Decreased levels of interleukin-10 and transforming growth factor-beta 2 in cerebrospinal fluid of patients with high grade astrocytoma

OBJECTIVE: Glioma cells can produce anti-inflammatory cytokines such as interleukin-10 (IL-10) and transforming growth factor-beta (TGF-beta) which inhibit T cell and monocyte function. It is unknown if production of these cytokines is limited to the site of tumor or these molecules are also released to cerebrospinal fluid and blood. The goal of our study was to determine if patients with astrocytoma have increased levels of IL-10 and TGF-beta 2 in cerebrospinal fluid (CSF) and serum. METHODS: CSF and serum samples were taken from 16 patients with astrocytoma of grade III or grade IV according to the WHO classification and from 28 age- and gender-matched controls (patients with normal pressure hydrocephalus or with lumbar disk herniation). Cytokine concentrations were measured using ELISA methods. RESULTS AND DISCUSSION: There was no difference in serum levels of IL-10 and TGF-beta 2 between groups. Patients with astrocytoma had decreased levels of IL-10 (0.9 +/- 1.2 versus 3.5 +/- 9.2 pg/ml, p=0.01) and TGF-beta 2 (0.0 +/- 0.0 versus 5.4 +/- 9.4 pg/ml, p=0.05) in CSF compared to controls. Because serum IL-10 and TGF-beta 2 levels are similar in patients with astrocytoma and in controls, these cytokines are probably not directly involved in peripheral monocyte and T cell deactivation.     

Increased plasma levels of 8-iso-PGF2alpha and IL-6 in an elderly population with depression

Oxidative damage and immune-inflammatory activation have been suggested to play a role in depression. The purpose of the study was to investigate possible associations and interactions of these pathophysiological mechanisms in geriatric depression by determining the levels of plasma 8-iso-prostaglandin F(2alpha) (8-iso-PGF(2alpha)) and interleukin-6 (IL-6) in elderly depressed individuals. Subjects over 60 years of age with depression and controls were randomly selected from a population in the community after screening with the Geriatric Depression Scale. Plasma concentrations of 8-iso-PGF2alpha and IL-6 were measured in both groups. Depressed patients had significantly higher mean (+/-S.D.) 8-iso-PGF2alpha levels compared to healthy controls (245.01+/-179.92 pg/ml vs 97.64+/-42.72 pg/ml, respectively). Similarly, the same groups demonstrated significantly elevated IL-6 levels compared with controls (58.73+/-39.90 pg/ml vs 15.41+/-9.27 pg/ml). This study indicates an association between increased levels of plasma 8-iso-PGF2alpha and IL-6 with depressive symptomatology in elderly individuals and indicates the necessity for further investigation, possibly within the framework of an integrated involvement of oxidative damage and inflammation in the pathophysiology of depression in the elderly.     

Studies on concentrations of NA and HVA and activity of DBH in the serum from schizophrenic patients, first-degree relatives and normal subjects.

The serum noradrenaline (NA), homovanillic acid (HVA) and dopamine beta-hydroxylase (DBH) have been examined in neuroleptic-free and -treated patients, healthy first-degree relatives of the patients and normal subjects. Analysis of variance (ANOVA) revealed significant differences in the concentrations of serum NA(F = 2.91, p < 0.05) and HVA (F = 3.58, p < 0.05), and in the activity of serum DBH (F = 2.77, p < 0.05) among the four groups. The serum NA was significantly higher in neuroleptic-free patients (475 +/- 220 pg/ml, n = 18), than in healthy first-degree relatives (343 +/- 189 pg/ml, n = 37, p < 0.05) or in normal subjects (354 +/- 111 pg/ml, n = 17, p < 0.05), and it also was significantly higher in neuroleptic-treated patients (442 +/- 223 pg/ml, n = 58) than in healthy first-degree relatives (p < 0.05) or in normal subjects (p < 0.05). There was a trend towards high serum HVA in neuroleptic-free patients (11.3 +/- 6.3 ng/ml, n = 17) compared with the other three groups. The serum DBH activity was high in neuroleptic-free patients (31.2 +/- 15.6 nmol/min/ml, n = 17), and significantly in comparison with those treated with neuroleptic drugs (21.6 +/- 10.9 nmol/min/ml, n = 56, p < 0.05). There was a significant negative correlation between HVA concentration and DBH activity in the serum from neuroleptic-free patients (r = -0.64, n = 16, p < 0.01), and there appeared to be three subgroups with alterations of serum DBH activity and HVA concentration.(ABSTRACT TRUNCATED AT 250 WORDS)     

