Pathological breakdown of the blood-brain barrier (BBB) is thought to constitute the beginning of the disease process in neuromyelitis optica (NMO). In the current study, we investigated possible ...molecular mechanisms responsible for the breakdown of BBB using NMO sera.
We analysed the effects of sera obtained from anti-aquaporin 4 (AQP4) antibody-positive NMO spectrum disorder (NMOSD) patients, multiple sclerosis (MS) patients and control subjects on the production of claudin-5, matrix-metalloproteinases (MMPs)-2/9, and vascular cell adhesion protein-1 (VCAM-1) in human brain microvascular endothelial cells (BMECs). We also examined whether immunoglobulin G (IgG) purified from NMOSD sera influences the claudin-5 or VCAM-1 protein expression.
The disturbance of BBB properties in BMECs following exposure to NMOSD sera was restored after adding the MMP inhibitor, GM6001. The secretion of MMP-2/9 by BMECs significantly increased after applying the NMOSD sera. The sera from NMOSD patients also increased both the MMP-2/9 secretion and the VCAM-1 protein level by BMECs. The IgG purified from NMOSD sera did not influence the BBB properties or the amount of MMP-2/9 proteins, although it did increase the amount of VCAM-1 proteins in BMECs. Reduction in anti-AQP4 antibody titre was not correlated with a reduction in VCAM-1 expression.
The autocrine secretion of MMP-2/9 by BMECs induced by humoral factors, other than IgG, in sera obtained from NMOSD patients potentially increases BBB permeability. IgG obtained from NMOSD sera, apart from anti-AQP4 antibodies, affect the BBB by upregulating VCAM, thereby facilitating the entry of inflammatory cells into the central nervous system.
We present the results of a search for extraterrestrial electron antineutrinos (v sub(e)'s) in the energy range 8.3 MeV < Ev sub(e) < 31.8 MeV using the KamLAND detector. In an exposure of 4.53 ...kton-year, we identify 25 candidate events. All of the candidate events can be attributed to background, most importantly neutral current atmospheric neutrino interactions, setting an upper limit on the probability of super(8)B solar converting into v sub(e)'s at 5.3 x 10 super(-5) (90% CL), if we assume an undistorted v sub(e) shape. This limit corresponds to a solar v sub(e) flux of 93 cm super(-2) s super(-1) or an event rate of 1.6 events (kton - year) super(-1) above the energy threshold Ev sub(e) > or =, slanted 8.3 MeV. The present data also allows us to set more stringent limits on the diffuse supernova neutrino flux and on the annihilation rates for light dark matter particles.
Abstract Glycated albumin (GA) is used alongside glycated hemoglobin (HbA1C ) as an indicator of glycemic control. Although serum GA levels are affected mainly by plasma glucose, they are also ...influenced by serum albumin metabolism. Thyroid hormone is known to promote albumin catabolism, and it is thus thought to affect serum GA levels. In the present study, the effects of thyroid hormone on serum GA measurements were investigated in patients with thyroid dysfunction. Six patients with untreated hypothyroidism and 17 patients with untreated thyrotoxicosis were investigated. Patients who had anemia or diabetes were excluded. A total of 25 non-diabetic, euthyroid individuals were enrolled as controls. HbA1C , serum GA, thyroid-stimulating hormone (TSH), free triiodothyronine (T3 ), and free thyroxine (T4 ) levels were measured in all these subjects, and their relationships were examined. Although no intergroup differences were observed for HbA1C , serum GA was significantly higher among patients with hypothyroidism than controls, and significantly lower among patients with thyrotoxicosis. Serum GA had a significant positive correlation with serum TSH and significant inverse correlations with free T3 and free T4. Thyroid hormone levels are inversely associated with serum GA levels. Cautions are necessary when evaluating serum GA levels in patients with thyroid dysfunction.
We report the novel regulation of proteolytic processing of amyloid precursor protein (APP) by DISC1, a major risk factor for psychiatric illnesses, such as depression and schizophrenia. RNAi ...knockdown of DISC1 in mature primary cortical neurons led to a significant increase in the levels of intracellular α-C-terminal fragment of APP (APP-CTFα) and the corresponding N-terminal-secreted ectodomain product sAPPα. DISC1 knockdown also elicited a significant decrease in the levels of amyloid beta (Aβ)42 and Aβ40. These aberrant proteolytic events were successfully rescued by co-expression of wild-type DISC1, but not by mutant DISC1 lacking the amino acids required for the interaction with APP, suggesting that APP-DISC1 protein interactions are crucial for the regulation of the C-terminal proteolysis. In a genetically engineered model in which a major full-length DISC1 isoform is depleted, consistent changes in APP processing were seen: an increase in APP-CTFα and decrease in Aβ42 and Aβ40 levels. Finally, we found that knockdown of DISC1 increased the expression of APP at the cell surface and decreased its internalization. The presented DISC1 mechanism of APP proteolytic processing and Aβ peptide generation, which is central to Alzheimer's disease pathology, suggests a novel interface between neurological and psychiatric conditions.
