Background
In the last decade, a disorder characterized by episodes of involuntary movements and dystonia has been recognized in Border Terriers.
Objectives
To define clinical features of paroxysmal ...dyskinesia (PD) in a large number of Border Terriers and to study the genetics of the disease.
Animals
110 affected and 128 unaffected client‐owned Border Terriers.
Methods
A questionnaire regarding clinical characteristics of PD was designed at Utrecht University and the University of Helsinki. Thirty‐five affected Border Terriers underwent physical examination and blood testing (hematology and clinical biochemistry). Diagnostic imaging of the brain was performed in 17 affected dogs and electroencephalograms (EEG) between episodes were obtained in 10 affected dogs. A genomewide association study (GWAS) was performed with DNA of 110 affected and 128 unaffected dogs.
Results
One hundred forty‐seven questionnaires were included in the study. The most characteristic signs during episodes were dystonia, muscle fasciculations, and falling over. The majority of owners believed that their dogs remained conscious during the episodes. A beneficial effect of anti‐epileptic therapy was observed in 29 of 43 dogs. Fifteen owners changed their dogs’ diet to a hypoallergenic, gluten‐free diet, and all reported reasonable to good improvement of signs. Clinical examinations and diagnostic test results were unremarkable. The GWAS did not identify significantly associated chromosome regions.
Conclusions and Clinical Importance
The survey results and EEG studies provided further evidence that the observed syndrome is a PD rather than epilepsy. Failure to achieve conclusive results by GWAS indicates that inheritance of PD in Border Terriers probably is complex.
Coeliac disease is caused by dietary gluten, triggering a chronic inflammation of the small intestine in genetically predisposed individuals. Recently, a risk locus on chromosome 2q11–q12, harbouring ...interleukin 18 receptor accessory protein (IL18RAP) and three other genes, was suggested for coeliac disease. IL18 has been shown to play an important role in T helper type 1 activity in coeliac disease, making this locus a highly interesting candidate. In this study, two previously indicated risk variants at the IL18RAP locus (rs13015714 and rs917997) were tested for genetic association in 1638 cases with coeliac disease and 1385 control individuals from the Finnish, Hungarian and Italian populations. The protein expression level of IL18RAP was also compared between risk allele carriers and non-carriers by Western blotting. Furthermore, immunohistochemical analysis was performed to study IL18RAP protein expression in small intestinal biopsies of untreated and treated coeliac patients and controls. We confirmed genetic association and dose effects of variants at the 2q12.1 locus with coeliac disease in the Hungarian population. The GA haplotype of the markers rs13015714 and rs917997 showed the strongest association (P = 0.0001, odds ratio = 1.475, 95% confidence interval 1.21–1.80). Two putative isoforms of IL18RAP were detected and the ratios and total levels of these isoforms may contribute to the aetiology of coeliac disease. Our study supports IL18RAP as a novel predisposing gene for coeliac disease and highlights the need for further functional studies on this relatively unknown gene in coeliac disease pathogenesis.
Coeliac disease is caused by dietary gluten, which triggers chronic inflammation of the small intestine in genetically predisposed individuals. In one quarter of the patients the disease manifests in ...the skin as dermatitis herpetiformis. Recently, a novel candidate gene, myosin IXB on chromosome 19p13, was shown to be associated with coeliac disease in the Dutch and Spanish populations. The same gene has previously been associated with inflammatory bowel disease, systemic lupus erythematosus and rheumatoid arthritis risk, making myosin IXB a potential shared risk factor in these inflammatory disorders.
In this study, previously reported myosin IXB variants were tested for genetic linkage and association with coeliac disease in 495 Hungarian and Finnish families and in an additional 270 patients and controls.
The results show significant linkage (logarithm of odds (LOD) 3.76, p = 0.00002) to 19p13 which supports the presence of a genuine risk factor for coeliac disease in this locus. Myosin IXB variants were not associated with coeliac disease in this study; however, weak evidence of association with dermatitis herpetiformis was found. The association could not explain the strong linkage seen in both phenotypes, indicating that the role of other neighbouring genes in the region cannot be excluded. Therefore, more detailed genetic and functional studies are required to characterise the role of the myosin IXB gene in both coeliac disease and dermatitis herpetiformis.
In celiac disease, gluten ingestion provokes small-bowel mucosal injury and production of IgA autoantibodies against transglutaminase 2 (TG2). It has been suggested that in celiac patients IgA could ...mediate the transepithelial passage of gluten peptides in a mechanism involving the transferrin receptor. As IgA1 with galactose-deficient
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-linked glycans has elevated affinity for the transferrin receptor, we assessed whether total serum IgA1 and IgA1 anti-TG2 autoantibodies in celiac patients are aberrantly glycosylated. We report that males with celiac disease have higher total serum levels of galactose-deficient IgA1 than non-celiac males. Furthermore,
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-glycans of the disease-specific TG2 IgA1 autoantibodies in celiac patients exhibited elevated galactose deficiency. A gluten-free diet had no effect on the total serum levels of galactose-deficient IgA1, whereas the amount of galactose-deficient anti-TG2 IgA1 decreased. Thus, the undergalactosylated IgA1 molecules are not pathognomonic for celiac disease, but galactose deficiency in IgA1 could be an aggravating factor.
