Disturbed function of the blood–cerebrospinal fluid barrier aggravates neuro-inflammation

Multiple sclerosis (MS) is a chronic neuro-inflammatory disorder, which is marked by the invasion of the central nervous system by monocyte-derived macrophages and autoreactive T cells across the brain vasculature. Data from experimental animal models recently implied that the passage of leukocytes across the brain vasculature is preceded by their traversal across the blood–cerebrospinal fluid barrier (BCSFB) of the choroid plexus. The correlation between the presence of leukocytes in the CSF of patients suffering from MS and the number of inflammatory lesions as detected by magnetic resonance imaging suggests that inflammation at the choroid plexus contributes to the disease, although in a yet unknown fashion. We here provide first insights into the involvement of the choroid plexus in the onset and severity of the disease and in particular address the role of the tight junction protein claudin-3 (CLDN3) in this process. Detailed analysis of human post-mortem brain tissue revealed a selective loss of CLDN3 at the choroid plexus in MS patients compared to control tissues. Importantly, mice that lack CLDN3 have an impaired BCSFB and experience a more rapid onset and exacerbated clinical signs of experimental autoimmune encephalomyelitis, which coincides with enhanced levels of infiltrated leukocytes in their CSF. Together, this study highlights a profound role for the choroid plexus in the pathogenesis of multiple sclerosis, and implies that CLDN3 may be regarded as a crucial and novel determinant of BCSFB integrity.     

Variation in inflammatory/regulatory cytokines in secondary, tertiary, and quaternary challenges with dengue virus

Abstract. Secondary heterologous dengue infection is a risk factor for severe disease manifestations because of the immune-enhancement phenomenon. Succeeding clinical infections are seldom reported, and the clinical course of tertiary and quaternary dengue infections is not clear. Cuba represents a unique environment to study tertiary/quaternary dengue infections in a population with known clinical and serologic dengue markers and no dengue endemicity. We took advantage of this exceptional epidemiologic condition to study the effect of primary, secondary, tertiary, and quaternary dengue infection exposure on the expression of pro-inflammatory and regulatory cytokines, critical in dengue infection pathogenesis, by using a dengue infection ex vivo model. Whereas secondary exposure induced a high cytokine response, we found a significantly lower expression of tumor necrosis factor-α, interferon-γ, interleukin-10, and tumor growth factor-β after tertiary and quaternary infectious challenge. Significant differences in expression of the cytokines were seen between the dengue immune profiles, suggesting that the sequence in which the immune system encounters serotypes may be important in determining the nature of the immune response to subsequent infections.     

Lymphoid progenitors in normal mouse lymph nodes develop into NK cells and T cells in vitro and in vivo

We have identified a population of normal mouse LN cells, termed LN lymphoid progenitor (LNLP), resembling common lymphoid progenitor (CLP) in the bone marrow. LNLPs lack lineage markers and express CD127, low levels of CD117 (c-Kit), and Sca-1, but lack fms-related tyrosine kinase 3. They efficiently differentiate in vitro into natural killer (NK) cells and T cells, but not mature B cells. LNLPs injected into nonirradiated lymphopenic mice that have no LN develop into mostly splenic T cells with low numbers of NK cells and B cells. When injected into irradiated mice, they generate NK cells and T cells, but not B cells, in the LN. By contrast, bone marrow CLPs develop into mostly B cells with very small numbers of T and NK cells in recipients' spleen and LN. LNLPs have NK and T-cell potentials, but little B-cell potential, and they can develop into NK cells within the LN of normal mice, but their contribution to the T-cell lineage is unknown.     

Subarachnoid haemorrhage WFNS grade V: is maximal treatment worthwhile?

Background

Aneurysmal subarachnoid haemorrhage (SAH) WFNS grade V is commonly known to be associated with high mortality and a very poor prognosis for survivors. Therefore, maximal invasive therapy is frequently delayed until any spontaneous improvement with or without an external ventricular drainage occurs. The aim of the study was to verify possible predictive factors and the probability of a favourable outcome in maximally treated patients.

Methods

One hundred and thirty-eight consecutive patients with WFNS grade V SAH were admitted between 03/2006 and 12/2010. Thirty-five patients died before aggressive therapy could proceed. One hundred and three patients received maximal treatment and were retrospectively evaluated. The outcome was assessed at discharge and in the follow-up with the Glasgow Outcome Scale. Univariate and multivariate linear regression models were performed to find predictors for an unfavourable outcome.

Results

Despite treatment, early mortality was 30 % (n?=?31). At discharge, the rate of both vegetative and severely disabled patients was 27 % (n?=?28). Favourable outcome at discharge was observed in 16 % (n?=?16) of cases, whereas in the follow-up it rose to 26 % (n?=?27). Multivariate full model regression identified intraventricular haematoma (IVH) and increasing age as independently predictive for poor outcome.

