Levosimendan has an inhibitory effect on platelet function

Levosimendan enhances cardiac contractility by increasing myocyte sensitivity to calcium, and induces vasodilatation. Although studies have evaluated the efficacy of levosimendan in heart failure, it is not clear whether it might produce functional influence on platelet response. In this study, the effect of levosimendan on platelet aggregation was investigated. Platelet function tests were performed in 12 healthy male volunteers. Three concentrations of levosimendan solution were prepared that would result in 10, 25, and 45 ng/ml levosimendan concentrations in the blood similar to that observed after clinical therapeutic intravenous application of 0.05-0.1 microg/kg/min. Each concentration of levosimendan solution and a control diluent without levosimendan were incubated with whole blood at 37 degrees C. After incubation for 15 min, aggregation responses were evaluated with adenosine diphosphate (ADP) (5 and 10 microM) and collagen (2 and 5 microg/ml) in platelet-rich plasma. Preincubation with all dilutions of levosimendan inhibited aggregation of platelets induced by ADP and collagen significantly. Levosimendan also inhibited significantly the secondary wave of platelet aggregation induced by ADP. The results showed that there was a relationship between levosimendan concentration and inhibition of platelet aggregation. In conclusion, this study with an in vitro model showed that levosimendan had a significant inhibitory effect on platelets in clinically relevant doses.     

Determinants of acceptance of end-of-life interventions: a comparison between withdrawing life-prolonging treatment and euthanasia in Austria

Background

End-of-life decisions remain a hotly debated issue in many European countries and the acceptance in the general population can act as an important anchor point in these discussions. Previous studies on determinants of the acceptance of end-of-life interventions in the general population have not systematically assessed whether determinants differ between withdrawal of life-prolonging treatment (WLPT) and euthanasia (EUT).

Methods

A large, representative survey of the Austrian adult population conducted in 2014 (n?=?1,971) included items on WLPT and EUT. We constructed the following categorical outcome: (1) rejection of both WLPT and EUT, (2) approval of WLPT but rejection of EUT, and (3) approval of both WLPT and EUT. The influence of socio-demographics, personal experiences, and religious and socio-cultural orientations on the three levels of approval were assessed via multinomial logistic regression analysis.

Results

Higher education and stronger socio-cultural liberal orientations increased the likelihood of approving both WLPT and EUT; personal experience with end-of-life care increased only the likelihood of approval of WLPT; and religiosity decreased approval of EUT only.

Conclusion

This study found evidence for both shared (education, liberalism) and different (religiosity, care experiences) determinants for the acceptance of WLPT and EUT.

     

Cross-Reactivity of Peanut Allergens

Peanut seeds are currently widely used as source of human food ingredients in the United States of America and in European countries due to their high quality protein and oil content. This article describes the classification and molecular biology of peanut seed allergens with particular reference to their cross-reactivities. Currently, the IUIS allergen nomenclature subcommittee accepts 12 peanut allergens. Two allergens belong to the cupin and four to the prolamin superfamily, and six are distributed among profilins, Bet v 1-like proteins, oleosins, and defensins. Clinical observations frequently report an association of peanut allergy with allergies to legumes, tree nuts, seeds, fruits and pollen. Molecular cross-reactivity has been described between members of the Bet v 1-like proteins, the non-specific lipid transfer proteins, and the profilins. This review also addresses the less well-studied cross-reactivity between cupin and prolamin allergens of peanuts and of other plant food sources and the recently discovered cross-reactivity between peanut allergens of unrelated protein families.     

MicroRNAs as potential biomarkers for gastric cancer

Gastric cancer is the fourth most common cancer in the world and the second leading cause of cancerrelated death.More than 80%of diagnoses occur at the middle to late stage of the disease,highlighting an urgent need for novel biomarkers detectable at earlier stages.Recently,aberrantly expressed microRNAs(miRNAs)have received a great deal of attention as potential sensitive and accurate biomarkers for cancer diagnosis and prognosis.This review summarizes the current knowledge about potential miRNA biomarkers for gastric cancer that have been reported in the publicly available literature between 2008 and 2013.Available evidence indicates that aberrantly expressed miRNAs in gastric cancer correlate with tumorigenesis,tumor proliferation,distant metastasis and invasion.Furthermore,tissue and cancer types can be classified using miRNA expression profiles and next-generation sequencing.As miRNAs in plasma/serum are well protected from RNases,they remain stable under harsh conditions.Thus,potential functions of these circulating miRNAs can be deduced and may implicate their diagnostic value in cancer detection.Circulating miRNAs,as well as tissue miRNAs,may allow for the detection of gastric cancer at an early stage,prediction of prognosis,and monitoring of recurrence and/or lymph node metastasis.Taken together,the data suggest that the participation of miRNAs in biomarker development will enhance the sensitivity and specificity of diagnostic and prognostic tests for gastric cancer.     