Background and purpose
In this pooled analysis of seven multicentre cohorts potential differences were investigated in the incidence, characteristics and outcomes between intracranial haemorrhages ...(ICHs) associated with the use of non‐vitamin K antagonist oral anticoagulants (NOAC‐ICH) or with vitamin K antagonists (VKA‐ICH) in ischaemic stroke patients after oral anticoagulant treatment initiation for atrial fibrillation (AF).
Methods
Data from 4912 eligible AF patients who were admitted in a stroke unit with ischaemic stroke or transient ischaemic attack and who were treated with either VKAs or NOACs within 3 months post‐stroke were included. Fatal ICH was defined as death occurring during the first 30 days after ICH onset. A meta‐analysis of available observational studies reporting 30‐day mortality rates from NOAC‐ICH or VKA‐ICH onset was additionally performed.
Results
During 5970 patient‐years of follow‐up 71 participants had an ICH, of whom 20 were NOAC‐ICH and 51 VKA‐ICH. Patients in the two groups had comparable baseline characteristics, except for the higher prevalence of kidney disease in VKA‐ICH patients. There was a non‐significant higher number of fatal ICH in patients with VKAs (11 events per 3385 patient‐years) than in those with NOACs (three events per 2623 patient‐years; hazard ratio 0.32, 95% confidence interval 0.09–1.14). Three‐month functional outcomes were similar (P > 0.2) in the two groups. The meta‐analysis showed a lower 30‐day mortality risk for patients with NOAC‐ICH compared to VKA‐ICH (relative risk 0.70, 95% confidence interval 0.51–0.95).
Conclusions
Non‐vitamin K oral anticoagulants for intracranial haemorrhages and VKA‐ICH occurring during secondary stroke prevention of AF patients have comparable baseline characteristics and outcomes except for the risk of fatal ICH within 30 days, which might be greater in VKA‐ICH.
First evidence of geometrical patterns and defined distances of biomolecules as fundamental parameters to regulate receptor binding and cell signaling have emerged recently. Here, we demonstrate the ...importance of controlled nanospacing of immunostimulatory agents for the activation of immune cells by exploiting DNA-based nanomaterials and pre-existing crystallography data. We created DNA origami nanoparticles that present CpG-motifs in rationally designed spatial patterns to activate Toll-like Receptor 9 in RAW 264.7 macrophages. We demonstrated that stronger immune activation is achieved when active molecules are positioned at the distance of 7 nm, matching the active dimer structure of the receptor. Moreover, we show how the introduction of linkers between particle and ligand can influence the spatial tolerance of binding. These findings are fundamental for a fine-tuned manipulation of the immune system, considering the importance of spatially controlled presentation of therapeutics to increase efficacy and specificity of immune-modulating nanomaterials where multivalent binding is involved.
To evaluate whether the pretreatment Alberta Stroke Programme Early CT Score (ASPECTS) assessed using diffusion-weighted imaging (DWI) predicts stroke outcomes at 3 months following IV recombinant ...tissue-type plasminogen activator (rt-PA) therapy.
Stroke patients treated with rt-PA (0.6 mg/kg alteplase) in 10 stroke centers in Japan were retrospectively studied. ASPECTS was assessed on DWI just prior to rt-PA injection. The primary outcome was a modified Rankin Scale (mRS) score of 0-2 at 3 months. Secondary outcomes included death at 3 months and symptomatic intracerebral hemorrhage (sICH) within 36 hours.
For the 477 patients (316 men, 71 +/- 11 years old) enrolled, the median NIH Stroke Scale score was 13 (interquartile range 7-18.5), the median ASPECTS on DWI was 8 (7-10), and sICH was identified in 15 patients (3.1%). At 3 months, 245 (51.4%) had an mRS score of 0-2, and 29 (6.1%) had died. Patients with an mRS score of 0-2 had higher median ASPECTS (9; interquartile range 8-10) than other patients (8; 6-9, p < 0.001). Using receiver operating characteristic curves, the optimal cutoff ASPECTS to predict an mRS score of 0-2 was > or =7. On multivariate regression analysis, ASPECTS > or =7 was related to an mRS score of 0-2 (odds ratio 1.85; 95% confidence interval 1.07-3.24), ASPECTS < or =4 was related to death (3.61; 1.23-9.91), and ASPECTS < or =5 was related to sICH (4.74; 1.54-13.64).
