Involvement of levels of Toll like receptor-4 in monocytes,CD4 + T-lymphocyte subsets,and cytokines in patients with immune thrombocytopenic purpura

Introduction

Toll-like receptors have been found to be associated with immune-mediated diseases but it is still not clear whether they play a role in immune thrombocytopenic purpura (ITP), especially TLR4. CD4 + T-lymphocyte abnormalities, including Th17, Th1, Th2, and regulator T cell (Treg), are considered important in ITP. There have been few studies regarding the expression of TLR4 and the relationships between TLR4 and Th17 levels in ITP.

Materials and Methods

In this study, we evaluated the expression of TLR4 in monocytes, the plasma concentrations of IL-23, IL-17 and the profiles of Th17, Th1, Th2 cells in 70 patients with ITP and 31 healthy controls. In addition, we evaluated IL-2 and Treg cells in 46 cases of 70 patients with ITP and the same 31 controls.

Results

Higher levels of TLR4 expression, higher relative numbers of Th17 and Th1 cells and lower levels of Treg cells were observed in patients when compared with controls (p = 0.001 for TLR4; p < 0.001 for Th17; p = 0.014 for Th1; p = 0.001 for Treg). The levels of IL-23 and IL-2 were increased (p = 0.022 for IL-23; p = 0.025 for IL-2), the relative levels of Th2 and concentrations of IL-17 were similar across both groups (p = 0.446 for Th2; p = 0.316 for IL-17). A significant negative correlation was observed between levels of TLR4 and Treg(r = -0.544, p < 0.001), but a significantly positive correlation was observed between IL-2 and IL-23 concentration in patients (r = 0.441, p = 0.004). Neither the correlation between TLR4 and the other CD4⁺ T cells and cytokines nor the correlation between the three cytokines and CD4+ T cells was found to be statistically significant.

Conclusions

Our data showed that TLR4, CD4 + T cells (Th1, Th17 and Treg cells) and related cytokines (IL-23, IL-2) may take part in the pathogenesis of ITP. TLR4 may play a role through the TLR4-cytokine-CD4+ T lymphocyte cell pathway.     

Serum and cerebrospinal fluid levels of cytokines in acute encephalopathy associated with human herpesvirus-6 infection

Human herpesvirus-6 (HHV-6) is a causative agent of exanthema subitum. The immunological pathogenesis of acute encephalopathy associated with HHV-6 infection is still unclear. We measured the concentrations of interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), interleukin-2 (IL-2), IL-4, IL-6, IL-10, and soluble TNF receptor 1 (sTNFR1) in serum and cerebrospinal fluid (CSF) during the acute stage in 15 infants with acute encephalopathy and 12 with febrile seizures associated with HHV-6 infection. The serum IL-6, IL-10, sTNFR1, CSF IL-6, and sTNFR1 levels of infants with encephalopathy who had neurological sequelae (n = 9) were significantly higher than those with febrile seizures (p = 0.011, 0.043, 0.002, 0.029, and 0.005, respectively). In acute encephalopathy, serum IL-6, sTNFR1, and CSF IL-6 levels in infants with neurological sequelae were significantly higher than those without (n = 6) neurological sequelae (p = 0.043, 0.026, and 0.029, respectively), and serum IFN-γ, IL-6, IL-10, and sTNFR1 levels were significantly higher than those in the CSF (p = 0.037, 0.037, 0.001, and 0.021, respectively). There were no significant differences in serum or CSF cytokine levels between infants who were positive for HHV-6 DNA in the CSF (n = 6) compared to those who were negative (n = 9). We suggest that cytokines mediate the pathogenesis of acute encephalopathy associated with HHV-6 infection, and that the elevated levels of serum IL-6, sTNFR1, and CSF IL-6 are important for predicting neurological sequelae.     

