The thrombophilic network of autoantibodies in celiac disease

BACKGROUND: Celiac disease is a life-long autoimmune condition, affecting genetically susceptible individuals that may present with thromboembolic phenomena. This thrombophilia represents a puzzle with multiple constituents: hyperhomocysteinemia, B12 and\or folate deficiency, methylenetetrahydrofolate reductase mutations, and protein C and S deficiency due to vitamin K deficiency. However, the well known thrombogenic factors, antiphosphatidylserine/prothrombin and antiprothrombin have never been explored in celiac disease. METHODS: The serum autoantibody levels were determined in 248 individuals, classified into three groups. Group 1 comprised 70 children with definitive celiac disease (age: 7.04 ±4.3 years, male to female ratio 1.06) and group 2 comprised 88 normal children (age: 6.7 ±4.17 years, male to female ratio 0.87), representing controls. The pediatric populations were compared to group 3, which included 90 adults who were family members (parents) of group 1 (age: 34.6 ±11.35 years, male to female ratio 1.2). Antibodies were checked by enzyme-linked immunosorbent assay. RESULTS: Mean optical density levels of serum antiphosphatidylserine/prothrombin immunoglobulin G antibodies were 32.4 ±19.4, 3.6 ±2.5 and 16.1 ±15.8 absorbance units in groups 1, 2 and 3 respectively (P <0.0001), with 45.7%, 0% and 7.8% of groups 1, 2 and 3 respectively positive for the antibody (P <0.01). Mean optical density levels of serum antiphosphatidylserine/prothrombin immunoglobulin M antibodies were 14.2 ±8.7, 6.7 ±6.4 and 12.4 ±15.5 absorbance units in groups 1, 2 and 3 respectively (P <0.0001), with 7.1%, 3.4% and 9.9% of groups 1, 2 and 3 positive for the antibody. Mean optical density levels of serum antiprothrombin and antiphospholipid immunoglobulin G antibodies were higher in groups 1 and 3 compared with 2 (P <0.005) and in groups 1 and 2 compared with 3 (P <0.01), respectively. Groups 1, 2 and 3 were positive for antiphospholipid immunoglobulin G antibodies (groups 1 and 2 compared with 3) . Celiac disease sera harbor a higher antiprothrombin immunoglobulin G level compared with controls. CONCLUSIONS: It is suggested that the intestinal injury, endothelial dysfunction, platelet abnormality and enhanced apoptosis recently described in celiac disease are at the origin of the increased exposure of phospholipids or new epitopes representing autoantigens. Those autoantibodies might play a pathogenic role in the thrombophilia associated with celiac disease and represent markers for potential anticoagulant preventive therapy

Crises Press Coverage: Local & Foreign Reporting on the Arab-Israel Conflict

This study analyzes Israeli Haaretz and the American New York Times crisis press coverage on four short Arab-Israel crises, from the early 1950s to the late 1990s. To illuminate the similar and different reporting modes of the press from within and outside a conflict region, the article probes three hypotheses: reporting on the salient crisis events will differ (H1), reporting on conflict related events will differ (H2) and dominant media functions will differ (H3). Findings on most reporting variables examined in both newspapers support these hypotheses. Compared with the NYT, in Haaretz, overall crisis exposure was higher, crisis was addressed more frequently than conflict, use of pictures was negligible and surveillance substituted correlation. But in both papers, similar peaks and lulls were reported for all four short Arab-Israel crises, coverage of crisis was the overwhelming topic and surveillance was the dominant media function

Helicobacter pylori serology in autoimmune diseases - Fact or fiction?