Tc1/Tc2 and Th1/Th2 balance in Asian and Western types of multiple sclerosis, HTLV-I-associated myelopathy/tropical spastic paraparesis and hyperIgEaemic myelitis

CD8+ T cells, like CD4+ T cells, can differentiate into at least two subsets with distinct cytokine patterns: Tc1 cells produce Th1-like cytokines and Tc2 cells produce Th2-like cytokines. To clarify the immunopathological roles of Tc1 and Tc2 cells in central nervous system (CNS) inflammation, we examined intracellular cytokines in CD8+ and CD4+ T cells by flow cytometry and analyzed the Tc1/Tc2 balance as well as the Th1/Th2 balance in 80 patients with various CNS inflammatory diseases, including 20 with optico-spinal multiple sclerosis (OS-MS), 21 with conventional MS (C-MS), 22 with human T-lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and 17 with hyperIgEaemic myelitis. Twenty-two healthy subjects were also examined as controls. Patients with OS-MS showed a significantly higher percentage of INF-gamma+IL-4- CD8+ T cells as well as CD4+ T cells and a significantly higher intracellular interferon-gamma (IFN-gamma)/interleukin-4 (IL-4) ratio both in CD8+ and CD4+ T cells throughout the relapse and remission phases than the healthy controls. Furthermore, the patients with OS-MS showed a significantly lower percentage of INF-gamma-IL-4+ CD4+ T cells as well as CD8+ T cells during the relapse phase than the healthy controls. On the other hand, the patients with C-MS showed a significantly higher percentage of IFN-gamma-IL-4+ CD8+ T cells in addition to more IFN-gamma+IL-4- CD4+ T cells during the relapse phase than the healthy controls. The HAM/TSP patients showed a significantly higher percentage of INF-gamma+IL-4- CD8+ T cells and a significantly higher intracellular IFN-gamma/IL-4 ratio in CD8+ T cells than the healthy controls. In contrast, in hyperIgEaemic myelitis, in addition to a significantly lower intracellular IFN-gamma/IL-4 ratio in CD4+ T cells, a tendency toward a lower intracellular IFN-gamma/IL-4 ratio in CD8+ T cells in comparison to the healthy controls was observed. These results clarified for the first time the distinct Tc1/Tc2 balance in each disease condition as follows: Tc1 cell response is predominant in OS-MS and HAM/TSP, while Tc2 cell response is predominant in hyperIgEaemic myelitis and at relapse phase of C-MS. Furthermore, our results suggest that CD8+ T cells play an adjunctive role in disease induction and the clinical course of MS.     

Reduced serum BDNF levels in schizophrenic patients on clozapine or typical antipsychotics

Neurotrophic factors regulate neuronal development and synaptic plasticity, possibly playing a role in the pathophysiology of schizophrenia and other psychiatric disorders. Decreased brain-derived neurotrophic factor (BDNF) levels have been found in brains and in the serum of schizophrenic patients, but results are inconsistent. Also, clozapine may upregulate brain BDNF expression. In the present study, we assessed serum BDNF immunoreactivity in 44 schizophrenic patients (20 on clozapine and 24 on typical antipsychotics) and in 25 healthy volunteers. Serum BDNF levels were measured using an enzyme immunoassay. Healthy controls showed significantly higher levels of BDNF compared to the whole group of schizophrenic patients (p<0.001) as well as to the subgroups on typical antipsychotics and clozapine (p<0.001). Serum BDNF values for controls were 168.8+/-26.3pg/ml, for the clozapine group were 125.4+/-44.5pg/ml and for the group on typicals were 101.3+/-51.6pg/ml. BDNF values from patients on clozapine were non-significantly higher than values from patients on typical antipsychotics (p=0.09). Serum BDNF was strongly and positively correlated with clozapine dose (r=0.643; p=0.002) but not with other demographic characteristics. These results reinforce previous findings of reduced serum BDNF levels in schizophrenic patients and suggest a differential effect of clozapine compared to typical antipsychotics on such levels.     