Macrophage migration inhibitory factor in mild cognitive impairment and Alzheimer’s disease

Inflammatory processes may substantially contribute to the cerebral pathology in Alzheimer’s disease (AD) and accelerate the disease progression. The macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine which promotes the production of several inflammatory mediators such as TNF-α, IL-6 and IFN-γ, and plays a central regulatory role in the pathogenesis of several inflammatory and autoimmune diseases. There is now first evidence that MIF may be involved in the neuroinflammation in AD. To determine whether MIF production is up-regulated early in the course of AD, we compared the levels of MIF assessed by ELISA in the cerebrospinal fluid (CSF) of 31 patients with AD, 28 patients with amnestic mild cognitive impairment (MCI), and 19 subjects without cognitive deficits. Additionally, we measured the CSF concentrations of the inflammatory mediators TNF-α, IL-6 and IFN-γ, which are thought to be both up-regulated by MIF and involved in the pathophysiology of AD. CSF MIF concentrations were significantly increased in AD (p = 0.003) and MCI patients (p < 0.001) compared to controls. The levels of TNF-α, IL-6 and IFN-γ did not differ significantly between the groups. There was a correlation only between the concentrations of MIF and of TNF-α in the AD group (r = 0.407; p = 0.023). These results demonstrate increased MIF production in AD and MCI suggesting that MIF may be involved in the occurring neuroinflammatory process at a clinical pre-dementia disease stage.     

Tau proteins in the cerebrospinal fluid of patients with subacute sclerosing panencephalitis

Neurodegenerative diseases characterized by cytoskeletal deformation and neurofibrillary tangles are associated with altered levels of tau and related proteins in cerebrospinal fluid (CSF). Neuronal or glial fibrillary tangles have been shown in 20% of subacute sclerosing panencephalitis (SSPE) patients. We therefore investigated CSF samples from 60 newly diagnosed SSPE and 31 neurological control patients for total tau (t-tau), phosphorylated tau (p-tau), and S100-B levels by ELISA. There was no difference between patient and control groups in t-tau and S100-B levels. p-Tau was lower in the SSPE group (p = 0.009). Past history of measles infection, measles immunization status, latent period between measles and onset of SSPE, duration of symptoms, frequency of myoclonia, neurological deficit index, stage and progression rate of the disease, CSF glucose levels and cell counts, CSF and serum measles IgG titer, distribution of lesions on brain magnetic resonance imaging were not related to t-tau, p-tau and S100-B levels. Mental status and age were negatively correlated with t-tau, and male gender and EEG abnormalities were associated with higher t-tau levels. The levels of tau proteins in our patients suggest there is no, or only scarce and immature, neurofibrillary tangle formation in SSPE. Autopsy studies showing neurofibrillary tangles might have examined older patients with longer disease and more parenchymal involvement.     

Biomarkers of chemotaxis and inflammation in cerebrospinal fluid and serum in individuals with HIV-1 subtype C versus B

A defective chemokine motif in the HIV-1 Tat protein has been hypothesized to alter central nervous system cellular trafficking and inflammation, rendering HIV-1 subtype C less neuropathogenic than B. To evaluate this hypothesis, we compared biomarkers of cellular chemotaxis and inflammation in cerebrospinal fluid (CSF) and serum in individuals infected with HIV-1 subtypes B (n?=?27) and C (n?=?25) from Curitiba, Brazil. None had opportunistic infections. Chemokines (MCP-1, MIP-1α, MIP-1β, RANTES, IP-10) and cytokines (TNF-α, IFN-γ, IL-1β, IL-2, IL-4, IL-6, IL-7, IL-10) were measured using the multiplex bead suspension array immunoassays or ELISA HD. CSF and serum biomarker concentrations were compared between subtype B and C groups and HIV-positive and HIV-negative subjects (N?=?19) using an independent group t test (unadjusted analysis) and linear regression (adjusted analysis), controlling for nadir CD4 and CSF and plasma HIV RNA suppression. CSF levels of cytokines and chemokines were significantly (p?<?0.05) elevated in HIV-positive versus HIV-negative participants for 7/13 biomarkers measured, but levels did not differ for subtypes B and C. Serum levels were significantly elevated for 4/13 markers, with no significant differences between subtypes B and C. Although pleocytosis was much more frequent in HIV-positive than in HIV-negative individuals (27 vs. 0 %), subtypes B and C did not differ (32 and 22 %; p?=?0.23). We did not find molecular evidence to support the hypothesis that intrathecal chemotaxis and inflammation is less in HIV-1 subtype C than in subtype B. Biomarker changes in CSF were more robust than in serum, suggesting compartmentalization of the immunological response to HIV.     