Celiac disease is an inflammatory enteropathy caused by intolerance to gluten. Previous linkage studies in the Dutch, Finnish and Hungarian populations have revealed a locus on chromosome 6q21-22 ...conferring susceptibility to celiac disease. This locus has previously been implicated in susceptibility to other autoimmune diseases such as Crohn's disease and type 1 diabetes. We performed fine mapping on 446 independent individuals with celiac disease and 641 controls of Dutch origin, testing 872 tagging SNPs in a 22 Mb region of chromosome 6. The 12 most promising SNPs were followed up in 2071 individuals from 284 Finnish and 357 Hungarian celiac disease families to identify risk variants in this region. Multiple markers in the region were significantly associated with celiac disease in the Dutch material. Two SNPs, rs9391227 and rs4946111, were significantly associated with celiac disease in the Finnish population. The association to rs9391227 represents the strongest association signal found in the Finnish (P = 0.003, OR 0.66) as well as the combined Dutch, Finnish and Hungarian populations (P = 3.6 × 10(-5), OR 0.76). The rs9391227 is situated downstream of the HECT domain and ankyrin repeat containing, E3 ubiquitin protein ligase 1 (HACE1) gene and is contained within a region of strong linkage disequilibrium enclosing HACE1. Two additional, independent, susceptibility variants in the 6q21-22 region were also found in a meta-analysis of the three populations. The 6q21-22 region was confirmed as a celiac disease susceptibility locus and harbors multiple independent associations, some of which may implicate ubiquitin-pathways in celiac disease susceptibility.
Association of the interleukin-23 receptor (IL23R) with inflammatory bowel disease (IBD) has been confirmed in several populations. IL23R also associates with psoriasis, suggesting that the gene may ...be an important candidate for many chronic inflammatory diseases.
We studied association of single-nucleotide variants in IL23R with IBD in Swedish patients, in both Crohn's disease (CD) and ulcerative colitis (UC) subsets. The same genetic variants were also studied in Finnish patients with psoriasis or celiac disease, and in Hungarian and Italian patients with celiac disease.
Association of IL23R with IBD was replicated in our Swedish patients, and linkage and association of the IL23R region with psoriasis was found in the Finnish population. The IL23R region was also linked to celiac disease in Finnish families, but no association of IL23R variants with celiac disease was found in the Finnish, Hungarian or Italian samples.
Our study is the first to demonstrate association of IL23R with CD and UC in Swedish patients with IBD. It is also the first study to report linkage and association of the IL23R region with psoriasis in the Finnish population. Importantly, this is the first report of linkage of the IL23R region to celiac disease, a chronic inflammatory condition in which IL23R has not been previously implicated.
Recent interest in intracranial pressure (ICP) in the upright posture has revealed that the mechanisms regulating postural changes in ICP are not fully understood. We have suggested an explanatory ...model where the postural changes in ICP depend on well-established hydrostatic effects in the venous system and where these effects are interrupted by collapse of the internal jugular veins (IJVs) in more upright positions. The aim of this study was to investigate this relationship by simultaneous invasive measurements of ICP, venous pressure, and IJV collapse in healthy volunteers. ICP (monitored via the lumbar route), central venous pressure (peripherally inserted central catheter line), and IJV cross-sectional area (ultrasound) were measured in 11 healthy volunteers (47 ± 10 yr, mean ± SD) in 7 positions, from supine to sitting (0-69°). Venous pressure and anatomical distances were used to predict ICP in accordance with the explanatory model, and IJV area was used to assess IJV collapse. The hypothesis was tested by comparing measured ICP with predicted ICP. Our model accurately described the general behavior of the observed postural ICP changes (mean difference, -0.03 ± 2.7 mmHg). No difference was found between predicted and measured ICP for any tilt angle ( P values, 0.65-0.94). The results support the hypothesis that postural ICP changes are governed by hydrostatic effects in the venous system and IJV collapse. This improved understanding of postural ICP regulation may have important implications for the development of better treatments for neurological and neurosurgical conditions affecting ICP.
We present a new framework to study the time evolution and dynamics of the outer Van Allen belt electron fluxes. The framework is entirely based on the large‐scale solar wind storm drivers and their ...substructures. The Van Allen Probe observations, revealing the electron flux behavior throughout the outer belt, are combined with continuous, long‐term (over 1.5 solar cycles) geosynchronous orbit data set from GOES and solar wind measurements A superposed epoch analysis, where we normalize the timescales for each substructure (sheath, ejecta, and interface region) allows us to avoid smearing effects and to distinguish the electron flux evolution during various driver structures. We show that the radiation belt response is not random: The electron flux variations are determined by the combined effect of the structured solar wind driver and prestorm electron flux levels. In particular, we find that loss mechanisms dominate during stream interface regions, coronal mass ejection (CME) ejecta, and sheaths while enhancements occur during fast streams trailing the stream interface or the CME.
Key Points
We superpose the different substructures of each solar wind storm driver
During stream interface regions, CME ejecta and sheaths loss mechanisms dominate
Enhancements occur during fast streams trailing the stream interface or the CME
It has recently been proposed that ripples inherent to the bow shock during radial interplanetary magnetic field (IMF) may produce local high speed flows in the magnetosheath. These jets can have a ...dynamic pressure much larger than the dynamic pressure of the solar wind. On 17 March 2007, several jets of this type were observed by the Cluster spacecraft. We study in detail these jets and their effects on the magnetopause, the magnetosphere, and the ionospheric convection. We find that (1) the jets could have a scale size of up to a few RE but less than ~6 RE transverse to the XGSE axis; (2) the jets caused significant local magnetopause perturbations due to their high dynamic pressure; (3) during the period when the jets were observed, irregular pulsations at the geostationary orbit and localised flow enhancements in the ionosphere were detected. We suggest that these inner magnetospheric phenomena were caused by the magnetosheath jets.
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