Th1, Th2 and Th3 cytokine alteration in schizophrenia

BACKGROUND: Several studies have shown that there is an imbalance between T helper 1 (Th1) cytokines and T helper 2 (Th2) cytokines in patients with schizophrenia. The T helper 3 (Th3) cytokine, transforming growth factor beta-1 (TGF-beta1), has been shown to suppress the production of Th1 cytokines. Therefore it is hypothesized that it may play a role in schizophrenia by suppressing overactive Th1 system. METHODS: We recruited 88 schizophrenic patients and 88 matched controls. The basal plasma concentrations of IFN-gamma (Th1), IL-4 (Th2) and TGF-beta1 (Th3) were studied at the time the patients were admitted to the hospital and following 8 weeks of treatment with antipsychotics. RESULTS: The detection rate of plasma IFN-gamma and basal plasma TGF-beta1 level were significantly higher in schizophrenic patients than in controls whereas detection rate of plasma IL-4 was lower in patients. The ratio of Th1/Th2 cytokines (IFN-gamma/IL-4) was higher in schizophrenic patients. Following the neuroleptic treatment, the IFNgamma and TGF-beta1 levels returned to control values, and IL-4 concentration rose above the control value. CONCLUSION: Schizophrenic patients showed higher Th1/Th2 ratio which is attenuated by effective neuroleptic treatment. It is possible that TGF-beta1 plays a role in reducing the activity of Th1 cytokine.     

Soluble CD40 ligand:interleukin-10 ratio predicts in-hospital adverse events in patients with ST-segment elevation myocardial infarction

INTRODUCTION: The balance between pro-inflammatory and anti-inflammatory molecules is likely to modulate the processes that lead to atherogenesis and rapid coronary artery disease progression. We sought to compare the positive predictive values of serum soluble CD40 ligand (sCD40L)/interleukin-10 (IL-10) ratio, versus individual sCD40L, and IL-10 measurements regarding in-hospital events in patients admitted into the hospital with ST-segment elevation myocardial infarction (STEMI). METHODS: We recruited 96 patients with STEMI. sCD40L and IL-10 were measured at hospital admission in every patient. The composite of in-hospital death and heart failure represented the study end-point. Heart failure was defined as Killip class>1. Multivariable logistic regression analysis was performed to identify independent variables related to in-hospital events. RESULTS: Thirty two patients (33%) achieved the study end-point and 64 (67%) had no adverse events during hospital admission. IL-10 levels (pg/ml) were lower (28.2+/-9.8 versus 33.24+/-11.3, p=0.03) and sCD40L levels (pg/ml) higher (156.8+/-54.2 versus 135.4+/-38.70, p=0.02) in patients with events compared to those without events. Significantly higher odd ratios were found for sCD40L/IL-10 ratio (OR=2.10, 95% CI: 1.90 to 2.80, p=0.01) compared to individual sCD40L (OR=1.40, 95% CI: 0.90 to 2.20, p=0.08) and IL-10 (OR=0.70, 95% CI: 0.50 to 0.93, p=0.02) measurements. CONCLUSION: Our study showed that serum ratio of sCD40L/IL-10 is a better independent predictor of in-hospital adverse events than individual sCD40L and IL-10 measurements in patients with STEMI.     

Cerebrospinal fluid neuron-specific enolase: a further marker of Alzheimer's disease?

To investigate whether neuron-specific enolase (NSE) plays a role in dementia, we measured cerebrospinal fluid (CSF) concentrations of NSE, Abeta42 and total protein tau (h-tau) in different dementia patients. We studied 159 patients: 76 with Alzheimer's disease (AD), 35 with mild cognitive impairment (MCI), 28 with frontotemporal dementia (FTD), and 20 with Lewy body disease (LBD). Thirty healthy age-matched subjects were studied as controls. NSE was measured by immunoradiometric assay, Abeta42 and h-tau were dosed by ELISA assay. Mean CSF NSE was significantly higher in AD (15.1+/-9.9 ng/ml) than in controls (8.3+/-3.5 ng/ml, p<0.01), FTD (9.1+/-6.1 ng/ml, p<0.05) and MCI (9.7+/-7.8 ng/ml, p<0.05). Ab42 was significantly lower in AD (413.8+/-163.7 pg/ml) than in MCI (708.4+/-422.1 pg/ml, p<0.001) and controls (914.4+/-277.1 pg/ml, p<0.05); it was also significantly reduced in FTD (497.1+/-221.9 pg/ml) versus MCI (p<0.05) and controls (p<0.001); and in LBD patients (477.1+/-225.7 pg/ml) compared with MCI (p<0.05) and controls (p<0.001). H-tau concentration was significantly higher in AD (607.9+/-372.3 pg/ml, p<0.001) than in MCI (383.8+/-277.9 pg/ml, p<0.05), controls (176.6+/-43.9 pg/ml, p<0.001) and LBD (472.3+/-357.7 pg/ml, p<0.05); it was also increased in FTD (541.76+/-362.8 pg/ml) versus contro s (176.6+/-43.9 pg/ml, p<0.001). Furthermore, NSE was inversely correlated with Ab42 (r=-0.333, p=0<0001) and directly correlated with h-tau (r=0.370, p=0<0001). In conclusion, CSF NSE emerged as a specific indicator of AD and showed the same behaviour as the other accepted markers of AD, being correlated with both biomarkers.     

