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Dysregulation of Diverse Ion Transport Pathways Controlling Cell Volume Homoestasis Contribute to Neuroglial Cell Injury Following Ischemic Stroke
Alexithymia and its Relationship with Post-Traumatic Stress Disorder among Women with Breast Cancer
هدفت هذه الدراسة إلى الكشف عن مستوى الألكسيثيميا واضطراب ضغوط ما بعدة الصدمة لدى مريضات سرطان الثدي والعلاقة بينهما، تكونت عينة الدراسة من (70) مريضة بسرطان الثدي ممن يراجعن مستشفى الملك المؤسس عبد الله الجامعي. أشارت النتائج عدم وجود فروق في متوسطات الدرجات على مقياس الألكسيثيميا لدى مريضات سرطان الثدي تعزى إلى متغيرات: المستوى التعليمي، الحالة الاجتماعية، الحالة الوظيفية، بينما يوجد فروق تعزى لأثر العمر. إضافة إلى عدم وجود فروق في متوسطات الدرجات على مقياس اضطراب ما بعد الصدمة لدى مريضات سرطان الثدي تعزى إلى المتغيرات: العمر، الحالة الوظيفية، بينما يوجد فروق تعزى إلى المتغيرات: الحالة الاجتماعية في مجال استعادة الخبرة الصادمة، والمستوى التعليمي في مجال الاستثارة. كما أظهرت النتائج وجود علاقة ايجابية بين مقياس الألكسيثيميا ومجالاته وبين مقياس اضطراب ضغوط ما بعد الصدمة ومجالاته.This study aimed to detect the level of alexithymia and post-traumatic stress disorder in breast cancer patients and to find a relationship between them. The study sample consisted of (70) breast cancer patients who visit King Abdullah University Hospital. The results did not show differences of alexithymia among breast cancer patients due to variables: educational level, marital status, employment status, and there were differences due to the effect of age. The results also indicated there were differences in PTSD among breast cancer patients due to the variables: age, functional status, and there were differences attributed to the variables: marital status in the field of traumatic experience recovery, and educational level in the arousal field. The results also showed the existence of a statistically significant positive relationship between the alexithymia scale and its domains and between the PTSD scale and its domains
Co-occurrence of chronic kidney disease and glaucoma:Epidemiology and etiological mechanisms
As the histology, physiology, and pathophysiology of eyes and kidneys show substantial overlap, it has been suggested that eye and kidney diseases, such as glaucoma and chronic kidney disease (CKD), may be closely interlinked. We review the relationship between CKD and various subtypes of glaucoma, including primary open-angle glaucoma, primary angle- closure glaucoma, normal tension glaucoma, pseudoexfoliation syndrome, and several glaucoma endophenotypes. We also discuss the underlying pathogenic mechanisms and common risk factors for CKD and glaucoma, including atherosclerosis, the renin-angiotensin system, genes and genetic polymorphisms, vitamin D deficiency, and erythropoietin. The prevalence of glaucoma appears elevated in CKD patients, and vice versa, and the literature points to many intriguing associations; however, the associations are not always confirmed, and sometimes apparently opposite observations are reported. Glaucoma and CKD are complex diseases, and their mutual influence is only partially understood
Dysregulation of Diverse Ion Transport Pathways Controlling Cell Volume Homoestasis Contribute to Neuroglial Cell Injury Following Ischemic Stroke
WNK1-OSR1 kinase-mediated phospho-activation of Na+-K+-2Cl- cotransporter facilitates glioma migration
Background: The bumetanide (BMT)-sensitive Na+-K+-2Cl- cotransporter isoform 1 (NKCC1) maintains cell volume homeostasis by increasing intracellular K+ and Cl- content via regulatory volume increase (RVI). Expression levels of NKCC1 positively correlate with the histological grade and severity of gliomas, the most common primary adult brain tumors, and up-regulated NKCC1 activity facilitates glioma cell migration and apoptotic resistance to the chemotherapeutic drug temozolomide (TMZ). However, the cellular mechanisms underlying NKCC1 functional up-regulation in glioma and in response to TMZ administration remain unknown. Methods: Expression of NKCC1 and its upstream kinases With-No-K (Lysine) kinase 1 (WNK1) and oxidative stress-responsive kinase-1 (OSR1) in different human glioma cell lines and glioma specimens were detected by western blotting and immunostaining. Live cell imaging and microchemotaxis assay were applied to record glioma cell movements under different treatment conditions. Fluorescence indicators were utilized to measure cell volume, intracellular K+ and Cl- content to reflect the activity of NKCC1 on ion transportation. Small interfering RNA (siRNA)-mediated knockdown of WNK1 or OSR1 was used to explore their roles in regulation of NKCC1 activity in glioma cells. Results of different treatment groups were compared by one-way ANOVA using the Bonferroni post-hoc test in the case of multiple comparisons. Results: We show that compared to human neural stem cells and astrocytes, human glioma cells exhibit robust increases in the activation and phosphorylation of NKCC1 and its two upstream regulatory kinases, WNK1 and OSR1. siRNA-mediated knockdown of WNK1 or OSR1 reduces intracellular K+ and Cl- content and RVI in glioma cells by abolishing NKCC1 regulatory phospho-activation. Unexpectedly, TMZ activates the WNK1/OSR1/NKCC1 signaling pathway and enhances glioma migration. Pharmacological inhibition of NKCC1 with its potent inhibitor BMT or siRNA knockdown of WNK1 or OSR1 significantly decreases glioma cell migration after TMZ treatment. Conclusion: Together, our data show a novel role for the WNK1/OSR1/NKCC1 pathway in basal and TMZ-induced glioma migration, and suggest that glioma treatment with TMZ might be improved by drugs that inhibit elements of the WNK1/OSR1/NKCC1 signaling pathway
Testing linear hypotheses in high-dimensional regressions
For a multivariate linear model, Wilk's likelihood ratio test (LRT)
constitutes one of the cornerstone tools. However, the computation of its
quantiles under the null or the alternative requires complex analytic
approximations and more importantly, these distributional approximations are
feasible only for moderate dimension of the dependent variable, say .