Comparative Study of 6 Rotary Nickel-Titanium Systems and Hand Instrumentation for Root Canal Preparation in Severely Curved Root Canals of Extracted Teeth

IntroductionSome improvements have been developed with new generations of nickel-titanium (NiTi) rotary instruments that led to their successful and extensive application in clinical practice. The purpose of this in vitro study was to compare the root canal preparations performed by using GT Series X and Twisted File systems produced by innovative manufacturing process with Revo-S, RaCe, Mtwo, and ProTaper Universal systems manufactured directly from conventional nitinol and with stainless steel K-Flexofile instruments.MethodsThe mesiobuccal root canals of 140 maxillary first permanent molars that had between 30°–40° curvature angle and 4- to 9-mm curvature radius of the root canal were used. After root canal preparations made by using GT Series X, Twisted File, Revo-S, RaCe, Mtwo, and ProTaper Universal NiTi rotary systems and stainless steel K-Flexofile instruments, transportation occurred in the root canal, and alteration of working length (WL) was assessed by using a modified double-digital radiographic technique. The data were compared by the post hoc Tukey honestly significant difference test.ResultsNiTi rotary systems caused less canal transportation and alteration of WL than K-Flexofile instruments (P < .05). There was no significant difference between NiTi rotary system groups at any levels (P > .05) except 2.5 mm from the WL. At this level ProTaper Universal system caused significant canal transportation (P < .05).ConclusionsGT Series X and Twisted File rotary systems produced with innovative process were concluded to shape the curved canals to result in minimal canal transportation, similar to Revo-S, RaCe, Mtwo, and ProTaper Universal rotary systems manufactured by traditional methods.     

Plasmacytic differentiation in MALT lymphomas following treatment with rituximab

Mucosa-associated lymphoid tissue (MALT) lymphomas are B cell neoplasms which commonly affect the gastrointestinal (GI) tract. Gastrointestinal MALT lymphomas rarely show plasmacytic differentiation (PCD), and limited data on the potential influence of the anti-CD20 antibody rituximab (R) on PCD exist in the current literature. We have retrospectively analyzed patients with GI MALT lymphomas treated with R-containing regimens because restaging is routinely performed by repeated biopsies with pathohistological response assessment. Twenty-one patients with GI MALT lymphoma were identified to have undergone R-containing therapy. In 19 patients, the lymphoma originated in the stomach, while the colon was the primarily affected organ in two cases. Four patients received R monotherapy and 17 combinations of R with various chemotherapeutic agents. Only two patients with gastric MALT lymphoma had PCD before initiation of therapy. In 7 of 19 patients (37%) without PCD at diagnosis, restaging revealed PCD after or while on treatment with R-containing regimens. Out of these seven patients, only one patient had a complete response as opposed to 10/12 without PCD. These data suggest that R or R-containing treatment regimens may not optimally eradicate the plasma cell component and thus lead to PCD in patients with GI MALT lymphoma. In view of this, rebiopsy and histological re-assessment appear mandatory in patients failing/relapsing after R-containing regimens.     

Nanoparticle-based drug delivery systems: a commercial and regulatory outlook as the field matures

Introduction: Nanomedicine has emerged as a major field of academic research with direct impact on human health. While a first generation of products has been successfully commercialized and has significantly contributed to enhance patient’s life, recent advances in material design and the emergence of new therapeutics are contributing to the development of more sophisticated systems. As the field matures, it is important to comprehend the challenges related to nanoparticle commercial development for a more efficient and predictable path to the clinic.

Areas covered: The review provides an overview of nanoparticle-based delivery systems currently on the market and in clinical trials, and discuss the principal challenges for their commercial development, both from a manufacturing and regulatory perspective, to help gain understanding of the translational path for these systems.