Serum and CSF levels of MCP-1 and IP-10 in multiple sclerosis patients with acute and stable disease and undergoing immunomodulatory therapies

The two chemokines, monocyte chemoattractant protein (MCP)-1 and gamma-interferon inducible protein (IP)-10, are thought to be involved in the pathogenesis of multiple sclerosis (MS). We measured MCP-1 and IP-10 levels in serum and CSF samples from 38 acute and 25 stable MS patients and from 40 controls. The latter consisted in patients with other inflammatory neurological diseases (OIND) or with non-inflammatory neurological diseases, and healthy controls. CSF MCP-1 levels exceeded those found in serum in all the patients studied as well as in healthy controls. CSF MCP-1 levels were significantly lower in acute MS [468+/-(S.E.M.) 18 pg/ml] than in stable MS (857+/-104 pg/ml). When detectable, serum and CSF IP-10 levels were significantly higher in acute MS (serum 331+/-66 pg/ml; CSF 118+/-16 pg/ml) than in stable MS (serum 69+/-7 pg/ml; CSF 25+/-2 pg/ml). Among OIND patients, those with HIV-1-associated dementia showed high serum and CSF levels of both MCP-1 and IP-10. Those with encephalitis showed high serum and CSF levels of IP-10 and CSF mononuclear pleiocytosis. We also evaluated the effects of 6-methylprednisolone or IFN-beta1a therapy on circulating MCP-1 and IP-10 levels. Neither MCP-1 nor IP-10 post-therapy levels varied significantly from baseline values. Our findings suggest that (a) MCP-1 could be constitutively produced within the brain; (b) MCP-1 and IP-10 CSF levels in acute MS vary significantly from those in stable MS, and these variations are inverse; and (c) current MS therapies do not modify circulating levels of MCP-1 and IP-10.     

Interleukin-6 and interleukin-6 promoter polymorphism (-174) G > C in patients with spontaneous venous thromboembolism

Increased levels of interleukin-6 (IL-6) have been reported in patients with a history of venous thromboembolism (VTE); however, prospective studies did not confirm an association between inflammatory markers that are highly correlated with IL-6 and the risk ofVTE. It was the aim of our study to investigate the association of IL-6 and its promoter polymorphism (-174) G > C with the risk of spontaneousVTE. IL-6 was measured in 128 patients with deep venous thrombosis (DVT,70 w/58 m),105 with pulmonary embolism (PE, 58 w/47 m) and 122 healthy controls (60 w/62 m) with a highly sensitive ELISA (Quantikine HS Human IL-6 Immunoassay, RnDSystems). The promoter polymorphism was determined by genotyping, allele specific PCR was followed by high resolution gel-electrophoresis. Median concentrations [interquartile ranges] were 2.37 [1.51-3.89] (pg/ml) in patients with DVT, 2.83 [1.83-4.87] in those with PE and 2.51 [1.71-4.78] in controls (p = 0.6, p = 0.4). Hetero- or homozygous carriers of the C allele (71% in DVT, 67% in PE and 59% among controls) did not have higher IL-6 levels than homozygous carriers of the G allele (median 2.60 vs. 2.59 pg/ml, p = 0.7). In conclusion, we found no association of IL-6 and its promoter polymorphism (-174) G > C with the risk of spontaneous VTE.     

Beta blocker and angiotensin-converting enzyme inhibitor therapy is associated with decreased Th1/Th2 cytokine ratios and inflammatory cytokine production in patients with chronic heart failure