On the other hand, assuming that the data dimension as well as the number
of regression variables are fixed while the sample size grows, several
asymptotic approximations are proposed in the literature for Wilk's \bLa
including the widely used chi-square approximation. In this paper, we consider
necessary modifications to Wilk's test in a high-dimensional context,
specifically assuming a high data dimension and a large sample size .
Based on recent random matrix theory, the correction we propose to Wilk's test
is asymptotically Gaussian under the null and simulations demonstrate that the
corrected LRT has very satisfactory size and power, surely in the large and
large context, but also for moderately large data dimensions like or
. As a byproduct, we give a reason explaining why the standard chi-square
approximation fails for high-dimensional data. We also introduce a new
procedure for the classical multiple sample significance test in MANOVA which
is valid for high-dimensional data.Comment: Accepted 02/2012 for publication in "Statistics". 20 pages, 2 pages
and 2 table
Inference of hidden structures in complex physical systems by multi-scale clustering
We survey the application of a relatively new branch of statistical
physics--"community detection"-- to data mining. In particular, we focus on the
diagnosis of materials and automated image segmentation. Community detection
describes the quest of partitioning a complex system involving many elements
into optimally decoupled subsets or communities of such elements. We review a
multiresolution variant which is used to ascertain structures at different
spatial and temporal scales. Significant patterns are obtained by examining the
correlations between different independent solvers. Similar to other
combinatorial optimization problems in the NP complexity class, community
detection exhibits several phases. Typically, illuminating orders are revealed
by choosing parameters that lead to extremal information theory correlations.Comment: 25 pages, 16 Figures; a review of earlier work
Peripheral motor neuropathy is associated with defective kinase regulation of the KCC3 cotransporter
This is the author accepted manuscript. The final version is available from American Association for the Advancement of Science via the DOI in this record.Using exome sequencing, we identified a de novo mutation (c.2971A>G; T991A) in SLC12A6, the gene encoding the K(+)-Cl(-) cotransporter KCC3, in a patient with an early-onset, progressive, and severe peripheral neuropathy primarily affecting motor neurons. Normally, the WNK kinase-dependent phosphorylation of T(991) tonically inhibits KCC3; however, cell swelling triggers Thr(991) dephosphorylation to activate the transporter and restore cell volume. KCC3 T991A mutation in patient cells abolished Thr(991) phosphorylation, resulted in constitutive KCC3 activity, and compromised cell volume homeostasis. KCC3(T991A/T991A) mutant mice exhibited constitutive KCC3 activity and recapitulated aspects of the clinical, electrophysiological, and histopathological findings of the patient. These results suggest that the function of the peripheral nervous system depends on finely tuned, kinase-regulated KCC3 activity and implicate abnormal cell volume homeostasis as a previously unreported mechanism of axonal degeneration in humans.This work was supported by NIH research grant GM74771 (E.D.). K.T.K. was supported by a Harvard-MIT Neuroscience Grant, the Manton Center for Orphan Disease Research at Harvard Medical School, and the March of Dimes. C.G.B. is supported by intramural funds of the NINDS. B.F. and D.B.G. received support from NIH grants 2T32MH064913-11A1 and T32-AR056993, respectively
Stimulation of Na<sup>+</sup>/H<sup>+</sup> Exchanger Isoform 1 Promotes Microglial Migration
Regulation of microglial migration is not well understood. In this study, we proposed that Na+/H+ exchanger isoform 1 (NHE-1) is important in microglial migration. NHE-1 protein was co-localized with cytoskeletal protein ezrin in lamellipodia of microglia and maintained its more alkaline intracellular pH (pHi). Chemoattractant bradykinin (BK) stimulated microglial migration by increasing lamellipodial area and protrusion rate, but reducing lamellipodial persistence time. Interestingly, blocking NHE-1 activity with its potent inhibitor HOE 642 not only acidified microglia, abolished the BK-triggered dynamic changes of lamellipodia, but also reduced microglial motility and microchemotaxis in response to BK. In addition, NHE-1 activation resulted in intracellular Na+ loading as well as intracellular Ca2+ elevation mediated by stimulating reverse mode operation of Na+/Ca2+ exchange (NCXrev). Taken together, our study shows that NHE-1 protein is abundantly expressed in microglial lamellipodia and maintains alkaline pHi in response to BK stimulation. In addition, NHE-1 and NCXrev play a concerted role in BK-induced microglial migration via Na+ and Ca2+ signaling. © 2013 Shi et al
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