initially elevated levels fell to or below normal with resolution of the pathologic process.     

Apoptosis in neurones exposed to cerebrospinal fluid from patients with multiple sclerosis or acute polyradiculoneuropathy.

Primary cultures of murine cerebellar granule neurones were exposed to cerebrospinal fluid from patients with subtypes of multiple sclerosis or acute polyradiculoneuropathy (Guillain-Barré syndrome) for 2 days. Cells were then stained with Hoechst 33342 or terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling (TUNEL) to detect apoptotic bodies. The results were compared with control cultures exposed to cerebrospinal fluid from patients with no known neurological disease or deficit. There was no significant difference in the level of apoptosis induced between these controls and cultures not exposed to cerebrospinal fluid at all. Cultures exposed to cerebrospinal fluid samples from patients with relapsing-remitting multiple sclerosis did not have higher levels of apoptosis than cells exposed to controls, regardless of whether the sample was taken during relapse or remission. However, a significant increase in apoptosis was observed in cultures exposed to cerebrospinal fluid from patients with primary progressive multiple sclerosis, and apoptosis correlated with disease severity. This supports the existence of biochemical differences between subgroups of multiple sclerosis. A significant increase in apoptosis was also induced by cerebrospinal fluid samples from patients with acute polyradiculoneuropathy, suggesting the presence of neurotoxic factor(s) here also. The relevance to disease pathology is unclear.     

Effect of ACTH therapy on IgG synthesis in cerebrospinal fluid spaces in patients with disseminated sclerosis

In 33 cases of multiple sclerosis treated with ACTH (2500 u during 40 days) IgG and albumins were determined in the serum and cerebrospinal fluid by Mancini's method. These determinations served for calculation of the IgG: albumin ration and IgG index. After the treatment a significant reduction was found of the serum level of IgG and IgG index, without significant changes in albumin concentration. The effect of ACTH therapy on IgG synthesis within the CSF spaces was not significant in the whole group. In the subgroup of patients with initially demonstrated IgG synthesis within the CSF spaces (before the treatment) a significant decrease was found of the IgG index and a non-significant decrease of the absolute IgG level in the CSF. A comparison of the results with our previous investigations shows that ACTH, despite its positive effect on multiple sclerosis exacerbations exerts a much weaker effect on the local IgG synthesis in the central nervous system than high doses of prednisone, despite an evident reduction of serum IgG level by ACTH.     

Lipoprotein lipase in the blood and cerebrospinal fluid of patients with multiple sclerosis

The authors determined the activity of lipoprotein lipase in the blood and cerebrospinal fluid in 25 patients with exacerbation of multiple sclerosis and in 20 controls. A significant decrease in the activity of the enzyme was found in blood of the patients, while only trace activity was detected in the cerebrospinal fluid in both groups. The significant decrease of lipoprotein lipase activity in blood of patients the with multiple sclerosis requires further investigations.     

Interleukin-12 and interferon-gamma are not detectable in the cerebrospinal fluid of patients with amyotrophic lateral sclerosis.

The cause of sporadic amyotrophic lateral sclerosis (SALS) is unknown. We investigated the immune-mediated inflammatory hypothesis of SALS by assaying interleukin-12 (IL-12), interleukin-6 (IL-6) and interferon-gamma (IFN-gamma) in the cerebrospinal fluid (CSF) of patients with SALS. These cytokines were measured in the CSF from patients with SALS (n=11), patients with immune-mediated inflammatory central nervous system or nerve root disorders (n=12), and patients with other neurological diseases (n=15) by high sensitivity sandwich enzyme linked immunosorbent assay (ELISA). All samples were below the assay detection limits of 0.5 pg/ml for IL-12 and 8 pg/ml for IFN-gamma. There was no difference between the groups in the mean concentration of IL-6. There is no evidence in cerebrospinal fluid for induction of a T(H)1 immune response in SALS.     

Cerebrospinal fluid neuropeptide Y in Alzheimer's disease

The cerebrospinal fluid neuropeptide Y level was measured by radioimmunoassay in 20 patients with probable Alzheimer's disease and in 19 controls. The mean level was lower in patients (69.5 +/- 36.7 pg/ml) than in controls (103 +/- 21.8 pg/ml; p less than 0.001). Patients with a disease duration of greater than 2 years had cerebrospinal fluid neuropeptide Y levels lower than those with shorter disease duration (p less than 0.02). These results suggest that neuropeptide Y containing cells may be involved in Alzheimer's disease. No correlation was found between neuropeptide Y levels and degree of cognitive impairment or age at disease onset.     

The central mechanism of hypothalamic-pituitary-adrenocortical system hyperfunction in depressed patients

While hypercortisolemia is commonly observed in depression, exactly where in the hypothalamic-pituitary-adrenocortical (H-P-A) axis this dysfunction arises remains undefined. In attempting to distinguish between central or peripheral locus of dysfunction, we studied in 12 patients (10 females, two males) with primary major depression and eight age-matched controls (six females, two males) in their adrenal cortisol response to infused adrenocorticotropic hormone (ACTH) (cosyntropin 0.05 microg/kg bodyweight) while endogenous ACTH was suppressed with 1 mg of dexamethasone. Compared with the control group, pre-dexamethasone plasma baseline cortisol level was significantly higher in depressed patients while ACTH level remained normal. Post-dexamethasone responses of both hormones were greatly non-suppressed in the depressed group. Exogenous cosyntropin-elicited rise in plasma cortisol was significantly lower in depressed patients while the ACTH response was not significantly different. These findings suggest that an adrenal cortisol response to ACTH was significantly decreased during depression as compared with normals in Chinese depressed patients. Therefore, the central mechanism of hyperfunctioning H-P-A axis causing hypercortisolemia should be emphasized.