Anti-phospholipid-antibodies in patients with relapsing polychondritis

Relapsing polychondritis (RP) is an extremly rare multisystemic disease thought to be of autoimmune origin. In order to assess if RP is associated with anti-phospholipid antibodies (aPL), clinical data and sera of 21 patients with RP were collected in a multicentre study. Concentration of anti-cardiolipin antibodies (aCL) (IgG-, IgM-and IgA-isotypes), anti-phosphatidylserine-antibodies (aPS) (IgG-and IgM-isotypes) and anti-β-2-glycoprotein I-antibodies (aβ2 GPI) were measured by ELISA. In eight patients aCL were found to be elevated. One patient had elevated aPS. No patient had elevated aβ2 GPI. No patient had clinical signs and symptoms of a aPL syndrome. Interestingly, the two RP patients with the highest aPL had concomitant systemic lupus erythematosus (SLE). Therefore the presence of elevated aPL in RP is probably more closely related to an associated SLE than to RP itself. There is no convincing evidence that aPL are associated with RP

Joint Segmentation and Uncertainty Visualization of Retinal Layers in Optical Coherence Tomography Images using Bayesian Deep Learning

Optical coherence tomography (OCT) is commonly used to analyze retinal layers for assessment of ocular diseases. In this paper, we propose a method for retinal layer segmentation and quantification of uncertainty based on Bayesian deep learning. Our method not only performs end-to-end segmentation of retinal layers, but also gives the pixel wise uncertainty measure of the segmentation output. The generated uncertainty map can be used to identify erroneously segmented image regions which is useful in downstream analysis. We have validated our method on a dataset of 1487 images obtained from 15 subjects (OCT volumes) and compared it against the state-of-the-art segmentation algorithms that does not take uncertainty into account. The proposed uncertainty based segmentation method results in comparable or improved performance, and most importantly is more robust against noise

Quantitative Chevalley-Weil theorem for curves

The classical Chevalley-Weil theorem asserts that for an \'etale covering of projective varieties over a number field K, the discriminant of the field of definition of the fiber over a K-rational point is uniformly bounded. We obtain a fully explicit version of this theorem in dimension 1.Comment: version 4: minor inaccuracies in Lemma 3.4 and Proposition 5.2 correcte

Activation of SGK1 in endometrial epithelial cells in response to PI3K/AKT inhibition impairs embryo implantation

Background: Serum & Glucocorticoid Regulated Kinase 1 (SGK1) plays a fundamental role in ion and solute transport processes in epithelia. In the endometrium, down-regulation of SGK1 during the window of receptivity facilitates embryo implantation whereas expression of a constitutively active mutant in the murine uterus blocks implantation. Methods/Results: Here, we report that treatment of endometrial epithelial cells with specific inhibitors of the phosphoinositide 3-kinase (PI3K)/AKT activity pathway results in reciprocal activation of SGK1. Flushing of the uterine lumen of mice with a cell permeable, substrate competitive phosphatidylinositol analogue that inhibits AKT activation (AKT inhibitor III) resulted in Sgk1 phosphorylation, down-regulation of the E3 ubiquitin-protein ligase Nedd4-2, and increased expression of epithelial Na+ channels (ENaC). Furthermore, exposure of the uterine lumen to AKT inhibitor III prior to embryo transfer induced a spectrum of early pregnancy defects, ranging from implantation failure to aberrant spacing of implantation sites. Conclusion: Taken together, our data indicate that the balanced activities of two related serine/threonine kinases, AKT and SGK1, critically govern the implantation process

Sensory Electrical Stimulation Improves Foot Placement during Targeted Stepping Post-Stroke

Proper foot placement is vital for maintaining balance during walking, requiring the integration of multiple sensory signals with motor commands. Disruption of brain structures post-stroke likely alters the processing of sensory information by motor centers, interfering with precision control of foot placement and walking function for stroke survivors. In this study, we examined whether somatosensory stimulation, which improves functional movements of the paretic hand, could be used to improve foot placement of the paretic limb. Foot placement was evaluated before, during, and after application of somatosensory electrical stimulation to the paretic foot during a targeted stepping task. Starting from standing, twelve chronic stroke participants initiated movement with the non-paretic limb and stepped to one of five target locations projected onto the floor with distances normalized to the paretic stride length. Targeting error and lower extremity kinematics were used to assess changes in foot placement and limb control due to somatosensory stimulation. Significant reductions in placement error in the medial–lateral direction (p = 0.008) were observed during the stimulation and post-stimulation blocks. Seven participants, presenting with a hip circumduction walking pattern, had reductions (p = 0.008) in the magnitude and duration of hip abduction during swing with somatosensory stimulation. Reductions in circumduction correlated with both functional and clinical measures, with larger improvements observed in participants with greater impairment. The results of this study suggest that somatosensory stimulation of the paretic foot applied during movement can improve the precision control of foot placement

