Bipolar Role for Myelo-Monocytic Cells in Autoimmune Diseases and Psychiatric Disorders

__Abstract__ The immune system is a complex system of tissue with cells and messenger molecules interacting to protect an organism against pathogens. Autoimmunity is the failure of the immune system to recognize its own constituent parts as harmless self and therefore it leads to an immune response against its own cells and tissues. Diseases that are a results of autoimmunity are called autoimmune diseases. Autoimmune diseases discussed in this thesis are autoimmune thyroid disease (AITD), where thyrocytes of the thyroid gland are the target of the immune system and type 1 diabetes mellitus (T1DM), characterized by an autoimmune destruction of the insulin-producing β cells of the Islets of Langerhans in the pancreas. Various epidemiological studies have shown the association of psychiatric disease with AITD and T1D (and other autoimmune diseases), not only in patients, but also and independently in not affected family members of patients. This suggests a common underlying abnormality responsible for both the autoimmune endocrin

Prevalence of interferon type I signature in CD14 monocytes of patients with Sjögren's syndrome and association with disease activity and BAFF gene expression

Objective To determine the prevalence of upregulation of interferon (IFN) type I inducible genes, the so called "IFN type I signature", in CD14 monocytes in 69 patients with primary Sjögren's syndrome (pSS) and 44 healthy controls (HC) and correlate it with disease manifestations and expression of B cell activating factor (BAFF). Methods Expression of IFI44L, IFI44, IFIT3, LY6E and MX1 was measured using real time quantitative PCR in monocytes. Expression values were used to calculate IFN type I scores for each subject. pSS patients positive for the IFN type I signature (IFN score≥10) and patients negative for the signature (IFN score<10) were then compared for clinical disease manifestations and BAFF expression. A bioassay using a monocytic cell line was performed to study whether BAFF mRNA expression was inducible by IFN type I activity in serum of patients with pSS. Results An IFN type I signature was present in 55% of patients with pSS compared with 4.5% of HC. Patients with the IFN type I signature showed: (a) higher EULAR Sjögren'

Observer variability of absolute and relative thrombus density measurements in patients with acute ischemic stroke

Introduction: Thrombus density may be a predictor for acute ischemic stroke treatment success. However, only limited data on observer variability for thrombus density measurements exist. This study assesses the variability and bias of four common thrombus density measurement methods by expert and non-expert observers. Methods: For 132 consecutive patients with acute ischemic stroke, three experts and two trained observers determined thrombus density by placing three standardized regions of interest (ROIs) in the thrombus and corresponding contralateral arterial segment. Subsequently, absolute and relative thrombus densities were determined using either one or three ROIs. Intraclass correlation coefficient (ICC) was determined, and Bland–Altman analysis was performed to evaluate interobserver and intermethod agreement. Accuracy of the trained observer was evaluated with a reference expert observer using the same statistical analysis. Results: The highest interobserver agreement was obtained for absolute thrombus measurements using three ROIs (ICCs ranging from 0.54 to 0.91). In general, interobserver agreement was lower for relative measurements, and for using one instead of three ROIs. Interobserver agreement of trained non-experts and experts was similar. Accuracy of the trained observer measurements was comparable to the expert interobserver agreement and was better for absolute measurements and with three ROIs. The agreement between the one ROI and three ROI methods was good. Conclusion: Absolute thrombus density measurement has superior interobserver agreement compared to relative density measurement. Interobserver variation is smaller when multiple ROIs are used. Trained non-expert observers can accurately and reproducibly assess absolute thrombus densities using three ROIs

Two-year clinical follow-up of the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in The Netherlands (MR CLEAN): Design and statistical analysis plan of the extended follow-up study