Background: The pathogenesis of autoimmunity is presumed to be a complex process including genetic predisposition, hormonal balance and environmental factors such as infectious agents . Helicobacter pylori , a common bacterial infectious agent has been associated with a variety of autoimmune disorders. However, this bacteria is also thought to play a protective role in the development of multiple sclerosis (MS), systemic lupus erythematosus (SLE) and inflammatory bowel disease (IBD). We tested various links between anti- H. pylori (anti-HP) antibodies and a wide profile of autoimmune diseases and autoantibodies. Methods: A total of 1290 patients diagnosed with 14 different autoimmune diseases from two geographical areas (Europe and Latin America) and two groups of healthy matching controls (n = 385) were screened for the presence of H. pylori IgG antibodies by ' pylori detect ' kit. In parallel, a large profile belonging to three groups of autoantibodies was tested in all sera (anti-nuclear antibodies, autoantibodies associated with thrombophilia and gastrointestinal diseases). Results: Our data demonstrate associations between anti-HP antibodies and anti-phospholipid syndrome, giant cell arteritis, systemic sclerosis and primary biliary cirrhosis. Our data also support a previously known negative association between the prevalence of anti-HP antibodies and IBD. Additionally, links were made between seropositivity to H. pylori and the presence of anti-nuclear antibodies, dsDNA, anti-Ro and some thrombophiliaassociated antibodies, as well as negative associations with gastrointestinal-associated antibodies. Conclusions: Whether these links are epiphenomenal or H. pylori does play a causative role in the autoimmune diseases remains uncertain. The negative associations could possibly support the notion that in susceptible individuals infections may protect from the development of autoimmune diseases

Cellular Architecture Mediates DivIVA Ultrastructure and Regulates Min Activity in Bacillus subtilis

The assembly of the cell division machinery at midcell is a critical step of cytokinesis. Many rod-shaped bacteria position septa using nucleoid occlusion, which prevents division over the chromosome, and the Min system, which prevents division near the poles. Here we examined the in vivo assembly of the Bacillus subtilis MinCD targeting proteins DivIVA, a peripheral membrane protein that preferentially localizes to negatively curved membranes and resembles eukaryotic tropomyosins, and MinJ, which recruits MinCD to DivIVA. We used structured illumination microscopy to demonstrate that both DivIVA and MinJ localize as double rings that flank the septum and first appear early in septal biosynthesis. The subsequent recruitment of MinCD to these double rings would separate the Min proteins from their target, FtsZ, spatially regulating Min activity and allowing continued cell division. Curvature-based localization would also provide temporal regulation, since DivIVA and the Min proteins would localize to midcell after the onset of division. We use time-lapse microscopy and fluorescence recovery after photobleaching to demonstrate that DivIVA rings are highly stable and are constructed from newly synthesized DivIVA molecules. After cell division, DivIVA rings appear to collapse into patches at the rounded cell poles of separated cells, with little or no incorporation of newly synthesized subunits. Thus, changes in cell architecture mediate both the initial recruitment of DivIVA to sites of cell division and the subsequent collapse of these rings into patches (or rings of smaller diameter), while curvature-based localization of DivIVA spatially and temporally regulates Min activity

HPA axis activity in patients with panic disorder: review and synthesis of four studies

Dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis may play a role in panic disorder. HPA studies in patients with panic disorder, however, have produced inconsistent results. Seeking to understand the inconsistencies, we reexamined endocrine data from four studies of patients with panic disorder, in light of animal data highlighting the salience of novelty, control, and social support to HPA axis activity. Patients with panic disorder were studied (1) at rest over a full circadian cycle, (2) before and after activation by a panicogenic respiratory stimulant (doxapram) that does not directly stimulate the HPA axis, and (3) before and after a cholecystokinin B (CCK-B) agonist that is panicogenic and does directly stimulate the HPA axis. Patients with panic disorder had elevated overnight cortisol levels, which correlated with sleep disruption. ACTH and cortisol levels were higher in a challenge paradigm (doxapram) than in a resting state study, and paradigm-related ACTH secretion was exaggerated in patients with panic disorder. Panic itself could be elicited without HPA axis activation. Patients with panic disorder showed an exaggerated ACTH response to pentagastrin stimulation, but this response was normalized by prior exposure to the experimental context or psychological preparation to reduce novelty and enhance sense of control. Novelty is one of a number of contextual cues known from animal work to activate the HPA axis. The HPA axis abnormalities seen in patients with panic disorder in the four experiments reviewed here might all be due to exaggerated HPA axis reactivity to novelty cues. Most of the published panic/HPA literature is consistent with the hypothesis that HPA axis dysregulation in panic is due to hypersensitivity to contextual cues. This hypothesis requires experimental testing. Depression and Anxiety 24:66–76, 2007. Published 2006 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/55906/1/20220_ftp.pd

