Impact of Alemtuzumab Scheduling on Graft-versus-Host Disease after Unrelated Donor Fludarabine and Melphalan Allografts.

Alemtuzumab conditioning is highly effective at reducing the incidence of acute and chronic graft-versus-host disease (GVHD) in reduced-intensity fludarabine and melphalan transplantation with cyclosporine monotherapy. Less frequent and lower dose scheduling may be used with sibling donors, but an optimal regimen for matched unrelated donors has not been defined. In this retrospective observational study of 313 patients, the incidence and severity of GVHD was compared in patients receiving 3 different dose schedules: the standard 100-mg regimen (20 mg on days -7 to -3), 60 mg (30 mg on days -4 and -2), or 50 mg (10 mg on days -7 to -3).

B-Cell-Based and Soluble Biomarkers in Body Liquids for Predicting Acute/Chronic Graft-versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the main curative therapy for hematological malignancy such as leukemias, lymphomas, or multiple myelomas and some other hematological disorders. In this therapy, cure of hematological diseases relies on graft-versus-malignancy effects by allogenic immune cells. However, severe posttransplant treatment-associated complications such as acute graft-versus-host disease (aGvHD) and chronic graft-versus-host disease (cGvHD) limit this approach.

Role of JNK during buccopharyngeal membrane perforation, the last step of embryonic mouth formation.

Background: The buccopharyngeal membrane is a thin layer of cells covering the embryonic mouth. The perforation of this structure creates an opening connecting the external and the digestive tube which is essential for oral cavity formation. In humans, persistence of the buccopharyngeal membrane can lead to orofacial defects such as choanal atresia, oral synechiaes, and cleft palate.

Recent Developments in Cellular Immunotherapy for HSCT-Associated Complications.

Allogeneic hematopoietic stem cell transplantation is associated with serious complications, and improvement of the overall clinical outcome of patients with hematological malignancies is necessary. During the last decades, posttransplant donor-derived adoptive cellular immunotherapeutic strategies have been progressively developed for the treatment of graft-versus-host disease (GvHD), infectious complications, and tumor relapses. To date, the common challenge of all these cell-based approaches is their implementation for clinical application.

Human Regulatory T Cells Mediate Transcriptional Modulation of Dendritic Cell Function.

Regulatory T cells (Treg) attenuate dendritic cell (DC) maturation and stimulatory function. Current knowledge on the functional impact of semimature DC is limited to CD4 T cell proliferation and cytokine production. Little is known about the molecular basis underpinning the functional effects of Treg-treated DC (Treg-DC).

Human instrumental performance in ratio and interval contingencies: A challenge for associative theory.

Associative learning theories regard the probability of reinforcement as the critical factor determining responding. However, the role of this factor in instrumental conditioning is not completely clear. In fact, free-operant experiments show that participants respond at a higher rate on variable ratio than on variable interval schedules even though the reinforcement probability is matched between the schedules.

Milestones of Hematopoietic Stem Cell Transplantation - From First Human Studies to Current Developments.

Since the early beginnings, in the 1950s, hematopoietic stem cell transplantation (HSCT) has become an established curative treatment for an increasing number of patients with life-threatening hematological, oncological, hereditary, and immunological diseases. This has become possible due to worldwide efforts of preclinical and clinical research focusing on issues of transplant immunology, reduction of transplant-associated morbidity, and mortality and efficient malignant disease eradication. The latter has been accomplished by potent graft-versus-leukemia (GvL) effector cells contained in the stem cell graft.

Impact of genomic risk factors on survival after haematopoietic stem cell transplantation for patients with acute leukaemia.

The EBMT risk score is an established tool successfully used in the prognosis of survival post-HSCT and is applicable for a range of haematological disorders. One of its main advantages is that score generation involves summation of clinical parameters that are available pretransplant. However, the EBMT risk score is recognized as not being optimal.