Background: MR CLEAN was the first randomized trial to demonstrate the short-term clinical effectiveness of endovascular treatment in patients with acute ischemic stroke caused by large vessel occlusion in the anterior circulation. Several other trials confirmed that endovascular treatment improves clinical outcome at three months. However, limited data are available on long-term clinical outcome. We aimed to estimate the effect of endovascular treatment on functional outcome at two-year follow-up in patients with acute ischemic stroke. Secondly, we aimed to assess the effect of endovascular treatment on major vascular events and mortality during two years of follow-up. Methods: MR CLEAN is a multicenter clinical trial with randomized treatment allocation, open-label treatment, and blinded endpoint evaluation. Patients included were 18 years or older with acute ischemic stroke caused by a proven anterior proximal artery occlusion who could be treated within six hours after stroke onset. The intervention contrast was endovascular treatment and usual care versus no endovascular treatment and usual care. The current study extended the follow-up duration from three months to two years. The primary outcome is the score on the modified Rankin scale at two years. Secondary outcomes include all-cause mortality and the occurrence of major vascular events within two years of follow-up. Discussion: The results of our study provide information on the long-term clinical effectiveness of endovascular treatment, which may have implications for individual treatment decisions and estimates of cost-effectiveness. Trial registration:NTR1804. Registered on 7 May 2009; ISRCTN10888758. Registered on 24 July 2012 (main MR CLEAN trial); NTR5073. Registered on 26 February 2015 (extended follow-up study)

Emergence of surfactant-​free micelles from ternary solutions

Curious effects ranging from enzyme activity to anomalies in evapn. rates that have been known for over fifty years suggest the existence and thermodn. stability of surfactant-free micelles. Only recently, joint X-ray, light and neutron scattering expts. have demonstrated that aggregates and bulk pseudo-phases coexist in presumably normal solns., in which a water insol. component is solubilized in a certain domain of concn. of a hydrotrope component like ethanol. Nevertheless, nothing is known about the mol.-level shape and structure of such aggregates. In this work we characterize mixts. of octanol, ethanol, and water by mol. dynamics simulations. For compns. in the "pre-ouzo" region (close to the single phase stability limit) we observe micelle-like aggregates that are clearly distinct from simple crit. d. fluctuations. We define an ethanol partition in the pseudo-phase from an integral of the van der Waals dispersion energy term. From this partition, octanol-rich aggregates swollen with ethanol appear with an emerging interface. Ethanol is present in the water pseudo-phase with an exponential decay similar to the one predicted by Marcelja and Radic forty years ago

The immune theory of psychiatric diseases: A key role for activated microglia and circulating monocytes

This review describes a key role for mononuclear phagocytes in the pathogenesis of major psychiatric disorders. There is accumulating evidence for activation of microglia (histopathology and PET scans) and circulating monocytes (enhanced gene expression of immune genes, an overproduction of monocyte/macro-phage-related cytokines) in patients with bipolar disorder, major depressive disorder, and schizophrenia. These data are strengthened by observations in animal models, such as the MIA models, the chronic stress models, and the NOD mouse model. In these animal models of depressive-, anxiety-, and schizophrenia-like behavior, similar activations of microglia and circulating monocytes can be found. These animal models also make in-depth pathogenic studies possible and show that microglia activation impacts neuronal development and function in brain areas congruent with the altered depressive and schizophrenia-like behaviors

Animal models for cystic fibrosis: a systematic search and mapping review of the literature. Part 2: nongenetic models

Various animal models are available to study cystic fibrosis (CF). These models may help to enhance our understanding of the pathology and contribute to the development of new treatments. We systematically searched all publications on CF animal models. Because of the large number of models retrieved, we split this mapping review into two parts. Previously, we presented the genetic CF animal models. In this paper we present the nongenetic CF animal models. While genetic animal models may, in theory, be preferable for genetic diseases, the phenotype of a genetic model does not automatically resemble human disease. Depending on the research question, other animal models may thus be more informative. We searched Pubmed and Embase and identified 12,303 unique publications (after duplicate removal). All references were screened for inclusion by two independent reviewers. The genetic animal models for CF (from 636 publications) were previously described. The non-genetic CF models (from 189 publications) are described in this paper, grouped by model type: infection-based, pharmacological, administration of human materials, xenografts and other. As before for the genetic models, an overview of basic model characteristics and outcome measures is provided. This CF animal model overview can be the basis for an objective, evidence-based model choice for specific research questions. Besides, it can help to retrieve relevant background literature on outcome measures of interest