Expression of leukemia inhibitory factor in the cerebrospinal fluid of patients with multiple sclerosis

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system, characterized by infiltration of immune cells in the central nervous system, localized myelin destruction and loss of oligodendrocytes. Early detection of MS may be possible via blood and cerebrospinal fluid (CSF) tests based on disease pathology. Leukemia inhibitory factor (LIF), a neurotrophic cytokine, has previously been shown to limit autoimmune demyelination and oligodendrocyte loss in a murine model of MS. Given its potential role in neural cell death and survival, in the present study we measured expression of LIF in serum and CSF from patients with relapsing-remitting MS (n = 46) and control subjects (n = 42). We used western blot analysis and enzyme-linked immunosorbent assays (ELISA), to study LIF expression. Western blot analysis revealed that LIF was present in all CSF samples, and densitometric analysis showed that relative expression was significantly higher in CSF from patients with MS than in controls (p < 0.001). ELISA analysis showed that the concentrations of LIF in both the serum (87.5 ± 11.46 ng/mL) and CSF (56 ± 10.72 ng/mL) of MS patients were significantly higher than those in control subjects (52 ± 8.23 ng/mL, 7.8 ± 3.76 ng/mL, respectively; p < 0.0001 for both serum and CSF), despite there being no significant difference in total protein concentration between the two groups (p = 0.52 for serum, p = 0.2 for CSF). Our data suggest that serum and CSF concentrations of LIF may provide additional useful information during the differential diagnosis of MS. Our findings also indicate that LIF could be significantly involved in the pathophysiology of MS.     

Evaluation of interleukin 10 and interferon-α in the cerebrospinal fluid and serum of patients with multiple sclerosis

The activities of IL-10, a cytokine produced by TH2 cells, monocytes and B-cells, and IFN-α, a product of activated macrophages/monocytes, were investigated in the CSF and serum samples of 25 subjects with clinically definite multiple sclerosis (MS), of whom 14 were in the active and nine in the stable phase, and of 15 controls with other noninflammatory neurological diseases (OND). Elevated CSF IL-10 and IFN-α levels were found in MS patients in the stable phase with respect to patients in the active phase (p > 0.001), while no significant differences were observed in the mean serum levels between MS patients (both in the active and stable phase) and controls. Finally, a significant correlation was detected between IL-10 and IFN-α in the CSF of MS patients in remission. This study suggests that IL-10 may downregulate MS progression.     

Low serum IL-10 concentrations and loss of regulatory association between IL-6 and IL-10 in adults with major depression