16/6-idiotype expressing antibodies induce brain inflammation and cognitive impairment in mice: the mosaic of central nervous system involvement in lupus

Background: The 16/6-idiotype (16/6-Id) of the human anti-DNA antibody was found to induce experimental lupus in naive mice, manifested by production of autoantibodies, leukopenia and elevated inflammatory markers, as well as kidney and brain involvement. We assessed behavior and brain pathology of naive mice injected intracerebra-ventricularly (ICV) with the 16/6-Id antibody. Methods: C3H female mice were injected ICV to the right hemisphere with the human 16/6-Id antibody or commercial human IgG antibodies (control). The mice were tested for depression by the forced swimming test (FST), locomotor and explorative activity by the staircase test, and cognitive functions were examined by the novel object recognition and Y-maze tests. Brain slices were stained for inflammatory processes. Results: 16/6-Id injected mice were cognitively impaired as shown by significant differences in the preference for a new object in the novel object recognition test compared to controls (P = 0.012). Similarly, the preference for spatial novelty in the Y-maze test was significantly higher in the control group compared to the 16/6-Id-injected mice (42% vs. 9%, respectively, P = 0.065). Depression-like behavior and locomotor activity were not significantly different between the16/6-Id-injected and the control mice. Immunohistochemistry analysis revealed an increase in astrocytes and microglial activation in the hippocampus and amygdala, in the 16/6-Id injected group compared to the control. Conclusions: Passive transfer of 16/6-Id antibodies directly into mice brain resulted in cognitive impairments and histological evidence for brain inflammation. These findings shed additional light on the diverse mosaic pathophysiology of neuropsychiatric lupus

Ultrasensitivity of the Bacillus subtilis sporulation decision

Starving Bacillus subtilis cells execute a gene expression program resulting in the formation of stress-resistant spores. Sporulation master regulator, Spo0A, is activated by a phosphorelay and controls the expression of a multitude of genes, including the forespore- specific sigma factor σF and the mother cell-specific sigma factor σE. Identification of the system-level mechanism of the sporulation decision is hindered by a lack of direct control over Spo0A activity. This limitation can be overcome by using a synthetic system in which Spo0A activation is controlled by inducing expression of phosphorelay kinase KinA. This induction results in a switch-like increase in the number of sporulating cells at a threshold of KinA. Using a combination of mathematical modeling and single-cell microscopy, we investigate the origin and physiological significance of this ultrasensitive threshold. The results indicate that the phosphorelay is unable to achieve a sufficiently fast and ultrasensitive response via its positive feedback architecture, suggesting that the sporulation decision is made downstream. In contrast, activation of σF in the forespore and of σE in the mother cell compartments occurs via a cascade of coherent feed-forward loops, and thereby can produce fast and ultrasensitive responses as a result of KinA induction. Unlike σF activation, σE activation in the mother cell compartment only occurs above the KinA threshold, resulting in completion of sporulation. Thus, ultrasensitive σE activation explains the KinA threshold for sporulation induction. We therefore infer that under uncertain conditions, cells initiate sporulation but postpone making the sporulation decision to average stochastic fluctuations and to achieve a robust population response