The effect of age on outcome after intraarterial treatment in acute ischemic stroke: a MR CLEAN pretrial study

Background: In recent randomized controlled trials (RCTs) intra-arterial treatment (IAT) has been proven effective and safe for patients with acute ischemic stroke (AIS). So far, there seemed to be no interaction between older age (>80) and main treatment effect. We studied the association of older age with outcome and adverse events after IAT in a cohort of intra arterially treated patients. Methods and findings: Data from all AIS patients with proven proximal anterior circulation cerebral artery occlusion who were intra arterially treated between 2002 until the start of the MR CLEAN trial were studied retrospectively. Duration of the procedure, recanalization (Thrombolysis In Cerebral Infarction score (TICI)), early neurological recovery (i.e. decrease on NIHSS of ≥ 8 points) after one week or at discharge, good functional outcome at discharge by modified Rankin Scale (mRS ≤ 2) and the occurrence of neurological and non-neurological adverse events were assessed and the association with age was investigated. In total 315 patients met our inclusion criteria. Median age was 63 years (range 22-93) and 17 patients (5.4 %) were over 80. Age was inversely associated with good functional outcome (adjusted Odds Ratio (aOR) 0.80, 95 % CI: 0.66-0.98) for every 10 years increase of age. Age was not associated with longer duration of the procedure, lower recanalization rate or less early neurological recovery. The risk of all adverse events (aOR 1.27; 95 % CI: 1.08-1.50) and non-neurological adverse events (aOR 1.34; 95 % CI: 1.11-1.61) increased, but that of peri-procedural adverse events (aOR 0.79; 95 % CI: 0.66-0.94) decreased with age. Conclusion: Higher age is inversely associated with good functional outcome after IAT in

The effect of age on outcome after intra-arterial treatment in acute ischemic stroke : A MR CLEAN pretrial study

Background: In recent randomized controlled trials (RCTs) intra-arterial treatment (IAT) has been proven effective and safe for patients with acute ischemic stroke (AIS). So far, there seemed to be no interaction between older age (>80) and main treatment effect. We studied the association of older age with outcome and adverse events after IAT in a cohort of intra arterially treated patients. Methods and findings: Data from all AIS patients with proven proximal anterior circulation cerebral artery occlusion who were intra arterially treated between 2002 until the start of the MR CLEAN trial were studied retrospectively. Duration of the procedure, recanalization (Thrombolysis In Cerebral Infarction score (TICI)), early neurological recovery (i.e. decrease on NIHSS of ≥ 8 points) after one week or at discharge, good functional outcome at discharge by modified Rankin Scale (mRS ≤ 2) and the occurrence of neurological and non-neurological adverse events were assessed and the association with age was investigated. In total 315 patients met our inclusion criteria. Median age was 63 years (range 22-93) and 17 patients (5.4 %) were over 80. Age was inversely associated with good functional outcome (adjusted Odds Ratio (aOR) 0.80, 95 % CI: 0.66-0.98) for every 10 years increase of age. Age was not associated with longer duration of the procedure, lower recanalization rate or less early neurological recovery. The risk of all adverse events (aOR 1.27; 95 % CI: 1.08-1.50) and non-neurological adverse events (aOR 1.34; 95 % CI: 1.11-1.61) increased, but that of peri-procedural adverse events (aOR 0.79; 95 % CI: 0.66-0.94) decreased with age. Conclusion: Higher age is inversely associated with good functional outcome after IAT in patients with AIS. However, treatment related adverse events are not related to age. These findings may help decision making when considering treatment of older patients with AIS