ASPECTS on DWI was independently predictive of functional and vital outcomes at 3 months, as well as sICH within 36 hours, following rt-PA therapy for stroke patients.
To assess the production mechanism of anti-GQ1b autoantibody in Fisher syndrome (FS).
The authors conducted a prospective case-control serologic study of five antecedent infections (Campylobacter ...jejuni, cytomegalovirus, Epstein-Barr virus, Mycoplasma pneumoniae, and Haemophilus influenzae) in 73 patients with FS and 73 sex- and age-matched hospital controls (HCs). Serologic evidence in FS patients of C. jejuni (21%) and H. influenzae (8%) infections was present significantly more often than in the HCs. None of the five pathogens examined was found in the 49 (67%) patients with FS. Anti-GQ1b IgG antibody was detected in most FS patients infected with C. jejuni or H. influenzae. Mass spectrometry analysis identified a C. jejuni strain (CF93-6) carrying a GT1a-like lipo-oligosaccharide (LOS) that had been isolated from an FS patient. Immunization of complex ganglioside-lacking knockout mice with the GT1a-like LOS generated IgG class monoclonal antibodies (mAbs) that reacted with GQ1b and GT1a. Thin-layer chromatography with immunostaining showed that anti-GQ1b mAb bound to the C. jejuni LOS (50% of the 20 FS-related strains) more commonly than in the Guillain-Barré syndrome (GBS)-related (7% of 70) or enteritis-related (20% of 65) strains. Anti-GM1 and anti-GD1a mAbs also reacted with the LOS from some FS-related strains (both 20%), but binding frequencies were higher in the GBS-related strains (74 and 57%). The GQ1b epitope was detected in 4 (40%) of the 10 FS-related H. influenzae strains but was absent in strains from patients with GBS (n = 4) and uncomplicated respiratory infections (n = 10).
C. jejuni and H. influenzae are related to Fisher syndrome (FS) development, and production of anti-GQ1b autoantibody is mediated by the GQ1b-mimicking lipo-oligosaccharides on those bacteria. The causative agents remain unclear in the majority of patients with FS.
Ganglioside epitopes on Campylobacter jejuni are hypothesized as the key to the development and characterization of Guillain-Barré syndrome (GBS), but a comprehensive theory has yet to be ...established. A C jejuni gene, cst-II, involved in the biosynthesis of ganglioside-like lipo-oligosaccharide, shows a polymorphism (Asn/Thr51) that affects ganglioside epitopes.
To examine the hypothesis that this polymorphism determines autoantibody reactivity, and thereby neurologic presentations in GBS.
C jejuni isolates were collected from 105 GBS (including its variants) and 65 uncomplicated enteritis patients. The authors examined the frequency of cst-II and polymorphism (Asn/Thr51) in connection with the bacterial ganglioside epitopes, autoantibody reactivities against GM1, GD1a, and GQ1b, and patients' neurologic findings.
Neuropathic strains more frequently had cst-II, in particular cst-II (Thr51), than did enteritic ones (85% vs 52%; p < 0.001). Strains with cst-II (Asn51) regularly expressed the GQ1b epitope (83%), whereas those with cst-II (Thr51) had the GM1 (92%) and GD1a (91%) epitopes. The presence of these bacterial epitopes in neuropathy patients corresponded to autoantibody reactivity. Patients infected with C jejuni (Asn51) more often were positive for anti-GQ1b IgG (56% vs 8%; p < 0.001) and had ophthalmoparesis (64% vs 13%; p < 0.001) and ataxia (42% vs 11%; p = 0.001). Patients who had C jejuni (Thr51) more frequently were positive for anti-GM1 (88% vs 35%; p < 0.001) and anti-GD1a IgG (52% vs 24%; p = 0.006) and had limb weakness (98% vs 71%; p < 0.001).
The genetic polymorphism of C jejuni determines autoantibody reactivity as well as the clinical presentation of Guillain-Barré syndrome (GBS), possibly through modification of the host-mimicking molecule. The GBS paradigm is the first to explain the detailed pathogenesis of a postinfectious, autoimmune-mediated, molecular mimicry-triggering disorder.
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