When Actin is Not Actin' Like It Should: A New Category of Distinct Primary Immunodeficiency Disorders.

An increasing number of primary immunodeficiencies (PIDs) have been identified over the last decade, which are caused by deleterious mutations in genes encoding for proteins involved in actin cytoskeleton regulation. These mutations primarily affect hematopoietic cells and lead to defective function of immune cells, such as impaired motility, signaling, proliferative capacity, and defective antimicrobial host defense. Here, we review several of these immunological "actinopathies" and cover both clinical aspects, as well as cellular mechanisms of these PIDs.

Different MDSC Activity of G-CSF/Dexamethasone Mobilized Neutrophils: Benefits to the Patient?

Human neutrophils exert a well-known role as efficient effector cells to kill pathogenic micro-organisms. Apart from their role in innate immunity, neutrophils also have the capacity to suppress T cell-mediated immune responses as so-called granulocyte-myeloid-derived suppressor cells (g-MDSCs), impacting the clinical outcome of various disease settings such as cancer. Patients undergoing chemotherapy because of an underlying malignancy can develop prolonged bone marrow suppression and are prone to serious infections because of severe neutropenia.

Cost-Effectiveness of Surgery Versus Organ Preservation in Advanced Laryngeal Cancer.

Objective: Treatment decision-making for patients with laryngeal cancer consists of a complex trade-off between survival and quality of life. For decision makers on coverage and guidelines, costs come in addition to this equation. Our aim was to perform a cost-effectiveness analysis of surgery (laryngectomy with or without radiotherapy) versus organ preservation (OP: radiotherapy, chemo- and/or bioradiation) in advanced laryngeal cancer patients from a healthcare perspective.

Development and validation of a universal blood donor genotyping platform: a multinational prospective study.

Each year, blood transfusions save millions of lives. However, under current blood-matching practices, sensitization to non-self-antigens is an unavoidable adverse side effect of transfusion. We describe a universal donor typing platform that could be adopted by blood services worldwide to facilitate a universal extended blood-matching policy and reduce sensitization rates.

Bilirubin-A Possible Prognostic Mortality Marker for Patients with ECLS.

Extracorporeal life support (ECLS) is a promising therapeutic option for patients with refractory cardiogenic shock. However, as the mortality rate still remains high, there is a need for early outcome parameters reflecting therapy success or futility. Therefore, we investigated whether liver enzyme levels could serve as prognostic mortality markers for patients with ECLS.

Influence of Hyperglycemia on Dexmedetomidine-Induced Cardioprotection in the Isolated Perfused Rat Heart.

Pharmacological preconditioning (PC) and postconditioning (PoC), for example, by treatment with the α2-adrenoreceptor agonist Dexmedetomidine (Dex), protects hearts from ischemia-reperfusion (I/R) injury in experimental studies, however, translation into the clinical setting has been challenging. Acute hyperglycemia adversely affects the outcome of patients with myocardial infarction. Additionally, it also blocks cardioprotection by multiple pharmacological agents.

Clinical relevance of the anatomy of the long head bicipital groove, an evidence-based review.

Pathology in the bicipital groove can be a source of anterior shoulder pain. Many studies have compared treatment techniques for the long head biceps tendon (LHBT) without showing any clinically significant differences. As the LHBT is closely related to the bicipital groove, anatomical aspects of this groove could also be implicated in surgical outcomes.

Activation of PKG and Akt Is Required for Cardioprotection by Ramelteon-Induced Preconditioning and Is Located Upstream of mKCa-Channels.

Ramelteon is a Melatonin 1 (MT1)-and Melatonin 2 (MT2)-receptor agonist conferring cardioprotection by pharmacologic preconditioning. While activation of mitochondrial calcium-sensitive potassium (mK)-channels is involved in this protective mechanism, the specific upstream signaling pathway of Ramelteon-induced cardioprotection is unknown. In the present study, we (1) investigated whether Ramelteon-induced cardioprotection involves activation of protein kinase G (PKG) and/or protein kinase B (Akt) and (2) determined the precise sequence of PKG and Akt in the signal transduction pathway of Ramelteon-induced preconditioning.

The Melatonin Receptor Agonist Ramelteon Induces Cardioprotection that Requires MT2 Receptor Activation and Release of Reactive Oxygen Species.

Purpose: The melatonin receptor (MT) agonist ramelteon has a higher affinity to MT1 than for MT2 receptors and induces cardioprotection by involvement of mitochondrial potassium channels. Activation of mitochondrial potassium channels leads to release of free radicals. We investigated whether (1) ramelteon-induced cardioprotection is MT2 receptor specific and (2) if free radicals are involved in ramelteon-induced cardioprotection.

MKL1 deficiency results in a severe neutrophil motility defect due to impaired actin polymerization.

Megakaryoblastic leukemia 1 (MKL1) promotes the regulation of essential cell processes, including actin cytoskeletal dynamics, by coactivating serum response factor. Recently, the first human with MKL1 deficiency, leading to a novel primary immunodeficiency, was identified. We report a second family with 2 siblings with a homozygous frameshift mutation in MKL1.

Capillaroscopy in childhood-onset systemic lupus erythematosus: a first systematic review.