OBJECTIVE: To examine the potential impact of beta-blockers and angiotensin-converting enzyme (ACE) inhibitors, medications which modulate beta-adrenergic signaling, on immune function in patients with chronic heart failure (HF). METHODS: 118 patients attending an HF center were tested for circulating levels of norepinephrine (NE), T cells and the inflammation-associated cytokine interleukin 6 (IL-6). Levels of the cytokines interferon-gamma (IFNgamma), IL-10, and tumor necrosis factor-alpha (TNFalpha) produced by cultured peripheral blood mononuclear cells (PBMC) were measured in culture supernatants following T cell stimulation in vitro. RESULTS: NE levels were significantly lower in patients receiving ACE inhibitors (p = 0.0263), with a trend toward lower NE in patients receiving beta-blockers. All patients exhibited relatively normal levels of T cells, and there was a trend toward higher levels of total (CD3+) and helper (CD4+) T cells (p = 0.0578 and 0.0932, respectively) in patients receiving either type of medication. The ratios of Th1 (IFNgamma) to Th2 (IL-10) cytokines were lower in patients receiving a combination of beta-blocker and ACE inhibitor therapy (p = 0.0373). NYHA class was a significant predictor of serum IL-6 (p < 0.0001). There was a trend toward lower levels of serum IL-6 in patients receiving both types of medications (p = 0.0606). TNFalpha production by CD3/CD28-stimulated PBMC was significantly lower in patients receiving ACE inhibitor medications (p = 0.0223). CONCLUSIONS: These results suggest that high sympathetic tone associated with chronic HF affects Th1/Th2 and inflammatory cytokine production, and that these effects can be modulated by medications. In addition to improvement in clinical parameters relating to cardiovascular function, beta-blocker and ACE inhibitor medications also appear to have a beneficial effect on the immune system in HF.     

Serum and cerebrospinal fluid concentration of inflammatory proteins MIP-1-alpha and MIP-1-beta and of interleukin 8 in the course of borreliosis

Chemokines constitute a group of cytokines with a strong chemotactic action, playing an important role in the pathogenesis of inflammatory responses, including infectious meningitis. The results of in vitro experiments suggest synthesis of chemokines during Borrelia burgdorferi infection. The aim of this study was to investigate serum and cerebrospinal fluid (CSF) concentrations of the following chemokines: interleukin-8 (Il-8) and macrophage inflammatory protein 1 alpha and 1 beta (MIP-1 alpha and MIP-1 beta) in patients with neuroborreliosis. The study group consisted of 20 patients admitted to Neuroinfections and Infectious Diseases Department of the Medical University in Bia?ystok. The control group consisted of 12 healthy persons from whom blood samples were obtained, and 10 patients without meningitis, from whom CSF samples were taken for diagnostic purposes. Chemokine concentrations were measured with ELISA kits before treatment (baseline) and after 2 weeks of antibiotic therapy (post-treatment). Mean serum concentrations of chemokine were elevated in neuroborreliosis patients at baseline (Il-8--mean +/- SD = 668.25 +/- 661.51 pg/ml, MIP-1 alpha--124.90 +/- 89.37 pg/ml, MIP-1 beta--233.40 +/- 298.40 pg/ml) as compared to these in the control group (Il-8-23.72 +/- 7.68 pg/ml, MIP-1 alpha--36.81 +/- 4.74 pg/ml, MIP-1 beta--70.41 +/- 16.41 pg/ml). Post-treatment mean concentrations of Il-8 (197.70 +/- 285.56 pg/ml) and MIP-1 beta (102.70 +/- 42.56 pg/ml) remained significantly elevated, while the mean concentration of MIP-1 alpha (53.65 +/- 38.50 pg/ml) was insignificantly higher than that in the control group. The Il-8 mean concentration was the most elevated comparing to the controls and has decreased most significantly during the treatment. CSF concentrations of chemokines were significantly elevated both at baseline (Il-8--754.95 +/- 535.83 pg/ml, MIP-1 alpha--24.35 +/- 4.88 pg/ml, MIP-1 beta--27.6 +/- 8.38 pg/ml) and post-treatment (Il-8--98.20 +/- 74.74 pg/ml, MIP-1 alpha--18.60 +/- 2.87 pg/ml, MIP-1 beta--16.90 +/- 4.38 pg/ml) in comparison with the controls (Il-8--10.43 +/- 2.70 pg/ml, MIP-1 alpha--8.17 +/- 1.54 pg/ml, MIP-1 beta--7.27 +/- 1.58 pg/ml). MIP-1 alpha and MIP-1 beta CSF concentrations were significantly lower than their concentrations in serum. The Il-8 CSF concentration did not differ significantly from its serum concentration. However, in some patients Il-8 CSF concentration was much higher than that in the serum, which suggests its significant synthesis within the cns and its role in the pathogenesis of B. burgdorferi meningitis. Chemokine CSF concentrations were not correlated with cytosis and CSF protein concentration. The results indicate the induction of Il-8, MIP-1 alpha and MIP-1 beta synthesis in the course of neuroborreliosis and a decrease of their concentrations during 2 weeks of treatment, however, without reaching the normal values.     