Elevated circulating pro-inflammatory cytokines are associated with symptoms of depression, and disorders involving chronic inflammation are often co-morbid with major depression. Since healthy immune regulation is accomplished through counter-balancing effects of pro- and anti-inflammatory cytokines, we hypothesized that depressed subjects (compared to controls) would express lower concentrations of the anti-inflammatory/immunoregulatory cytokine interleukin (IL)-10, and a higher IL-6/IL-10 ratio. We also examined the possibility that depressed subjects may exhibit a deficiency in the regulatory loop involving IL-6 induced secretion of IL-10. Therefore, we hypothesized that circulating IL-6 and IL-10 would be positively correlated in controls, while the correlation would be weaker in depressed subjects. Resting state serum cytokine concentrations were quantified in 12 unmedicated depressed subjects, and 11 age, gender, and ethnicity-matched controls. Depressed subjects showed significantly lower IL-10 (p = 0.03, Cohen’s d = −0.96), non-significantly higher IL-6, and significantly higher IL-6/IL-10 ratios (p = 0.05, Cohen’s d = 0.50). Across all participants, higher scores on the self-rated Inventory of Depressive Symptoms were associated with lower IL-10 (r(21) = −0.57, p = 0.005) and non-significantly higher IL-6/IL-10 ratios (r(21) = 0.38, p = 0.07), but not related to IL-6 concentrations. As hypothesized, IL-6 and IL-10 concentrations were strongly and positively correlated in controls (r(9) = 0.81, p = 0.003), but were completely dissociated in depressed subjects (r(10) = 0.01, p = 0.98). These results suggest that lower IL-10 levels, a higher IL-6/IL-10 ratio, and the apparent absence of a counter-balancing, immunoregulatory increase in IL-10 in response to elevated IL-6 concentrations contribute to the pro-inflammatory physiological milieu that is known to be associated with major depression. Therefore, reduced induction/availability of IL-10, that would normally inhibit pro-inflammatory cytokine actions and resolve inflammation, may contribute to the depressogenic as well as the inflammatory disease-promoting effects of chronic, low-level elevations in pro-inflammatory cytokines.     

Cerebrospinal fluid markers of neuroinflammation in delirium: A role for interleukin-1β in delirium after hip fracture

Objective

Exaggerated central nervous system (CNS) inflammatory responses to peripheral stressors may be implicated in delirium. This study hypothesised that the IL-1β family is involved in delirium, predicting increased levels of interleukin-1β (IL-1β) and decreased IL-1 receptor antagonist (IL-1ra) in the cerebrospinal fluid (CSF) of elderly patients with acute hip fracture. We also hypothesised that Glial Fibrillary Acidic Protein (GFAP) and interferon-γ (IFN-γ) would be increased, and insulin-like growth factor 1 (IGF-1) would be decreased.

Methods

Participants with acute hip fracture aged > 60 (N = 43) were assessed for delirium before and 3–4 days after surgery. CSF samples were taken at induction of spinal anaesthesia. Enzyme-linked immunosorbent assays (ELISA) were used for protein concentrations.

Results

Prevalent delirium was diagnosed in eight patients and incident delirium in 17 patients. CSF IL-1β was higher in patients with incident delirium compared to never delirium (incident delirium 1.74 pg/ml (1.02–1.74) vs. prevalent 0.84 pg/ml (0.49–1.57) vs. never 0.66 pg/ml (0–1.02), Kruskal–Wallis p = 0.03). CSF:serum IL-1β ratios were higher in delirious than non-delirious patients. CSF IL-1ra was higher in prevalent delirium compared to incident delirium (prevalent delirium 70.75 pg/ml (65.63–73.01) vs. incident 31.06 pg/ml (28.12–35.15) vs. never 33.98 pg/ml (28.71–43.28), Kruskal–Wallis p = 0.04). GFAP was not increased in delirium. IFN-γ and IGF-1 were below the detection limit in CSF.

Conclusion

This study provides novel evidence of CNS inflammation involving the IL-1β family in delirium and suggests a rise in CSF IL-1β early in delirium pathogenesis. Future larger CSF studies should examine the role of CNS inflammation in delirium and its sequelae.     

Brain derived neurotrophic factor, cardiopulmonary fitness and cognition in patients with coronary artery disease

Objective

To assess serum brain derived neurotrophic factor (BDNF) concentrations as a correlate of cardiopulmonary fitness and as a predictor of cognitive performance in subjects with coronary artery disease (CAD).

Methods

Serum BDNF concentrations were assayed by ELISA and fitness was assessed using a standardized exercise stress test. The Mini Mental Status Examination (MMSE), California Verbal Learning Test 2nd Ed., Stroop, Trail Making Test B and the Digit Symbol-Coding task were administered. The val66met BDNF genotype and serum interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) concentrations were determined as potential confounders.