The future of pharmacogenetics in the treatment of heart failure

Heart failure is a common disease with high levels of morbidity and mortality. Current treatment comprises β-blockers, ACE inhibitors, aldosterone antagonists and diuretics. Variation in clinical response seen in patients begs the question of whether there is a pharmacogenetic component yet to be identified. To date, the genes most studied involve the β-1, β-2, α-2 adrenergic receptors and the renin-angiotensin-aldosterone pathway, mainly focusing on SNPs. However results have been inconsistent. Genome-wide association studies and next-generation sequencing are seen as alternative approaches to discovering genetic variations influencing drug response. Hopefully future research will lay the foundations for genotype-led drug management in these patients with the ultimate aim of improving their clinical outcome.</p

Belowground DNA-based techniques: untangling the network of plant root interactions

Contains fulltext : 91591.pdf (publisher's version ) (Closed access)7 p

Accelerated apoptotic death and <i>in vivo</i> turnover of erythrocytes in mice lacking functional mitogen- and stress-activated kinase MSK1/2

The mitogen- and stress-activated kinase MSK1/2 plays a decisive role in apoptosis. In analogy to apoptosis of nucleated cells, suicidal erythrocyte death called eryptosis is characterized by cell shrinkage and cell membrane scrambling leading to phosphatidylserine (PS) externalization. Here, we explored whether MSK1/2 participates in the regulation of eryptosis. To this end, erythrocytes were isolated from mice lacking functional MSK1/2 (msk−/−) and corresponding wild-type mice (msk+/+). Blood count, hematocrit, hemoglobin concentration and mean erythrocyte volume were similar in both msk−/− and msk+/+ mice, but reticulocyte count was significantly increased in msk−/− mice. Cell membrane PS exposure was similar in untreated msk−/− and msk+/+ erythrocytes, but was enhanced by pathophysiological cell stressors ex vivo such as hyperosmotic shock or energy depletion to significantly higher levels in msk−/− erythrocytes than in msk+/+ erythrocytes. Cell shrinkage following hyperosmotic shock and energy depletion, as well as hemolysis following decrease of extracellular osmolarity was more pronounced in msk−/− erythrocytes. The in vivo clearance of autologously-infused CFSE-labeled erythrocytes from circulating blood was faster in msk−/− mice. The spleens from msk−/− mice contained a significantly greater number of PS-exposing erythrocytes than spleens from msk+/+ mice. The present observations point to accelerated eryptosis and subsequent clearance of erythrocytes leading to enhanced erythrocyte turnover in MSK1/2-deficient mice

Very Cold Gas and Dark Matter

We have recently proposed a new candidate for baryonic dark matter: very cold molecular gas, in near-isothermal equilibrium with the cosmic background radiation at 2.73 K. The cold gas, of quasi-primordial abundances, is condensed in a fractal structure, resembling the hierarchical structure of the detected interstellar medium. We present some perspectives of detecting this very cold gas, either directly or indirectly. The H$_2$ molecule has an "ultrafine" structure, due to the interaction between the rotation-induced magnetic moment and the nuclear spins. But the lines fall in the km domain, and are very weak. The best opportunity might be the UV absorption of H$_2$ in front of quasars. The unexpected cold dust component, revealed by the COBE/FIRAS submillimetric results, could also be due to this very cold H$_2$ gas, through collision-induced radiation, or solid H$_2$ grains or snowflakes. The $\gamma$-ray distribution, much more radially extended than the supernovae at the origin of cosmic rays acceleration, also points towards and extended gas distribution.Comment: 16 pages, Latex pages, crckapb macro, 3 postscript figures, uuencoded compressed tar file. To be published in the proceeedings of the "Dust-Morphology" conference, Johannesburg, 22-26 January, 1996, D. Block (ed.), (Kluwer Dordrecht

LEFTY2 inhibits endometrial receptivity by downregulating Orai1 expression and store-operated Ca²+ entry

Early embryo development and endometrial differentiation are initially independent processes, and synchronization, imposed by a limited window of implantation, is critical for reproductive success. A putative negative regulator of endometrial receptivity is LEFTY2, a member of the transforming growth factor (TGF)-β family. LEFTY2 is highly expressed in decidualizing human endometrial stromal cells (HESCs) during the late luteal phase of the menstrual cycle, coinciding with the closure of the window of implantation. Here, we show that flushing of the uterine lumen in mice with recombinant LEFTY2 inhibits the expression of key receptivity genes, including Cox2, Bmp2, and Wnt4, and blocks embryo implantation. In Ishikawa cells, a human endometrial epithelial cell line, LEFTY2 downregulated the expression of calcium release-activated calcium channel protein 1, encoded by ORAI1, and inhibited store-operated Ca2+ entry (SOCE). Furthermore, LEFTY2 and the Orai1 blockers 2-APB, MRS-1845, as well as YM-58483, inhibited, whereas the Ca2+ ionophore, ionomycin, strongly upregulated COX2, BMP2 and WNT4 expression in decidualizing HESCs. These findings suggest that LEFTY2 closes the implantation window, at least in part, by downregulating Orai1, which in turn limits SOCE and antagonizes expression of Ca2+-sensitive receptivity genes