The proteome pattern cGvHD_MS14 allows early and accurate prediction of chronic GvHD after allogeneic stem cell transplantation.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) may be curative, but is associated with significant morbidity and mortality. Chronic graft-versus-host disease (cGvHD), characterized by inflammation and fibrosis of multiple target organs, considerably contributes to the morbidity and mortality even years after allo-HSCT. Diagnosis of cGvHD is based on clinical features and histology of biopsies.

New Approaches to Investigate Drug-Induced Hypersensitivity.

The workshop on "New Approaches to Investigate Drug-Induced Hypersensitivity" was held on June 5, 2014 at the Foresight Center, University of Liverpool. The aims of the workshop were to (1) discuss our current understanding of the genetic, clinical, and chemical basis of small molecule drug hypersensitivity, (2) highlight the current status of assays that might be developed to predict potential drug immunogenicity, and (3) identify the limitations, knowledge gaps, and challenges that limit the use of these assays and utilize the knowledge gained from the workshop to develop a pathway to establish new and improved assays that better predict drug-induced hypersensitivity reactions during the early stages of drug development. This perspective reviews the clinical and immunological bases of drug hypersensitivity and summarizes various experts' views on the different topics covered during the meeting.

Understanding perceptual judgment in autism spectrum disorder using the drift diffusion model.

Objective: Two-alternative forced-choice tasks are widely used to gain insight into specific areas of enhancement or impairment in individuals with autism spectrum disorder (ASD). Data arising from these tasks have been used to support myriad theories regarding the integrity, or otherwise, of particular brain areas or cognitive processes in ASD. The drift diffusion model (DDM) provides an account of the underlying processes which give rise to accuracy and reaction time (RT) distributions, and parameterizes these processes in terms which have direct psychological interpretation.

Cytomegalovirus-Specific T Cells Isolated by IFN-γ Secretion Assay Do Not Induce Significant Graft-Versus-Host Reactions In Vitro.

Background: Graft-versus-host (GvH) disease (GvHD) remains a serious concern for patients undergoing antiviral cellular therapy. Despite the major improvements in cellular immunotherapy, the immunogenicity of virus-specific T cells has not yet been fully defined. This present study aims to examine how cytomegalovirus (CMV)-specific cytotoxic T lymphocytes (CTLs) respond to allogeneic antigen stimulation and whether they give rise to GvHD target tissue damage.

Tissue-Specific Expression Patterns of MicroRNA during Acute Graft-versus-Host Disease in the Rat.

MicroRNAs (miRNA) have emerged as central regulators of diverse biological processes and contribute to driving pathology in several diseases. Acute graft-versus-host disease (aGvHD) represents a major complication after allogeneic hematopoietic stem cell transplantation, caused by alloreactive donor T cells attacking host tissues leading to inflammation and tissue destruction. Changes in miRNA expression patterns occur during aGvHD, and we hypothesized that we could identify miRNA signatures in target tissues of aGvHD that may potentially help understand the underlying molecular pathology of the disease.

An important role for adenine, cholera toxin, hydrocortisone and triiodothyronine in the proliferation, self-renewal and differentiation of limbal stem cells in vitro.

The cornea is a self-renewing tissue located at the front of the eye. Its transparency is essential for allowing light to focus onto the retina for visual perception. The continuous renewal of corneal epithelium is supported by limbal stem cells (LSCs) which are located in the border region between conjunctiva and cornea known as the limbus.

Returning to contingency: the forward trauma team.

During Herrick 19, Main Operating Base Price Role 1 treatment facility saw one of the busiest periods of Role 1 trauma care within the British Afghanistan campaign. Within 5 months 73 trauma casualties were treated, 48 of whom were category A. This article shares the experiences of this Role 1 and its unusual context, and discusses the relevance with regard to future medical planning.

Mitochondrial DNA plasticity is an essential inducer of tumorigenesis.

Although mitochondrial DNA has been implicated in diseases such as cancer, its role remains to be defined. Using three models of tumorigenesis, namely glioblastoma multiforme, multiple myeloma and osteosarcoma, we show that mitochondrial DNA plays defining roles at early and late tumour progression. Specifically, tumour cells partially or completely depleted of mitochondrial DNA either restored their mitochondrial DNA content or actively recruited mitochondrial DNA, which affected the rate of tumorigenesis.