Results

In subjects with CAD (n = 88; 85.2% male, mean age 62.8 ± 10.5 yr), cardiopulmonary fitness was associated with higher serum BDNF concentrations (β = .305, p = .013). Higher serum BDNF concentrations were associated with higher MMSE scores (F(1, 87) = 15.406, p < .0005) and better performance on the Digit Symbol-Coding task (F(1, 87) = 9.620, p = .003). IL-6, TNF-α and the val66met genotype did not influence these results.

Conclusion

Serum BDNF concentrations were associated with cardiopulmonary fitness, psychomotor processing speed and overall cognition in subjects with CAD.     

Vasopressin and oxytocin in CSF and plasma of patients with aneurysmal subarachnoid haemorrhage

Objective

Clinicopathological studies on patients succumbing to subarachnoid haemorrhage (SAH) demonstrated hypothalamic lesions. The implication of the hypothalamic neuropeptides arginine-vasopressin (AVP) and oxytocin (OXT) has not been linked to aneurysmal SAH yet. This study investigates AVP and OXT in CSF and plasma of patients with spontaneous aneurysmal SAH and their association with outcome.

Methods

CSF and plasma samples of 12 patients with aneurysmal SAH were prospectively studied for 2 weeks. AVP and OXT were measured by radioimmunoassay. Outcome was assessed on Glasgow-Outcome-Scale. Twenty-nine patients without neuropsychiatric disturbances served as controls. Differences in neuropeptide concentration time courses were assessed by regression models. Group comparisons were performed by Kruskal–Wallis and correlations by Spearman tests.

Results

Regression of CSF levels between patients with poor and good outcome revealed significantly lower levels of AVP in patients with poor outcome (p = 0.012) while OXT showed a trend towards lower levels (p = 0.063). In plasma, no significant differences between outcome groups were found. Group comparisons between poor outcome patients and controls revealed significant differences in CSF for AVP (p = 0.001) and OXT (p = 0.015). In plasma, AVP yielded significantly different results while OXT did not. No differences were found between the good outcome group and controls. Plasma and CSF concentrations showed no significant correlation.

Conclusion

Patients with poor outcome after aneurysmal SAH have lower AVP and OXT levels in CSF than patients with good outcome while neuropeptide levels in plasma failed to reflect differences in outcome. The data indicate hypothalamic damage as an aetiologic factor for outcome after aneurysmal SAH.     

Decreased Tim-3 and its correlation with Th1 cells in patients with immune thrombocytopenia

Here we evaluate the expression of Tim-3 in CD4 + T cells from patients with immune thrombocytopenia (ITP). We also counted platelets and evaluated plasma IFN-γ, IL-18 and IL-4 levels in patients with active ITP (n = 26), patients with ITP in remission (n = 23) and in healthy subjects (n = 34) by enzyme linked immunosorbent assay (ELISA). Using real-time quantitative polymerase chain reaction (RT-PCR), the mRNA expression of IL-18, IFN-γ, IL-4, T-box (T-bet) and Tim-3 was studied in the blood. The CD4 + Tim-3 + cells in blood were evaluated by flow cytometry and are expressed as a percentage of the total number of CD4 + cells. The Tim-3 positive cells within the circulating CD4 + population of newly diagnosed patients were significantly decreased compared to controls. However, T-bet, IL-18 and IFN-γ levels were significantly elevated in patients. Tim-3 mRNA expression was significantly lower in the peripheral mononuclear cells (PBMCs) of ITP patients compared to controls. The decreased levels of Tim-3 during active stages of disease suggest a possible role in the pathogenesis and course of ITP and restoration of Tim-3 may be a reasonable therapeutic strategy for ITP.     