Th2 shift in juvenile muscular atrophy of distal upper extremity: a combined allergological and flow cytometric analysis

Juvenile muscular atrophy of the distal upper extremity (JMADUE) is considered to be a type of flexion myelopathy; however, we recently reported cases of JMADUE associated with airway allergy successfully treated by plasma exchange. To further characterize the allergo-immunological features of JMADUE, 11 consecutive JMADUE patients in the neurology clinic at Kyushu University Hospital were studied. Past and present together with family histories of common allergic disorders were investigated. Total serum IgE was measured by an enzyme linked immunosorbent assay (ELISA) and allergen-specific IgE by a liquid phase enzyme immunoassay. Intracellular interferon (IFN) gamma-, interleukin (IL)-4-, IL-5- and IL-13-producing T cells in peripheral blood were analyzed by flow cytometry. Data from 42 healthy subjects were used as controls for allergological studies. Flow cytometric data from 21 healthy subjects were also used for comparison. The patients exhibited significantly higher frequencies of coexisting airway allergies such as allergic rhinitis (p=0.0057) and pollinosis (p=0.0064), family histories of allergic disorders (p=0.0075), and mite antigen specific IgE (p=0.0361) compared with the healthy subjects. Patients with JMADUE had a significantly higher percentage of IFNgamma-IL-4+CD4+T cells (p=0.0017), but not IL-5- or IL-13-producing CD4+T cells, and a reduced intracellular IFNgamma/IL-4 ratio in CD4+T cells (p=0.002) compared to the controls. These findings suggest that JMADUE has a significant T helper 2 (Th2) shift, which may in part contribute to the development of spinal cord damage.     

The release of tumor necrosis factor-alpha is associated with ischemic tolerance in human stroke

Tumor necrosis factor (TNF)-alpha overexpression has been related to experimental ischemic tolerance when transient ischemia precedes cerebral infarction. We investigated TNF-alpha and interleukin (IL)-6 plasma concentrations in 283 patients with an acute stroke within 24 hours after symptom onset. An ipsilateral transient ischemic attack (TIA) within 72 hours before stroke was recorded in 38 patients. The infarct volume measured on computed tomography on days 4 to 7 and the frequency of poor outcome (Barthel Index score < 85) at 3 months were significantly lower in patients with prior TIA. Plasma concentrations of TNF-alpha were higher (42.5 +/- 9.9 vs 13.1 +/- 6.4pg/ml, p < 0.0001) and IL-6 levels were lower (10.1 +/- 6.2 vs 28.3 +/- 17.3pg/ml, p < 0.0001) in patients with prior TIA. A new variable termed TNF-alpha/IL-6 index was considered positive when TNF-alpha was greater than 30pg/ml and IL-6 was less than 30pg/ml. Positive TNF-alpha/IL-6 index was found in 92% of patients with prior TIA and in 1% of those without. TNF-alpha/IL-6 index (p = 0.0003) and TIA (p = 0.0001) were associated with good outcome in logistic regression analysis after adjusting for potential confounding factors. Ischemic tolerance in acute stroke is associated with increased plasma levels of TNF-alpha in the presence of reduced concentrations of IL-6.     

Increased interleukin-1 production by peripheral blood mononuclear cells in patients with multiple sclerosis.

The production of interleukin-1 (IL-1) by peripheral blood mononuclear cells (MNC) was assessed in patients with relapsing multiple sclerosis (MS) in both the active and inactive phase, in chronic progressive MS patients, in other neurological diseases, and in healthy subjects. Production was determined by measuring the IL-1 concentration in cultures with MNC supernatants using enzyme-linked immunosorbent assay (ELISA). IL-1 in sera of MS patients and healthy subjects also was investigated. MNC IL-1 alpha production was significantly higher in MS patients (180.2 +/- 177.5 pg/ml) than in healthy subjects (66.2 +/- 66.0 pg/ml) (P less than 0.05). Relapsing MS patients in the active phase had significantly higher MNC IL-1 alpha concentrations (360.1 +/- 130.0 pg/ml) than normal subjects (P less than 0.001), but MNC IL-1 alpha production in patients with relapsing MS in the inactive phase (65.3 +/- 52.8 pg/ml) or chronic progressive MS (80.9 +/- 71.9 pg/ml) was not increased significantly. MNC IL-1 beta production in MS patients was not elevated significantly. IL-1 alpha and -1 beta were not detected in sera of MS patients. The correlation between increased IL-1 alpha production and the clinical course of MS suggests that activated MNC may play a role in the pathogenesis of MS.     