Maternal hormonal milieu influence on fetal brain development

An adverse maternal hormonal environment during pregnancy can be associated with abnormal brain growth. Subtle changes in fetal brain development have been observed even for maternal hormone levels within the currently accepted physiologic ranges. In this review, we provide an update of the research data on maternal hormonal impact on fetal neurodevelopment, giving particular emphasis to thyroid hormones and glucocorticoids. Thyroid hormones are required for normal brain development. Despite serum TSH appearing to be the most accurate indicator of thyroid function in pregnancy, maternal serum free T4 levels in the first trimester of pregnancy are the major determinant of postnatal psychomotor development. Even a transient period of maternal hypothyroxinemia at the beginning of neurogenesis can confer a higher risk of expressive language and nonverbal cognitive delays in offspring. Nevertheless, most recent clinical guidelines advocate for targeted high-risk case finding during first trimester of pregnancy despite universal thyroid function screening. Corticosteroids are determinant in suppressing cell proliferation and stimulating terminal differentiation, a fundamental switch for the maturation of fetal organs. Not surprisingly, intrauterine exposure to stress or high levels of glucocorticoids, endogenous or synthetic, has a molecular and structural impact on brain development and appears to impair cognition and increase anxiety and reactivity to stress. Limbic regions, such as hippocampus and amygdala, are particularly sensitive. Repeated doses of prenatal corticosteroids seem to have short-term benefits of less respiratory distress and fewer serious health problems in offspring. Nevertheless, neurodevelopmental growth in later childhood and adulthood needs further clarification. Future studies should address the relevance of monitoring the level of thyroid hormones and corticosteroids during pregnancy in the risk stratification for impaired postnatal neurodevelopment.This work was supported by the grant "Doutoramento em Medicina Jose de Mello Saude 2014" by Jose de Mello Saude to AM

Molecular psychiatry of zebrafish

Due to their well-characterized neural development and high genetic homology to mammals, zebrafish (Danio rerio) have emerged as a powerful model organism in the field of biological psychiatry. Here, we discuss the molecular psychiatry of zebrafish, and its implications for translational neuroscience research and modeling central nervous system (CNS) disorders. In particular, we outline recent genetic and technological developments allowing for in vivo examinations, high-throughput screening and whole-brain analyses in larval and adult zebrafish. We also summarize the application of these molecular techniques to the understanding of neuropsychiatric disease, outlining the potential of zebrafish for modeling complex brain disorders, including attention-deficit/hyperactivity disorder (ADHD), aggression, post-traumatic stress and substance abuse. Critically evaluating the advantages and limitations of larval and adult fish tests, we suggest that zebrafish models become a rapidly emerging new field in modern molecular psychiatry research

Minimising fear and anxiety in working dogs:a review

The causes of fear and anxiety in working dogs are multifactorial and may include inherited characteristics that differ between individuals (e.g. Goddard and Beilharz, 1982; 1984a,b ), influences of the environment ( Lefebvre et al., 2007 ), and learned experiences during particular sensitive periods ( Appleby et al., 2002 ) and throughout life. Fear-related behavior compromises performance, leads to significant numbers of dogs failing to complete training (e.g., Murphy, 1995; Batt et al., 2008 ), early withdrawals from working roles ( Caron-Lormier et al., 2016 ), and can jeopardize dog and handler safety. Hence, amelioration of fear and anxiety is critical to maintain dogs in working roles and to ensure their well-being. Although current methods of selection and training are seemingly effective at producing many dogs which work in a remarkable array of environments, some dogs do not make the grade, and longevity of service is not always maximized. Programs should strive for optimal efficiency and they need to continually analyze the value of each component of their program, seek evidence for its value and explore potential evidence-based improvements. Here we discuss scientific evidence for methods and strategies which may be of value in reducing the risk of fear behaviors developing in the working dog population and suggest potentially valuable techniques and future research to explore the benefit of these approaches. The importance of environmental influences, learning opportunities, and effects of underlying temperament on the outward expression of fear and anxiety should not be underestimated. Identification of characteristics which predict resilience to stress are valuable, both to enable careful breeding for these traits and to develop predictive tests for puppies and procured animals. It is vitally important to rear animals in optimal environments and introduce them to a range of stimuli in a positive, controlled, and gradual way, as these can all help minimize the number of dogs which develop work-inhibiting fears. Future research should explore innovative methods to best measure the relative resilience of dogs to stressful events. This could include developing optimal exposure protocols to minimize the development of fear and anxiety, and exploring the influence of social learning and the most effective elements of stimulus presentation