Decreased brain-derived neurotrophic factor in medicated and drug-free bipolar patients

Bipolar disorder (BD) has been associated with abnormalities in neuroplasticity and previous studies suggest an important role for BDNF in the pathophysiology of BD. The confounding effect of the use of medication in these studies has been considered a limitation. Thus, studies with both drug-free and medicated patients are necessary to assess the role of medication in serum BDNF levels. Twenty-two manic and depressed drug-free and 22 medicated BD type I patients were matched to 22 controls according to sex and age in a cross-sectional study. BDNF serum levels were assessed using sandwich-ELISA. Serum BDNF levels in drug-free (0.23 ± 0.09), and medicated (0.29 ± 0.19) BD patients were decreased when compared to controls (0.40 ± 0.12) - drug-free/medicated vs. control p < 0.001. The BDNF levels did not differ between medicated and drug-free BD patients. When analyzing patients according to mood states, serum BDNF levels were lower in BD patients during both manic (0.28 ± 0.11) and depressive episodes (0.22 ± 0.17), as compared with healthy controls (0.40 ± 0.12) - manic/depressed patients vs. controls p < 0.001. Results suggest that the association of lower serum BDNF and BD mood episodes is kept even in medicated patients, which strengthens the notion that BDNF serum levels may be considered a biomarker of mood episodes in BD.     

Open study of pranlukast add-on therapy in intractable partial epilepsy

Innovative treatments of epileptic seizures are needed to improve the outcome of epilepsy. We studied the effect of pranlukast on seizure outcome in patients with intractable partial epilepsy. An open study was conducted to evaluate the clinical efficacy of 24-week pranlukast add-on therapy in 50 patients with intractable partial seizures. Serum concentrations of matrix metalloproteinase (MMP)-9 were determined using Biotrak Activity Assay System. Cytokines in cerebrospinal fluid (CSF) were measured by the BioPlex (BioRad) system and soluble TNF receptor1 (sTNFR1) in CSF was measured by the ELISA. Surface markers of lymphocytes in CSF were examined by cell-sorter. Seizure-free rate (SFR) was 13.6%, responder rate (RR) was 47.7%, and aggravation rate (AR) was 18.2% at the 13–24 week period after starting pranlukast. In patients with increased serum MMP-9 before pranlukast therapy (baseline), comparison of paired serum levels showed a significant decrease after pranlukast therapy. Baseline CSF levels of IL-1β and IL-6 were elevated in patients compared with disease controls. Of four patients with paired data, three (including a responder to pranlukast) showed decreased pro-inflammatory cytokines (IL-1β, IL-6, and TNFα), and four showed decreased sTNFR1, after pranlukast treatment, and only a responder had markedly decreased frequency of CD8+ T cells in CSF. Pranlukast reduces seizure frequencies probably by pleiotropic effects including normalization of MMP-9 in sera, reduced leakage of pro-inflammatory cytokines into CNS, and inhibition of extravasation of leucocytes from brain capillaries. Further investigations by double-blind control study and animal models are warranted.     

Serum brain-derived neurotrophic factor in bipolar and unipolar depression: A potential adjunctive tool for differential diagnosis

The differential diagnosis of Bipolar Disorder (BD) and Major Depressive Disorder (MDD) is a diagnostic challenge during depressive episodes. Noteworthy, the proper differentiation between BD depressive state and MDD has important treatment implications. BDNF levels may be valuable adjunctive tool for this differential diagnosis. Ten subjects with MDD, forty with BD type I and thirty healthy comparison subjects were recruited. All subjects had BDNF serum levels measured and, in patients, BDNF serum levels were assessed during acute depressive episode. Optimal sensitivity and specificity of serum BDNF for the differential diagnosis of unipolar and bipolar depression were determined by the receiver operating characteristic (ROC) curve analysis, using a nonparametric approach. Serum BDNF levels in depressive BD patients were lower compared to MDD patients and controls (0.15 ± 0.08, 0.35 ± 0.08, and 0.38 ± 0.12, respectively, p < 0.001). The area under the curve (AUC) of the ROC analysis in BD depression vs. MDD was 0.95 (ranged from 0.89 to 1.00). Overall, the AUC of the ROC analysis (BD depression vs. MDD and controls) was 0.94 (95% CI 0.89 to 0.99, p < 0.001). A proposed “best” cutoff of 0.26 resulted in 88% sensitivity and 90% specificity. Serum BDNF levels appear as a promising tool to discriminate bipolar from unipolar depression. Our results suggest the role of BDNF as an adjunctive tool to promote prompt and accurate diagnosis of BD. However, further investigation and replication of these results are warranted.     