Measuring neural excitation and inhibition in autism: Different approaches, different findings and different interpretations.

The balance of neural excitation and inhibition (E/I balance) is often hypothesised to be altered in autism spectrum disorder (ASD). One widely held view is that excitation levels are elevated relative to inhibition in ASD. Understanding whether, and how, E/I balance may be altered in ASD is important given the recent interest in trialling pharmacological interventions for ASD which target inhibitory neurotransmitter function.

Influence of chloride on the chronic toxicity of sodium nitrate to Ceriodaphnia dubia and Hyalella azteca.

While it has been well established that increasing chloride concentration in water reduces the toxicity of nitrite to freshwater species, little work has been done to investigate the effect of chloride on nitrate toxicity. We conducted acute and chronic nitrate (as sodium nitrate) toxicity tests with the cladoceran Ceriodaphnia dubia and the amphipod Hyalella azteca (chronic tests only) over a range of chloride concentrations spanning natural chloride levels found in surface waters representative of watersheds of the Great Lakes Region. Chronic nitrate toxicity test results with both crustaceans were variable, with H.

Registering methodology for imaging and analysis of residual-limb shape after transtibial amputation.

Successful prosthetic rehabilitation following lower-limb amputation depends upon a safe and comfortable socket-residual limb interface. Current practice predominantly uses a subjective, iterative process to establish socket shape, often requiring several visits to a prosthetist. This study proposes an objective methodology for residual-limb shape scanning and analysis by high-resolution, automated measurements.

Effectiveness of interventions to indirectly support food and drink intake in people with dementia: Eating and Drinking Well IN dementiA (EDWINA) systematic review.

Background: Risks and prevalence of malnutrition and dehydration are high in older people but even higher in older people with dementia. In the EDWINA (Eating and Drinking Well IN dementiA) systematic review we aimed to assess effectiveness of interventions aiming to improve, maintain or facilitate food/drink intake indirectly, through food service or dining environment modification, education, exercise or behavioural interventions in people with cognitive impairment or dementia (across all settings, levels of care and support, types and degrees of dementia).

Methods: We comprehensively searched Medline and twelve further databases, plus bibliographies, for intervention studies with ≥3 cognitively impaired adult participants (any type/stage).

Autologous tolerogenic dendritic cells for rheumatoid and inflammatory arthritis.

Objectives: To assess the safety of intra-articular (IA) autologous tolerogenic dendritic cells (tolDC) in patients with inflammatory arthritis and an inflamed knee; to assess the feasibility and acceptability of the approach and to assess potential effects on local and systemic disease activities.

Methods: An unblinded, randomised, controlled, dose escalation Phase I trial. TolDC were differentiated from CD14+ monocytes and loaded with autologous synovial fluid as a source of autoantigens.

A Toroidal Probe for Measuring Surgically Exposed Joint Centers.

Maintaining the hip center can improve the success of a total hip arthroplasty. A novel probe design, based on mating a toroid with a sphere, was used for kinematic measurements of the femoral head center and implant center in a pre-clinical study of hip joints. In an electromagnetically tracked implementation tested in a laboratory environment, the device measured a spherical center to within 1.

Personalized Guides for Registration in Surgical Navigation.

Personalized guides are increasingly used in orthopedic procedures but do not provide for intraoperative re-planning. This work presents a tracked guide that used physical registration to provide an anatomy-to-tracking coordinate frame transformation for surgical navigation. In a study using seven femoral models derived from clinical CT scans used for hip resurfacing, a guide characterization FRE of 0.

Superior orientation discrimination and increased peak gamma frequency in autism spectrum conditions.

While perception is recognized as being atypical in individuals with autism spectrum conditions (ASC), the underlying mechanisms for such atypicality are unclear. Here we test the hypothesis that individuals with ASC will show enhanced orientation discrimination compared with neurotypical observers. This prediction is based both on anecdotal report of superior discriminatory skills in ASC and also on evidence in the auditory domain that some individuals with ASC have superior pitch discrimination.