L-Carnitine Suppresses Transient Receptor Potential Vanilloid Type 1 Activation in Human Corneal Epithelial Cells

Tear film hyperosmolarity induces dry eye syndrome (DES) through transient receptor potential vanilloid type 1 (TRPV1) activation. L-carnitine is a viable therapeutic agent since it protects against this hypertonicity-induced response. Here, we investigated whether L-carnitine inhibits TRPV1 activation by blocking heat- or capsaicin-induced increases in Ca2+ influx or hyperosmotic stress-induced cell volume shrinkage in a human corneal epithelial cell line (HCE-T). Single-cell fluorescence imaging of calcein/AM-loaded cells or fura-2/AM-labeled cells was used to evaluate cell volume changes and intracellular calcium levels, respectively. Planar patch-clamp technique was used to measure whole-cell currents. TRPV1 activation via either capsaicin (20 & mu;mol/L), hyperosmolarity (& AP;450 mosmol/L) or an increase in ambient bath temperature to 43 & DEG;C induced intracellular calcium transients and augmented whole-cell currents, whereas hypertonicity induced cell volume shrinkage. In contrast, either capsazepine (10 & mu;mol/L) or L-carnitine (1-3 mmol/L) reduced all these responses. Taken together, L-carnitine and capsazepine suppress hypertonicity-induced TRPV1 activation by blocking cell volume shrinkage

L-carnitine suppresses transient receptor potential vanilloid type 1 activity and myofibroblast transdifferentiation in human corneal keratocytes

Corneal stromal wound healing is a well-balanced process promoted by overlapping phases including keratocyte proliferation, inflammatory-related events, and tissue remodeling. L-carnitine as a natural antioxidant has shown potential to reduce stromal fibrosis, yet the underlying pathway is still unknown. Since transient receptor potential vanilloid 1 (TRPV1) is a potential drug target for improving the outcome of inflammatory/fibrogenic wound healing, we investigated if L-carnitine can mediate inhibition of the fibrotic response through suppression of TRPV1 activation in human corneal keratocytes (HCK). We determined TRPV1-induced intracellular calcium transients using fluorescence calcium imaging, channel currents by planar patch-clamping, and cell migration by scratch assay for wound healing. The potential L-carnitine effect on TRPV1-induced myofibroblast transdifferentiation was evaluated by immunocytochemical detection of alpha smooth muscle actin. RT-PCR analysis confirmed TRPV1 mRNA expression in HCK. L-carnitine (1 mmol/l) inhibited either capsaicin (CAP) (10 µmol/l), hypertonic stress (450 mOsmol/l), or thermal increase (>43 °C) induced Ca2+ transients and corresponding increases in TRPV1-induced inward and outward whole-cell currents. This was accompanied by suppression of injury-induced increases in myofibroblast transdifferentiation and cell migration. In conclusion, L-carnitine contributes to inhibit stromal scarring through suppressing an injury-induced intrinsic TRPV1 activity that is linked with induction of myofibroblast transdifferentiation in HCK cells

S2k guidelines for the diagnosis and treatment of herpes zoster and postherpetic neuralgia

The present guidelines are aimed at residents and board-certified specialists in the fields of dermatology, ophthalmology, ENT, pediatrics, neurology, virology, infectious diseases, anesthesiology, general medicine and any other medical specialties involved in the management of patients with herpes zoster. They are also intended as a guide for policymakers and health insurance funds. The guidelines were developed by dermatologists, virologists, ophthalmologists, ENT physicians, neurologists, pediatricians and anesthesiologists/pain specialists using a formal consensus process (S2k). Readers are provided with an overview of the clinical and molecular diagnostic workup, including antigen detection, antibody tests and viral culture. Special diagnostic situations and complicated disease courses are discussed. The authors address general and special aspects of antiviral therapy for herpes zoster and postherpetic neuralgia. Furthermore, the guidelines provide detailed information on pain management including a schematic overview, and they conclude with a discussion of topical treatment options