Expert opinion: Clinical translation of nanoparticle-based delivery systems remains challenging on account of their 3D nanostructure and requires robust nano-manufacturing process along with adequate analytical tools and methodologies. By identifying early enough in the development the product critical attributes and understanding their impact on the therapeutic performance, the developers of nanopharmaceuticals will be better equipped to develop efficient product pipelines. Second-generation products are expected to broaden nanopharmaceutical global market in the upcoming years.     

PLGA based drug delivery systems: Promising carriers for wound healing activity

Wound treatment remains one of the most prevalent and economically burdensome healthcare issues in the world. Current treatment options are limited and require repeated administrations which led to the development of new therapeutics to satisfy the unmet clinical needs. Many potent wound healing agents were discovered but most of them are fragile and/or sensitive to in vivo conditions. Poly(lactic‐co‐glycolic acid) (PLGA) is a widely used biodegradable polymer approved by food and drug administration and European medicines agency as an excipient for parenteral administrations. It is a well‐established drug delivery system in various medical applications. The aim of the current review is to elaborate the applications of PLGA based drug delivery systems carrying different wound healing agents and also present PLGA itself as a wound healing promoter. PLGA carriers encapsulating drugs such as antibiotics, anti‐inflammatory drugs, proteins/peptides, and nucleic acids targeting various phases/signaling cycles of wound healing, are discussed with examples. The combined therapeutic effects of PLGA and a loaded drug on wound healing are also mentioned.     

Control of Immune Response to Allogeneic Embryonic Stem Cells by CD3 Antibody–Mediated Operational Tolerance Induction

Implantation of embryonic stem cells (ESCs) and their differentiated derivatives into allogeneic hosts triggers an immune response that represents a hurdle to clinical application. We established in autoimmunity and in transplantation that CD3 antibody therapy induces a state of immune tolerance. Promising results have been obtained with CD3 antibodies in the clinic. In this study, we tested whether this strategy can prolong the survival of undifferentiated ESCs and their differentiated derivatives in histoincompatible hosts. Recipients of either mouse ESC–derived embryoid bodies (EBs) or cardiac progenitors received a single short tolerogenic regimen of CD3 antibody. In immunocompetent mice, allogeneic EBs and cardiac progenitors were rejected within 20–25 days. Recipients treated with CD3 antibody showed long‐term survival of implanted cardiac progenitors or EBs. In due course, EBs became teratomas, the growth of which was self‐limited. Regulatory CD4⁺FoxP3⁺ T cells and signaling through the PD1/PDL1 pathway played key roles in the CD3 antibody therapeutic effect. Gene profiling emphasized the importance of TGF‐β and the inhibitory T cell coreceptor Tim3 to the observed effect. These results demonstrate that CD3 antibody administered alone promotes prolonged survival of allogeneic ESC derivatives and thus could prove useful for enhancing cell engraftment in the absence of chronic immunosuppression.     

Blood polymorphonuclear leukocyte migration as a predictive marker for infections in severe trauma: comparison with various inflammation parameters

Objective To assess in patients with multiple trauma the relevance of the following as predictive markers for infections: the inflammation parameters white blood count, body temperature, blood polymorphonuclear leukocyte (PMN) migration; blood levels of C-reactive protein, PMN elastase, procalcitonin, neopterin, interleukin 6, interleukin 8, malondialdehyde, total antioxidative status; the stress parameters cortisol and lactate.Design Prospective observational cohort study.Setting Intensive Care Unit of a university surgical department.Patients Twenty-six patients with multiple trauma of differing severity.Measurements and results Trauma severity was estimated by the ISS. PMN migration upon F-Met-Leu-Phe stimulation was determined in fresh whole blood in a ready-for-use, one-way membrane filter assay and evaluated by automated image analysis. The other parameters were measured with commercially available tests. During hospitalization, nine patients developed infections, and 17 patients were free of infection. PMN migration below a critical minimum preceded infections in eight of the infected, but occurred in only three of the non-infected patients (positive/negative predictive values 0.72/0.93; sensitivity/specificity 0.88/0.82; likelihood ratio 5.0). Fever (38.0 °C) had predictive values of 0.83/0.80 and a high likelihood ratio of 9.4, but a low sensitivity/specificity of 0.55/0.94. The other parameters were without significance. Procalcitonin, elastase, C-reactive protein, neopterin and lactate correlated positively with the injury severity score.Conclusion PMN migration proved to be a highly sensitive predictive marker for infections. The whole-blood PMN migration test may facilitate early aggressive antimicrobial therapy.Coauthors are listed in alphabetical order