IgE alone stimulates mast cell adhesion to fibronectin via pathways similar to those used by IgE + antigen but distinct from those used by Steel factor

We recently demonstrated that immunoglobulin E (IgE), in the absence of cross-linking agents, activates signaling pathways in healthy murine bone marrow-derived mast cells (BMMCs) and that this activation enhances BMMC survival, at least in part, via secretion of autocrine-acting cytokines. We report herein that IgE alone also triggers the adhesion of both BMMCs and connective tissue mast cells (CTMCs) to the connective tissue component, fibronectin (FN). This adhesion occurs to the same extent as that triggered by optimal levels of Steel factor (SF) or IgE + antigen (IgE + Ag) and is mediated by an increased avidity of the integrin very late antigen 5 (VLA-5). Moreover, this IgE-induced adhesion, which is prolonged compared with that elicited by SF or IgE + Ag, requires phosphatidylinositol 3-kinase (PI3K), phospholipase C gamma (PLCgamma), and extracellular calcium but not extracellular-regulated kinase (Erk) or p38. Interestingly, we found, using the calcium channel blocker, 2-APB (2-aminoethoxydiphenyl borate) and Lyn-/- BMMCs that both IgE- and IgE + Ag-induced adhesion to FN require extracellular calcium entry, whereas SF does not. Furthermore, our data suggest that FN acts synergistically with IgE to prolong intracellular phosphorylation events and to enhance IgE-induced inflammatory cytokine production and BMMC survival.     

Multiple independent origins of mitochondrial gene order in birds

Mitochondrial genomes of all vertebrate animals analyzed to date have the same 37 genes, whose arrangement in the circular DNA molecule varies only in the relative position of a few genes. This relative conservation suggests that mitochondrial gene order characters have potential utility as phylogenetic markers for higher-level vertebrate taxa. We report discovery of a mitochondrial gene order that has had multiple independent originations within birds, based on sampling of 137 species representing 13 traditionally recognized orders. This provides evidence of parallel evolution in mitochondrial gene order for animals. Our results indicate operation of physical constraints on mitochondrial gene order changes and support models for gene order change based on replication error. Bird mitochondria have a displaced O_L (origin of light-strand replication site) as do various other Reptilia taxa prone to gene order changes. Our findings point to the need for broad taxonomic sampling in using mitochondrial gene order for phylogenetic analyses. We found, however, that the alternative mitochondrial gene orders distinguish the two primary groups of songbirds (order Passeriformes), oscines and suboscines, in agreement with other molecular as well as morphological data sets. Thus, although mitochondrial gene order characters appear susceptible to some parallel evolution because of mechanistic constraints, they do hold promise for phylogenetic studies.     

Maternal Self-confidence Postpartum and at Pre-school Age: The Role of Depression,Anxiety Disorders,Maternal Attachment Insecurity

The aim of this study was to analyze the impact of maternal postpartum depression and/or anxiety disorders according to DMS-IV on maternal self-confidence throughout infancy and early childhood. Exploratively, associations between maternal attachment insecurity and maternal self-confidence at pre-school age were examined. The sample (N = 54) of this prospective longitudinal study was comprised of n = 27 women with postpartum depression and/or anxiety disorders according to DSM-IV criteria and n = 27 healthy women without present or history of mental health disorders or psychotherapy. Data was collected in the postpartum period (M = 60.08 days) and at pre-school age (M = 4.7 years). Subjects were recruited between 2004 and 2011 in South Germany. Data revealed a significant difference in maternal self-confidence between clinical and control group at child′s pre-school age: Women with postpartum depression and/or anxiety disorder scored lower on maternal self-confidence than healthy controls, but only if they had current SCID-diagnoses or partly remitted symptoms. According to explorative analyses maternal attachment insecurity turned out to be the strongest predictor of maternal self-confidence at pre-school age besides maternal mental health status. The results emphasize the impact of attachment insecurity and maternal mental health regarding maternal self-confidence leading to potential adverse long-term consequences for the mother–child relationship. Attachment based interventions taking maternal self-confidence into account are needed.     

Preconception Healthcare Delivery at a Population Level: Construction of Public Health Models of Preconception Care