Objectives: Recently, a systematic review indicated that, compared to healthy controls, adult patients with systemic lupus erythematosus (SLE) show a significantly more abnormal capillary morphology and greater number of haemorrhages in nailfold capillaroscopy and that these capillary changes are associated with disease activity. As yet, no systematic literature evaluation of capillaroscopy in childhood-onset SLE (cSLE) has been performed. Therefore, we aimed to systematically review the literature on nailfold capillary characteristics in cSLE.

Dynamic Transcriptome-Proteome Correlation Networks Reveal Human Myeloid Differentiation and Neutrophil-Specific Programming.

Human neutrophilic granulocytes form the largest pool of innate immune cells for host defense against bacterial and fungal pathogens. The dynamic changes that accompany the metamorphosis from a proliferating myeloid progenitor cell in the bone marrow into a mature non-dividing polymorphonuclear blood cell have remained poorly defined. Using mass spectrometry-based quantitative proteomics combined with transcriptomic data, we report on the dynamic changes of five developmental stages in the bone marrow and blood.

Activated neutrophils exert myeloid-derived suppressor cell activity damaging T cells beyond repair.

Myeloid-derived suppressor cells (MDSCs) have the capacity to suppress T-cell-mediated immune responses and impact the clinical outcome of cancer, infections, and transplantation settings. Although MDSCs were initially described as bone marrow-derived immature myeloid cells (either monocytic or granulocytic MDSCs), mature neutrophils have been shown to exert MDSC activity toward T cells in ways that remain unclear. In this study, we demonstrated that human neutrophils from both healthy donors and cancer patients do not exert MDSC activity unless they are activated.

Impact of Ca-Sensitive Potassium Channels in Levosimendan-Induced Postconditioning.

Purpose: Small and big conductance Ca-sensitive potassium (K) channels are involved in cardioprotective measures aiming at reducing myocardial reperfusion injury. For levosimendan, infarct size-reducing effects were shown. Whether activation of these channels is involved in levosimendan-induced postconditioning is unknown.

Influence of Hyperglycemia During Different Phases of Ischemic Preconditioning on Cardioprotection-A Focus on Apoptosis and Aggregation of Granulocytes.

Background: Ischemic preconditioning (IPC) protects the myocardium against ischemia/reperfusion injury. Evidence suggests that hyperglycemia inhibits IPC-induced cardioprotection. The effects of hyperglycemia initiated during different phases of IPC on myocardial injury were characterized with emphasis on apoptosis and aggregation of polymorphonuclear granulocytes (PMN).

Haemotherapy with Fibrinogen for Perioperative Bleeding Prevention-A View on Arterial Thrombogenesis and Myocardial Infarction in the Rat In Vivo.

Major blood loss during cardiac surgery is associated with increased morbidity and mortality. Clinical pilot studies indicated that preoperative fibrinogen supplementation reduces postoperative blood loss without increasing thrombotic complications. However, an increase in fibrinogen concentration might rather aggravate pre-existing thrombosis than increase the incidence of thrombotic events.

Milrinone-Induced Pharmacological Preconditioning in Cardioprotection: Hints for a Role of Mitochondrial Mechanisms.

The activation of mitochondrial calcium-sensitive potassium (mBK) channels is crucially involved in cardioprotection induced by preconditioning. For milrinone (Mil)-induced preconditioning, the involvement of mBK-channels and further mitochondrial signaling is unknown. We hypothesize that (1) Mil-induced preconditioning is concentration-dependent and (2) that the activation of mBK-channels, release of reactive oxygen species (ROS), and the mitochondrial permeability transition pore (mPTP) could be involved.

European Society of Anaesthesiology Task Force on Nitrous Oxide: a narrative review of its role in clinical practice.

Nitrous oxide (NO) is one of the oldest drugs still in use in medicine. Despite its superior pharmacokinetic properties, controversy remains over its continued use in clinical practice, reflecting in part significant improvements in the pharmacology of other anaesthetic agents and developing awareness of its shortcomings. This narrative review describes current knowledge regarding the clinical use of NO based on a systematic and critical analysis of the available scientific literature.

Impact of Anesthetics on Cardioprotection Induced by Pharmacological Preconditioning.

Anesthetics, especially propofol, are discussed to influence ischemic preconditioning. We investigated whether cardioprotection by milrinone or levosimendan is influenced by the clinically used anesthetics propofol, sevoflurane or dexmedetomidine. Hearts of male Wistar rats were randomised, placed on a Langendorff system and perfused with Krebs⁻Henseleit buffer (KHB) at a constant pressure of 80 mmHg.

Cardioprotective Properties of Omecamtiv Mecarbil against Ischemia and Reperfusion Injury.

Omecamtiv mecarbil (OM) is a first-in-class myosin activator. It was developed as a new inotropic therapy option for heart failure and is currently the object of a phase 3 clinical trial program. OM activates ryanodine receptors, which were shown to be involved in cardioprotection induced by conditioning strategies.

Overview of European forensic youth care: towards an integrative mission for prevention and intervention strategies for juvenile offenders.

All over Europe youth delinquency is decreasing; our understanding of the factors related to juvenile delinquency and the characteristics of effective forensic youth care has increased substantially. However, effective prevention and intervention strategies are not always employed due to financial, demographical and socio-political challenges countries face, while the burden of mental health in juvenile justice populations is high. With this commentary, we highlight the importance of international collaboration to set out a direction to improve forensic youth care, to bundle our strengths and overcome our challenges.