Vascular endothelial growth factor (VEGF) induced downstream responses to transient receptor potential vanilloid 1 (TRPV1) and 3-lodothyronamine (3-T1AM) in human corneal keratocytes

This study was undertaken to determine if crosstalk among the transient receptor potential (TRP) melastatin 8 (TRPM8), TRP vanilloid 1 (TRPV1), and vascular endothelial growth factor (VEGF) receptor triad modulates VEGF-induced Ca2+ signaling in human corneal keratocytes. Using RT-PCR, qPCR and immunohistochemistry, we determined TRPV1 and TRPM8 gene and protein coexpression in a human corneal keratocyte cell line (HCK) and human corneal cross sections. Fluorescence Ca2+ imaging using both a photomultiplier and a single cell digital imaging system as well as planar patch-clamping measured relative intracellular Ca2+ levels and underlying whole-cell currents. The TRPV1 agonist capsaicin increased both intracellular Ca2+ levels and whole-cell currents, while the antagonist capsazepine (CPZ) inhibited them. VEGF-induced Ca2+ transients and rises in whole-cell currents were suppressed by CPZ, whereas a selective TRPM8 antagonist, AMTB, increased VEGF signaling. In contrast, an endogenous thyroid hormone-derived metabolite 3-lodothyronamine (3-T(1)AM) suppressed increases in the VEGF-induced current. The TRPM8 agonist menthol increased the currents, while AMTB suppressed this response. The VEGF-induced increases in Ca2+ influx and their underlying ionic currents stem from crosstalk between VEGFR and TRPV1, which can be impeded by 3-T(1)AM-induced TRPM8 activation. Such suppression in turn blocks VEGF-induced TRPV1 activation. Therefore, crosstalk between TRPM8 and TRPV1 inhibits VEGFR-induced activation of TRPV1

Clinical Outcomes of 217 Patients with Acute Erythroleukemia According to Treatment Type and Line: A Retrospective Multinational Study

Acute erythroleukemia (AEL) is a rare disease typically associated with a poor prognosis. Themedian survival ranges between 3–9months frominitial diagnosis. Hypomethylating agents (HMAs) have been shown to prolong survival in patients with myelodysplastic syndromes (MDS) and AML, but there is limited data of their efficacy in AEL. We collected data from 210 AEL patients treated at 28 international sites. Overall survival (OS) and PFS were estimated using the Kaplan-Meier method and the log-rank test was used for subgroup comparisons. Survival between treatment groups was compared using the Cox proportional hazards regression model. Eighty-eight patients were treated with HMAs, 44 front line, and 122 with intensive chemotherapy (ICT). ICT led to a higher overall response rate (complete or partial) compared to first-line HMA (72% vs. 46.2%, respectively; p 0.001), but similar progression-free survival (8.0 vs. 9.4 months; p = 0.342). Overall survival was similar for ICT vs. HMAs (10.5 vs. 13.7months; p = 0.564), but patients with high-risk cytogenetics treated with HMA first-line lived longer (7.5 for ICT vs. 13.3 months; p = 0.039). Our results support the therapeutic value of HMA in AEL

Guidance on noncorticosteroid systemic immunomodulatory therapy in noninfectious uveitis: fundamentals of care for uveitis (focus) initiative