Interleukin-1β and tumor necrosis factor-α in cerebrospinal fluid of children with bacterial meningitis

Certain cytokines may contribute to the sequence of events that lead to meningeal inflammation in bacterial meningitis. The purpose of this study was to determine the levels of cytokines in the cerebrospinal fluid (CSF) of children with bacterial meningitis and aseptic meningitis of different etiologies. We determined the concentrations of interleukin-1beta (IL-1beta) and tumor necrosis factor (TNF-alpha) in the CSF of 171 specimens of 144 patients whose cases were classified as follow: bacterial meningitis (n=23), aseptic meningitis (n=26) and non-meningitis (n=95). The detectable IL-1beta concentration (> or =20 pg/ml) in the bacterial meningitis, aseptic meningitis and non-meningitis groups were observed with 78.3%, 3.8%, and 8.4%, respectively. Significantly higher serum IL-1beta concentrations were detected in those with bacterial meningitis than those with aseptic meningitis (538.93+/-605.32 pg/ml vs 2.52+/-11.57 pg/ml; P<0.001) or among non-meningitis subjects (2.90+/-11.91 pg/ml; P<0.001). The mean TNF-alpha concentration was 148.74+/-338.77 pg/ml. There was significantly more TNF-alpha than aseptic meningitis (6.85+/-17.93 pg/ml; P<0.001) or non-meningitis (7.67+/-16.07 pg/ml; P<0.001). With regard to diagnosis, measurement of IL-1beta and TNF-alpha levels showed sensitivities of 78% and 74%, respectively; specificities of 96% and 81%, respectively. It is suggested that the levels of these cytokines, especially IL-1beta and TNF-alpha, are useful markers for distinguishing bacterial meningitis from aseptic meningitis.     

High soluble Fas and soluble Fas Ligand serum levels before stent implantation are protective against restenosis

Percutaneous coronary intervention (PCI) represents the most important treatment of coronary artery stenosis today. But instent restenosis (ISR) is a limitation for the outcome. Fas and Fas Ligand have been implicated in apoptosis and vessel wall inflammation. Their role in ISR is not known so far. In this prospective study we studied 137 patients with stable coronary artery disease who underwent elective PCI. Blood samples were taken directly before and 24 hours after PCI. Soluble (s)Fas and sFas Ligand serum levels were measured by ELISA. Restenosis was evaluated six to eight months later either by coronary angiography or by exercise testing. During the follow-up period, 18 patients (13%) developed ISR. At baseline, patients with ISR had significantly lower median sFas, as well as sFas Ligand levels compared to patients without ISR (sFAS: ISR 492 pg/ml, no ISR 967 pg/ml, p=0.014; sFAS Ligand: ISR: 26 pg/ml, no ISR: 42 pg/ml, p=0.001). After PCI median sFas levels significantly decreased in patients with ISR compared to patients without ISR [ISR: -152 pg/ml (IQR -36 to -227), no ISR: -38 pg/ml (IQR -173 to +150 pg/ml), p=0.03]. sFas Ligand levels after PCI significantly increased in ISR patients compared to patients without ISR [ISR: 14 pg/ml (IQR -3 to +26 pg/ml), no ISR -6 pg/ml (IQR -22 to +21 pg/ml), p=0.014]. In conclusion, sFas and sFas Ligand seem to be associated with the development of ISR. Determination of serum levels before and after PCI might help identifying patients at higher risk of ISR.     

Phenytoin-Induced Elevation of Serum Estradiol and Reproductive Dysfunction in Men with Epilepsy