A key challenge of preconception healthcare is identifying how it can best be delivered at a population level. To review current strategies of preconception healthcare, explore methods of preconception healthcare delivery, and develop public health models which reflect different preconception healthcare pathways. Preconception care strategies, programmes and evaluations were identified through a review of Medline and Embase databases. Search terms included: preconception, pre-pregnancy, intervention, primary care, healthcare, model, delivery, program, prevention, trial, effectiveness, congenital disorders OR abnormalities, evaluation, assessment, impact. Inclusion criteria for review articles were: (1) English, (2) human subjects, (3) women of childbearing age, (4) 1980–current data, (5) all countries, (6) both high risk and universal approaches, (7) guidelines or recommendations, (8) opinion articles, (9) experimental studies. Exclusion criteria were: (1) non-human subjects, (2) non-English, (3) outside of the specified timeframe, (4) articles on male healthcare. The results of the literature review were synthesised into public health models of care: (1) primary care; (2) hospital-based and inter-conception care; (3) specific preconception care clinics; and, (4) community outreach. Fifteen evaluations of preconception care were identified. Community programmes demonstrated a significant impact on substance use, folic acid supplementation, diabetes optimization, and hyperphenylalaninemia. An ideal preconception visits entail risk screening, education, and intervention if indicated. Subsequently, four public health models were developed synthesizing preconception-care delivery at a population level. Heterogeneity of risk factors, health systems and strategies of care reflect the lack of consensus about the best way to deliver preconception care. The proposed models aim to reflect differing aspects of preconception healthcare delivery.     

Low prevalence of patellar tendon abnormality and low incidence of patellar tendinopathy in female collegiate volleyball players

ABSTRACT

The prevalence of patellar tendinopathy has been reported to be as high as 50% in elite male volleyball (VB) players; however, the rate of injury in female collegiate VB athletes is unknown. The purpose of this study was to 1) identify the prevalence of ultrasonographic evidence of patellar tendon abnormality at the start of the preseason in female collegiate VB players; 2) report the incidence of tendinopathy during the season; and 3) determine if the preseason presence of tendon abnormality is associated with onset of disease. One hundred and six female collegiate VB players had both patellar tendons imaged. Incidence of patellar tendinopathy was tracked during the course of the 4-month season. Twenty-two athletes presented with ultrasonographic evidence of patellar tendon abnormality in at least one knee at the start of the preseason. The incidence of time-loss patellar tendinopathy was 0.26 (95% CI: 0.04, 0.85) per 1000 athletic exposures. This study was unable to determine if preseason presence of tendon abnormality was associated with a greater risk of tendinopathy due to power. The prevalence of tendon abnormality in the preseason and the incidence of patellar tendinopathy in female collegiate VB players are lower than that observed in other populations.     

Lenalidomide in relapsed and refractory multiple myeloma disease: feasibility and benefits of long-term treatment

Lenalidomide in combination with dexamethasone is an effective and well-established treatment of relapsed or refractory multiple myeloma (rrMM) disease. Due to the scarcity of reports assessing benefit and risk of long-term lenalidomide treatment in non-selected rrMM patients, we retrospectively analysed the long-term outcome in patients with rrMM treated with lenalidomide and dexamethasone. Sixty-seven patients (pts) who were treated with lenalidomide/dexamethasone for rrMM in the approved indication from 2007 to 2011 were included in this retrospective, single-centre analysis. Kaplan-Meier survival estimates were compared between total population, patients on lenalidomide for more than 12 months (mo) and patients discontinuing therapy earlier than 12 months. Median overall survival (OS) of the total patient population was 33.2 mo. OS of pts treated beyond 12 mo was 42.9 mo compared to 20.2 mo (p?=?0.027) for pts stopping lenalidomide earlier than 12 mo for other reasons than progression disease (PD). OS of pts >12 mo on lenalidomide treatment did not significantly differ between pts who had received previous autologous transplantation, allogeneic transplantation or conventional therapy. Main non-hematologic toxicities were infections of grade 3/4 in 25 % and thrombembolic events of all grades in 18 % of patients. To the best of our knowledge, this is the first report on feasibility and efficacy of long-term lenalidomide treatment in a non-selected patient cohort. OS of pts >12 mo on lenalidomide is superior when compared to pts discontinued earlier for reasons other than PD. Our data confirm the current use of lenalidomide as a continuous long-term treatment strategy.     

Joint Congress of European Neurology 31 May–3 June 2014 Istanbul,Turkey

Neuromyelitis optica (NMO, Devic’s syndrome), long considered a clinical variant of multiple sclerosis, is now regarded as a distinct disease entity. Major progress has been made in the diagnosis and treatment of NMO since aquaporin-4 antibodies (AQP4-Ab; also termed NMO-IgG) were first described in 2004. In this review, the Neuromyelitis Optica Study Group (NEMOS) summarizes recently obtained knowledge on NMO and highlights new developments in its diagnosis and treatment, based on current guidelines, the published literature and expert discussion at regular NEMOS meetings. Testing of AQP4-Ab is essential and is the most important test in the diagnostic work-up of suspected NMO, and helps to distinguish NMO from other autoimmune diseases. Furthermore, AQP4-Ab testing has expanded our knowledge of the clinical presentation of NMO spectrum disorders (NMOSD). In addition, imaging techniques, particularly magnetic resonance imaging of the brain and spinal cord, are obligatory in the diagnostic workup. It is important to note that brain lesions in NMO and NMOSD are not uncommon, do not rule out the diagnosis, and show characteristic patterns. Other imaging modalities such as optical coherence tomography are proposed as useful tools in the assessment of retinal damage. Therapy of NMO should be initiated early. Azathioprine and rituximab are suggested as first-line treatments, the latter being increasingly regarded as an established therapy with long-term efficacy and an acceptable safety profile in NMO patients. Other immunosuppressive drugs, such as methotrexate, mycophenolate mofetil and mitoxantrone, are recommended as second-line treatments. Promising new therapies are emerging in the form of anti-IL6 receptor, anti-complement or anti-AQP4-Ab biologicals.     