Topic: An international, expert-led consensus initiative to develop systematic, evidence-based recommendations for the treatment of noninfectious uveitis in the era of biologics. Clinical Relevance: The availability of biologic agents for the treatment of human eye disease has altered practice patterns for the management of noninfectious uveitis. Current guidelines are insufficient to assure optimal use of noncorticosteroid systemic immunomodulatory agents. Methods: An international expert steering committee comprising 9 uveitis specialists (including both ophthalmologists and rheumatologists) identified clinical questions and, together with 6 bibliographic fellows trained in uveitis, conducted a Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocol systematic reviewof the literature (English language studies from January 1996 through June 2016; Medline [OVID], the Central Cochrane library, EMBASE,CINAHL,SCOPUS,BIOSIS, andWeb of Science). Publications included randomized controlled trials, prospective and retrospective studies with sufficient follow-up, case series with 15 cases or more, peer-reviewed articles, and hand-searched conference abstracts from key conferences. The proposed statements were circulated among 130 international uveitis experts for review.Atotal of 44 globally representativegroupmembersmet in late 2016 to refine these guidelines using a modified Delphi technique and assigned Oxford levels of evidence. Results: In total, 10 questions were addressed resulting in 21 evidence-based guidance statements covering the following topics: when to start noncorticosteroid immunomodulatory therapy, including both biologic and nonbiologic agents; what data to collect before treatment; when to modify or withdraw treatment; how to select agents based on individual efficacy and safety profiles; and evidence in specific uveitic conditions. Shared decision-making, communication among providers and safety monitoring also were addressed as part of the recommendations. Pharmacoeconomic considerations were not addressed. Conclusions: Consensus guidelines were developed based on published literature, expert opinion, and practical experience to bridge the gap between clinical needs and medical evidence to support the treatment of patients with noninfectious uveitis with noncorticosteroid immunomodulatory agents

Spin polarization in low-energy electron diffraction: surface analysis of Pt(111) [Abstract]

Feder R, Pleyer H, Bauer P, Müller N. Spin polarization in low-energy electron diffraction: surface analysis of Pt(111) [Abstract]. Surface Science Letters. 1981;109(2): A312

Mesenchymal Stem and Progenitor Cells in Normal and Dysplastic Hematopoiesis—Masters of Survival and Clonality?

Myelodysplastic syndromes (MDS) are malignant hematopoietic stem cell disorders that have the capacity to progress to acute myeloid leukemia (AML). Accumulating evidence suggests that the altered bone marrow (BM) microenvironment in general, and in particular the components of the stem cell niche, including mesenchymal stem cells (MSCs) and their progeny, play a pivotal role in the evolution and propagation of MDS. We here present an overview of the role of MSCs in the pathogenesis of MDS, with emphasis on cellular interactions in the BM microenvironment and related stem cell niche concepts. MSCs have potent immunomodulatory capacities and communicate with diverse immune cells, but also interact with various other cellular components of the microenvironment as well as with normal and leukemic stem and progenitor cells. Moreover, compared to normal MSCs, MSCs in MDS and AML often exhibit altered gene expression profiles, an aberrant phenotype, and abnormal functional properties. These alterations supposedly contribute to the “reprogramming” of the stem cell niche into a disease-permissive microenvironment where an altered immune system, abnormal stem cell niche interactions, and an impaired growth control lead to disease progression. The current article also reviews molecular targets that play a role in such cellular interactions and possibilities to interfere with abnormal stem cell niche interactions by using specific targeted drugs

La nécropole laténienne de Pottenbrunn (Basse-Autriche) comme miroir des relations est-ouest