Cerebrospinal fluid lactate in post-neurosurgical bacterial meningitis diagnosis

Background

Differential diagnosis between post-neurosurgical bacterial meningitis (PNBM) and aseptic meningitis is difficult. Inflammatory and biochemical cerebrospinal fluid (CSF) changes mimic those classically observed after CNS surgery. CSF lactate assay has therefore been proposed as a useful PNBM marker.

Objective

To evaluate the diagnostic accuracy of CSF lactate as a PNBM marker in patients hospitalized after a neurosurgical procedure.

Methods

Between July 2005 and June 2009, a prospective clinical study, in which all patients with clinical suspicion of PNBM were enrolled, was conducted at our neurosurgical Intensive Care Unit. PNBM diagnosis was categorized as proven, probable or negative before the analysis.

Results

Seventy-nine patients, 51 males with a mean age of 50 years (range 32–68 years) were included. Surgery was elective in 76% patients, mostly for brain tumors (57%); thirty PNBM episodes were identified. CSF parameters were significantly different in glucose concentration (27 mg% vs. 73 mg%, p < 0.001), lactate (8 mmol/L vs. 2.8 mmol/L, p < 0.001), CSF neutrophil pleocytosis (850 mm^–3 vs. 10 mm^–3, p < 0.001), and protein levels (449 mg% vs. 98 mg%) between the PNBM and non-PNBM groups. The ROC curve that best fits PNBM diagnosis is lactate.

Conclusion

Increased CSF lactate is a useful PNBM marker, with better predictive value than CSF hypoglycorrhachia or pleocytosis. Lactate levels ≥4 mmol/L showed 97% sensitivity and 78% specificity, with a 97% negative predictive value.     

The probiotic Bifidobacteria infantis: An assessment of potential antidepressant properties in the rat

It is becoming increasingly apparent that probiotics are important to the health of the host. The absence of probiotic bacteria in the gut can have adverse effects not only locally in the gut, but has also been shown to affect central HPA and monoaminergic activity, features that have been implicated in the aetiology of depression. To evaluate the potential antidepressant properties of probiotics, we tested rats chronically treated with Bifidobacteria infantis in the forced swim test, and also assessed the effects on immune, neuroendocrine and central monoaminergic activity. Sprague-Dawley rats were treated for 14 days with B. infantis. Probiotic administration in naive rats had no effect on swim behaviours on day 3 or day 14 following the commencement of treatment. However, there was a significant attenuation of IFN-γ, TNF-α and IL-6 cytokines following mitogen stimulation (p < 0.05) in probiotic-treated rats relative to controls. Furthermore, there was a marked increase in plasma concentrations of tryptophan (p < 0.005) and kynurenic acid (p < 0.05) in the bifidobacteria-treated rats when compared to controls. Bifidobacteria treatment also resulted in a reduced 5-HIAA concentration in the frontal cortex and a decrease in DOPAC in the amygdaloid cortex. The attenuation of pro-inflammatory immune responses, and the elevation of the serotonergic precursor, tryptophan by bifidobacteria treatment, provides encouraging evidence in support of the proposition that this probiotic may possess antidepressant properties. However, these findings are preliminary and further investigation into the precise mechanisms involved, is warranted.     

Serum and CSF biomarkers in acute pediatric neurological disorders

Background: There have been numerous reports regarding serum or cerebrospinal fluid (CSF) biomarkers in various disorders; however, the validities of such biomarkers for more precise diagnoses and prognosis estimates remain to be determined, especially in pediatric patients with neurological disorders. Methods: Serum/CSF S100B, neuron-specific enolase, and total tau (tTau) were measured in various acute pediatric neurological disorders, and their usefulness for diagnostic and prognostic predictions was validated using receiver operating characteristic curves and area under the curve (AUC) analysis. Results: A total of 336 serum and 200 CSF specimens from 313 patients were examined, and we identified statistically significant differences that were relevant from diagnostic and prognostic viewpoints. CSF and serum tTau levels could be good predictors for diagnosis (CSF tTau; AUC = 0.76) and prognosis (serum tTau; AUC = 0.78). Conclusions: Both CSF and serum tTau levels could be useful for precise diagnostic and prognostic estimations in acute pediatric neurological disorders. Further studies are needed to clarify the clinical significance of such biomarkers.     