Reproductive and sexual dysfunction in men with epilepsy has been attributed to androgen deficiency. Low serum free testosterone (FT) levels occur in both hypogonadotropic and hypergonadotropic hypogonadism. Antiepileptic drugs (AEDs) have been implicated. Proposed mechanisms include induction of increased sex hormone binding globulin (SHBG) resulting in decreased FT, as well as dysfunction or premature aging of the hypothalamopituitary-gonadal axis. In an investigation comparing serum reproductive steroid levels among 20 men receiving phenytoin (PHT) monotherapy for complex partial seizures, 21 untreated men with complex partial seizures, and 20 age-matched normal controls, total estradiol levels were significantly higher in the PHT group (56.3 +/- 29.4 pg/ml, mean +/- SD) than in the untreated (32.4 +/- 27.4 pg/ml, p less than 0.01) and normal control (34.3 +/- 12.7 pg/ml, p less than 0.05) groups. The physiologically active non-SHBG-bound serum estradiol levels were also significantly higher in the medicated group (45.1 +/- 21.7 pg/ml) than in the untreated (29.9 +/- 17.2 pg/ml, p less than 0.01) and normal control (31.1 +/- 11.4 pg/ml, p = 0.05) groups. These findings suggest that PHT may lower FT by induction of aromatase, enhancing FT conversion to estradiol, as well as SHBG synthetase. Estradiol exerts a potent inhibitory influence on luteinizing hormone secretion and has been suggested to play a major role in negative feedback in men as well as women. Suppression of LH secretion results in hypogonadotropic hypogonadism. Chronically low FT leads to testicular failure and hypergonadotropic hypogonadism. Finally, estradiol has been shown to produce premature aging of the hypothalamic arcuate nucleus, which secretes gonadotropin-releasing hormone.     

Cerebrospinal fluid somatostatin levels in febrile seizures and epilepsy in children

We analysed the level of cerebrospinal fluid (CSF) somatostatin in children with febrile seizures and epilepsy. In the febrile seizure group (n = 23), the somatostatin level was 83.9 +/- 11.2 pg/ml, which was significantly higher than that of age-matched controls. CSF samples obtained within 3 h of the last seizure had higher somatostatin levels (106.1 +/- 12.4 pg/ml;n = 14) than did the CSF obtained after 3 h (49.4 +/- 15.6 pg/ml;n = 9). The mean somatostatin level in the epilepsy group was 35.3 +/- 4.3 pg/ml (n = 34), and was distributed as follows: 27.6 +/- 3.6 pg/ml in the idiopathic generalized epilepsy group (n = 16), 44.0 +/- 9.4 pg/ml in the symptomatic generalized epilepsy group (n = 13), and 37.2 +/- 10.1 pg/ml in the partial epilepsy group (n = 5). The levels in each group were significantly higher than those in age-matched controls. Somatostatin is a hypothalamic tetradecapeptide with excitatory effects on neurons in children with febrile seizures and epilepsy. The finding that patients with convulsive disease had elevated levels of CSF somatostatin suggests that somatostatin release is somehow related to seizure activity. It remains to be determined whether this is due to increased release from over-active excitatory neurons or leakage from damaged or anoxic neurons, secondary to seizure activity.     

Vitamin D levels and bone turnover in epilepsy patients taking carbamazepine or oxcarbazepine

PURPOSE: Evidence suggests that enzyme-inducing antiepileptic drugs (AEDs) may decrease serum 25-hydroxyvitamin D (25-OHD) levels and increase bone turnover. We sought to determine whether these are affected by treatment with carbamazepine (CBZ) or oxcarbazepine (OXC). METHODS: We measured serum levels of 25-OHD, parathyroid hormone (PTH), osteocalcin (OCLN), bone alkaline phosphatase (BAP), and urinary N-telopeptides of type I collagen cross-links (NTX) in normal controls (n=24) and in epilepsy patients taking CBZ (n=21) or OXC (n=24) in monotherapy. CBZ patients were subsequently switched overnight to OXC monotherapy, and after 6 weeks, the tests were repeated. RESULTS: 25-OHD levels were lower in each drug-treated group (OXC, 19.4+/-2.3 pg/ml; CBZ, 20.4+/-2.4) than in the controls (27.5+/-2.8) (ANOVA, p=0.052). This difference was significant for the OXC group (p<0.05). PTH, BAP, and NTX did not differ significantly among groups. OCLN levels were somewhat elevated in the OXC group (2.79+/-0.47 ng/ml) and more clearly and significantly elevated in the CBZ group (3.63+/-0.36) compared with controls (2.38+/- 0.41) (p=0.053). Because the data were very similar between OXC and CBZ groups, they were combined to increase statistical power. The combined drug-treatment group had significantly higher BAP (p=0.02) and lower 25-OHD (p=0.015) than did controls. The latter remained significant even after accounting for the confounding effects of age on 25-OHD levels (p<0.05). No significant differences were found after CBZ patients were switched to OXC. CONCLUSIONS: Epilepsy patients taking OXC or CBZ have significantly lower 25-OHD than do normal controls, with a pattern of changes in other bone biomarkers suggestive of secondary hyperparathyroidism. It may be prudent for patients taking CBZ or OXC to be prescribed 25-OHD replacement.