Das birituelle Gräberfeld von Pottenbrunn, SG St. Pôlten, wurde v.a. in den Jahren 1981-1982 vom Bundesdenkmalamt (J.-W. Neugebauer) aufgedeckt. Es besteht aus 42 Grabanlagen mit 45 Bestattungen. Auffallend sind die zahlreichen, v.a. quadratischen Umhegungen, die die Gräber umgeben. 12 der Bestattungen sind im Brandritus niedergelegt, die ubrigen Gräbern sind Körperbestattungen. Grab 54 enthielt eine versilberte Hohlblechperle (Bommel) mit doppelter Fuchsschwanzkette. Bei diesem Artefakt handelt sich um die Umsetzung von zusammenstoGenden Pufferenden von Torqui vom Typ "Beine", wie sie vor allem im Marnegebiet und auch im Rheinland vorkommen, in Form einer zusammengelöteten Hohlperle. Vor allem in der Stufe Lt B1 tritt uns im Gräberfeld eine starke ,,Modestromung" aus dem Westen entgegen, die sich in bestimmten Varianten von Fibein vom Typ Duchcov ausdruckt. Sie haben ihre Verbreitung über die Champagne nach Böhmen-Mahren und der Schweiz, jetzt auch in Österreich. In der Stufe Lt B2/C1 ist das Gràberfeld ein Teil des ,,Ostkeltischen" Kreises, der, wirtschaftlich und kulturell konsolidiert, eigene Formen entwickelt. Dies zeigt sich z.B. in den Ortbändern vom Typ Kôsd D. Weiters konnte eine Untergruppe der eisernen Fibein mit hoher zweischleifiger Spannung und äusserer Sehne (Variante Pottenbrunn-Horny Jatov) herausgearbeitet wergeld.The La Tène cemetery of Pottenbrunn (Lower Austria) as a barometer of East-West relations. The bi-ritual cemetery of Pottenbrunn, SG St Pôlten, was excavated by the Bundesdenkmalamt (J.-W. Neugebauer) mainly in 1981-1982. It consists of 42 graves containing 45 individuals. Particularly striking are the numerous, mostly quadrilateral ditches which surround the graves. Twelve of the burials are cremations ; the remainder are inhumations. Grave 54 contained a hollow silvered bronze pendant with a double link-in-link chain. The shape of this pendant results from the transformation of tore terminals of Beine type in the form of a fused hollow pendant, found especially in the Marne but also in the Rhineland. There are signs in the Pottenbrunn cemetery during La Tène B1 of strong influences from the West, marked particularly by the occurrence of variants of Duchcov fibulae. Their distribution extends from Champagne to Bohemia, Moravia and Switzerland, and now may also be noted in Austria. In LT B2/C1 the Pottenbrunn cemetery is part of the 'Eastern Celtic' area, which developed its own forms within a consolidated economic and cultural context ; this is evident, for example, in sword chapes of Kôsd Type D. Further, one may also include here a sub-group of iron fibulae, the Pottenbrunn- Horny Jatov type, with high double-coiled spring with external chord.La nécropole bi-rituelle de Pottenbrunn (Skt. Pôlten) fut fouillée dans les années 1981-82 par J.-W. Neugebauer. Elle comprend 42 tombes avec 45 individus. Nombreux sont les enclos, principalement quadrilatéraux, qui entourent les sépultures. 12 d'entre elles sont des incinérations, les autres des inhumations. La tombe 54 contenait une perle creuse en tôle d'argent avec une double chaîne en queue de renard. Il s'agit de la transposition d'extrémités de torques à tampons du type " Beine " sous la forme de perles creuses soudées. C'est surtout dans l'horizon La Tène B1 de la nécropole que se développe un courant de mode occidental, qui s'exprime dans des variantes des fibules de Dux. Elles se répartissent de la Champagne à la Bohême, à la Moravie, à la Suisse, et maintenant aussi à l'Autriche. Dans l'horizon La Tène B2/C1, la nécropole se rattache au cercle de la culture celtique orientale, qui culturellement et socialement consolidé, développe ses propres formes, par exemple les fourreaux de type Kôsd D. On peut aussi isoler un sous-groupe de fibules en fer avec un haut ressort à deux spires et corde externe (Variante Pottenbrunn- Horny Jatov).Ramsl Peter C., Delnef Hélène, Pleyer A. La nécropole laténienne de Pottenbrunn (Basse-Autriche) comme miroir des relations est-ouest. In: Décors, images et signes de l’âge du Fer européen, XXVIe colloque de l’AFEAF, thème spécialisé. Tours : Fédération pour l'édition de la Revue archéologique du Centre de la France, 2003. pp. 247-258. (Supplément à la Revue archéologique du centre de la France, 24