mRNA expression of alpha and beta isoforms of glucocorticoid receptor in peripheral blood mononuclear cells of patients with tuberculosis and its relation with components of the immunoendocrine response

We have analyzed the expression of glucocorticoid receptor (GR) isoforms by real time RT-qPCR in PBMCs from 19 controls (HCo) and 28 TB patients (8 mild; 12 moderate; 8 severe), HIV(-) and similar sex and age distribution. mRNA hGRα/β ratios were found higher in TB patients respect to those in HCo. However, when analyzing for disease severity such overall trend was at the expense of mild and moderate patients, with severe cases showing a lower mRNA hGRα/β ratio with respect to the other patient groups. This suggested some degree of resistance to endogenous glucocorticoids in patients with severe TB, since hGRαα dimer mediates the biological functions of GC, with the GRβ isoform acting as an inhibitor of GC activity. Levels of IL-6, IL-18, IFN-γ and Cortisol were significantly increased in severe and moderate cases, whereas DHEA values were found decreased in them (p < 0.05 respect to HCo). Analysis on the relationship between plasma levels of these immuno-endocrine mediators with the mRNA expression of hGRα and hGRβ showed that IL-6 was positively associated with hGRα in mild TB patients (p < 0.01), whereas a negative correlation between IFN-γ and hGRβ was observed in severe cases (p < 0.01). As regard to hormones, DHEA was positively associated with hGRα in moderate and severe cases (p < 0.01). This group also showed a negative correlation between hGRα and Cortisol/DHEA ratios (p < 0.05). Changes in the systemic levels of cytokine and adrenal hormones are likely to affect GR expression in a differential fashion and according to the amount of pulmonary involvement.     

Relationship between dopamine D2 receptor occupancy, clinical response, and drug and monoamine metabolites levels in plasma and cerebrospinal fluid. A pilot study in patients suffering from first-episode schizophrenia treated with quetiapine

Combining measurements of the monoamine metabolites in the cerebrospinal fluid (CSF) and neuroimaging can increase efficiency of drug discovery for treatment of brain disorders. To address this question, we examined five drug-naïve patients suffering from schizophrenic disorder. Patients were assessed clinically, using the Positive and Negative Syndrome Scale (PANSS): at baseline and then at weekly intervals. Plasma and CSF levels of quetiapine and norquetiapine as well CSF 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 5-hydroxyindole-acetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) were obtained at baseline and again after at least a 4 week medication trail with 600 mg/day quetiapine. CSF monoamine metabolites levels were compared with dopamine D₂ receptor occupancy (DA-D₂) using [¹⁸F]fallypride and positron emission tomography (PET). Quetiapine produced preferential occupancy of parietal cortex vs. putamenal DA-D₂, 41.4% (p < 0.05, corrected for multiple comparisons). DA-D₂ receptor occupancies in the occipital and parietal cortex were correlated with CSF quetiapine and norquetiapine levels (p < 0.01 and p < 0.05, respectively). CSF monoamine metabolites were significantly increased after treatment and correlated with regional receptor occupancies in the putamen [DOPAC: (p < 0.01) and HVA: (p < 0.05)], caudate nucleus [HVA: (p < 0.01)], thalamus [MHPG: (p < 0.05)] and in the temporal cortex [HVA: (p < 0.05) and 5-HIAA: (p < 0.05)]. This suggests that CSF monoamine metabolites levels reflect the effects of quetiapine treatment on neurotransmitters in vivo and indicates that monitoring plasma and CSF quetiapine and norquetiapine levels may be of clinical relevance.