Efficacy and safety of treatment with biologicals (benralizumab,dupilumab, mepolizumab,omalizumab and reslizumab) for severe eosinophilic asthma. A systematic review for the EAACI Guidelines - recommendations on the use of biologicals in severe asthma

Five biologicals have been approved for severe eosinophilic asthma, a well-recognized phenotype. Systematic reviews (SR) evaluated the efficacy and safety of benralizumab, dupilumab, mepolizumab, omalizumab and reslizumab (alphabetical order) compared to standard of care for severe eosinophilic asthma. PubMed, Embase and Cochrane Library were searched to identify RCTs and health economic evaluations, published in English. Critical and important asthma-related outcomes were evaluated for each of the biologicals. The risk of bias and the certainty of the evidence were assessed using GRADE. 19 RCTs (three RCTs for benralizumab, three RCTs for dupilumab, three RCTs for mepolizumab, five RCTs for omalizumab and five RCTs for reslizumab), including subjects 12 to 75 years old (except for omalizumab including also subjects 6-11 years old), ranging from 12 to 56 weeks were evaluated. All biologicals reduce exacerbation rates with high certainty of evidence: benralizumab incidence rate ratio (IRR) 0.53 (95% CI 0.39 to 0.72), dupilumab (IRR) 0.43 (95% CI 0.32 to 0.59), mepolizumab IRR 0.49 (95% CI 0.38 to 0.66), omalizumab (IRR) 0.56 (95% CI 0.40 to 0.77) and reslizumab (IRR) 0.46 (95% CI 0.37 to 0.58). Benralizumab, dupilumab and mepolizumab reduce the daily dose of oral corticosteroids (OCS) with high certainty of evidence. All evaluated biologicals probably improve asthma control, QoL and FEV₁, without reaching the minimal important difference (moderate certainty). Benralizumab, mepolizumab and reslizumab slightly increase drug-related adverse events (AE) and drug-related serious AE (low to very low certainty of evidence). The incremental cost-effectiveness ratio per quality-adjusted life year value is above the willingness to pay threshold for all biologicals (moderate certainty). Potential savings are driven by decrease in hospitalizations, emergency and primary care visits. There is high certainty that all approved biologicals reduce the rate of severe asthma exacerbations and for benralizumab, dupilumab and mepolizumab for reducing OCS. There is moderate certainty for improving asthma control, QoL, FEV₁. More data on long-term safety are needed together with more efficacy data in the paediatric population.     

Participation and outcome in manualized self-help for bulimia nervosa and binge eating disorder — A systematic review and metaregression analysis

There is a growing body of research on manualized self-help interventions for bulimia nervosa (BN) and binge eating disorder (BED). Study and treatment dropout and adherence represent particular challenges in these studies. However, systematic investigations of the relationship between study, intervention and patient characteristics, participation, and intervention outcomes are lacking. We conducted a systematic literature review using electronic databases and hand searches of relevant journals. In metaregression analyses, we analyzed study dropout as well as more specific measures of treatment participation in manualized self-help interventions, their association with intervention characteristics (e.g. duration, guidance, intervention type [bibliotherapy, CD-ROM or Internet based intervention]) and their association with treatment outcomes. Seventy-three publications reporting on 50 different trials of manualized self-help interventions for binge eating and bulimia nervosa published through July 9th 2012 were identified. Across studies, dropout rates ranged from 1% to 88%. Study dropout rates were highest in CD-ROM interventions and lowest in Internet-based interventions. They were higher in samples of BN patients, samples of patients with higher degrees of dietary restraint at baseline, lower age, and lower body mass index. Between 6% and 88% of patients completed the intervention to which they had been assigned. None of the patient, study and intervention characteristics predicted intervention completion rates. Intervention outcomes were moderated by the provision of personal guidance by a health professional, the number of guidance sessions as well as participants' age, BMI, and eating disorder related attitudes (Restraint, Eating, Weight and Shape Concerns) at baseline (after adjusting for study dropout and intervention completion rates). Guidance particularly improved adherence and outcomes in samples of patients with bulimia nervosa; specialist guidance led to higher intervention completion rates and larger intervention effects on some outcomes than non-specialist guidance. Self-help interventions have a place in the treatment of BN and BED, especially if the features of their delivery and indications are considered carefully. To better determine who benefits most from what kind and “dosage” of self-help interventions, we recommend the use of consistent terminology as well as uniform standards for reporting adherence and participation in future self-help trials.