Conclusions

Despite treatment, initial mortality and severe disability remain high. Nevertheless, a favourable outcome was achieved in 26 % of aggressively treated patients, rendering the withdrawal of maximal therapy for WFNS grade V SAH patients unacceptable today. In cases of old patients with IVH, the indication for aggressive therapy should be put in place more carefully due to a very poor prognosis.     

Association Between Gout and All-Cause as well as Cardiovascular Mortality: A Systematic Review

Gout affects 1% to 2% of the population, and the prevalence is increasing due to changes in diet and the ageing of the population. Its development and risk factors have been explored frequently, and recommendations for the diagnosis and management of gout implemented. Nevertheless, there is a lack of knowledge regarding the long-term impact on gouty patients. This systematic review therefore evaluates the association between gout and all-cause as well as cardiovascular mortality. A systematic literature search was performed, and seven long-term studies were ultimately analyzed. Six of them used multivariate regressions to assess the adjusted mortality ratio in gouty patients with reference to patients without the disorder. Despite differences in study designs, study populations, and definitions of gout, the results were consistent: There was an independent association between gout and all-cause as well as cardiovascular mortality. Knowing that patients with gout are at risk emphasizes the need for adequate care.     

CRS-R score in disorders of consciousness is strongly related to spectral EEG at rest

Patients suffering from disorders of consciousness still present a diagnostic challenge due to the fact that their assessment is mainly based on behavioral scales with their motor responses often being strongly impaired. We therefore focused on resting electroencephalography (EEG) in order to reveal potential alternative measures of the patient’s current state independent of rather complex abilities (e.g., language comprehension). Resting EEG was recorded in nine minimally conscious state (MCS) and eight vegetative state/unresponsive wakefulness syndrome (VS/UWS) patients. Behavioral assessments were conducted using the Coma-Recovery Scale—Revised (CRS-R). The signal was analyzed in the frequency domain and association between resting EEG and CRS-R score as well as clinical diagnosis were calculated using Pearson correlation and repeated-measures ANOVAs. The analyses revealed robust positive correlations between CRS-R score and ratios between frequencies above 8 Hz and frequencies below 8 Hz. Furthermore, the frequency of the spectral peak was also highly indicative of the patient’s CRS-R score. Concerning differences between clinical diagnosis and healthy controls, it could be revealed that while VS/UWS patients showed higher delta and theta activity than controls, MCS did not differ from controls in this frequency range. Alpha activity, on the other hand, was strongly decreased in both patient groups as compared to controls. The strong relationship between various resting EEG parameters and CRS-R score provides significant clinical relevance. Not only is resting activity easily acquired at bedside, but furthermore, it does not depend on explicit cooperation of the patient. Especially in cases where behavioral assessment is difficult or ambiguous, spectral analysis of resting EEG can therefore complement clinical diagnosis.     

Exercise Reveals the Interrelation of Physical Fitness,Inflammatory Response,Psychopathology, and Autonomic Function in Patients With Schizophrenia

Maintaining and improving fitness are associated with a lower risk of premature death from cardiovascular disease. Patients with schizophrenia are known to exercise less and have poorer health behaviors than average. Physical fitness and physiological regulation during exercise tasks have not been investigated to date among patients with schizophrenia. We studied autonomic modulation in a stepwise exhaustion protocol in 23 patients with schizophrenia and in matched controls, using spirometry and lactate diagnostics. Parameters of physical capacity were determined at the aerobic, anaerobic, and vagal thresholds (VT), as well as for peak output. VT was correlated with psychopathology, as assessed by the Positive and Negative Syndrome Scale, with the inflammatory markers IL-1β, IL-6, and TNF-α and with peak output. The MANOVA for heart and breathing rates, as well as for vagal modulation and complexity behavior of heart rate, indicated a profound lack of vagal modulation at all intensity levels, even after the covariate carbon monoxide concentration was introduced as a measure of smoking behavior. Significantly decreased physical capacity was demonstrated at the aerobic, anaerobic, and VT in patients. After the exercise task, reduced vagal modulation in patients correlated negatively with positive symptoms and with levels of IL-6 and TNF-α. This study shows decreased physical capacity in patients with schizophrenia. Upcoming intervention studies need to take into account the autonomic imbalance, which might predispose patients to arrhythmias during exercise. Results of inflammatory parameters are suggestive of a reduced activity of the anti-inflammatory cholinergic pathway in patients, leading to a pro-inflammatory state.Key words: heart rate, physical exercise, respiration, schizophrenia, vagal threshold, cardiac death, inflammation, physical fitness