Longitudinal Analysis of T-Cell Receptor Variable β Chain Repertoire in Patients with Acute Graft-versus-Host Disease after Allogeneic Stem Cell Transplantation

AbstractT-cell receptor variable β chain (TCRBV) repertoire spectratyping involves the estimation of CDR3 length distributions for monitoring T-cell receptor diversity and has proven useful for analyses of immune reconstitution and T-cell clonal expansions in graft-versus-host disease (GVHD) and graft-versus-leukemia after allogeneic stem cell transplantation. We performed a longitudinal spectratype analysis of 23 TCRBV families in 28 patients who underwent allogeneic T cell–depleted peripheral blood stem cell transplantation. Sixteen patients subsequently developed acute GVHD. We recently developed statistical methods that bring increased power and flexibility to spectratype analysis and allow us to analyze TCRBV repertoire development under appropriately complex statistical models. Applying these methods, we found that patients with acute GVHD demonstrated TCRBV repertoire development statistically distinct from that repertoire development in patients without GVHD. Specifically, GVHD patients showed spectratypes indicative of lower diversity and greater deviation from the spectratypes expected in healthy individuals at intermediate times. Most individual TCRBV subfamilies had spectratypes statistically distinguishable between GVHD and non-GVHD patients at 6 months after transplantation. These results suggest that the T-cell receptor repertoire perturbations associated with acute GVHD are widely spread throughout the TCRBV families

Phase ordering and roughening on growing films

We study the interplay between surface roughening and phase separation during the growth of binary films. Already in 1+1 dimension, we find a variety of different scaling behaviors depending on how the two phenomena are coupled. In the most interesting case, related to the advection of a passive scalar in a velocity field, nontrivial scaling exponents are obtained in simulations.Comment: 4 pages latex, 6 figure

Anorexia nervosa in males: similarities and differences to anorexia nervosa in females

INTRODUCTION Previous single case reports of males with anorexia nervosa from our database focused on the roles of gender and general personal identity conflicts and panic/guilt over the consequences of impulsivity in precipitating out the illness (Davis & Crisp, 1993; Fry & Crisp, 1989; Toms & Crisp, 1972), the growth stunting but reversible effects of early onset (Toms & Crisp, 1972), and a 35-year long follow-up of a case first seen in 1959 (Crisp, 1995). Our first reported series of 13 male patients (Crisp & Toms, 1972) drew attention to the many similarities to a female population but emphasised, descriptively, the high prevalence of psychiatric morbidity in the parents, often bound in with phobic avoidance behaviours and commonly coupled with over-protectiveness of the patient during childhood

Developmental Dysfunction of the Central Nervous System Lymphatics Modulates the Adaptive Neuro-Immune Response in the Perilesional Cortex in a Mouse Model of Traumatic Brain Injury

Rationale The recently discovered meningeal lymphatic vessels (mLVs) have been proposed to be the missing link between the immune and the central nervous system. The role of mLVs in modulating the neuro-immune response following a traumatic brain injury (TBI), however, has not been analyzed. Parenchymal T lymphocyte infiltration has been previously reported as part of secondary events after TBI, suggestive of an adaptive neuro-immune response. The phenotype of these cells has remained mostly uncharacterized. In this study, we identified subpopulations of T cells infiltrating the perilesional areas 30 days post-injury (an early-chronic time point). Furthermore, we analyzed how the lack of mLVs affects the magnitude and the type of T cell response in the brain after TBI. Methods TBI was induced in K14-VEGFR3-Ig transgenic (TG) mice or in their littermate controls (WT; wild type), applying a controlled cortical impact (CCI). One month after TBI, T cells were isolated from cortical areas ipsilateral or contralateral to the trauma and from the spleen, then characterized by flow cytometry. Lesion size in each animal was evaluated by MRI. Results In both WT and TG-CCI mice, we found a prominent T cell infiltration in the brain confined to the perilesional cortex and hippocampus. The majority of infiltrating T cells were cytotoxic CD8+ expressing a CD44(hi)CD69+ phenotype, suggesting that these are effector resident memory T cells. K14-VEGFR3-Ig mice showed a significant reduction of infiltrating CD4+ T lymphocytes, suggesting that mLVs could be involved in establishing a proper neuro-immune response. Extension of the lesion (measured as lesion volume from MRI) did not differ between the genotypes. Finally, TBI did not relate to alterations in peripheral circulating T cells, as assessed one month after injury. Conclusions Our results are consistent with the hypothesis that mLVs are involved in the neuro-immune response after TBI. We also defined the resident memory CD8+ T cells as one of the main population activated within the brain after a traumatic injury.Peer reviewe

Adherence to Accelerometer Protocols Among Women From Economically Disadvantaged Neighborhoods

Background: Objective measurement of physical activity with accelerometers is a challenging task in community-based intervention research. Challenges include distribution of and orientation to monitors, nonwear, incorrect placement, and loss of equipment. Data collection among participants from disadvantaged populations may be further hindered by factors such as transportation challenges, competing responsibilities, and cultural considerations. Methods: Research staff distributed accelerometers and provided an orientation that was tailored to the population group. General adherence strategies such as follow-up calls, daily diaries, verbal and written instructions, and incentives were accompanied by population-specific strategies such as assisting with transportation, reducing obstacles to wearing the accelerometer, tailoring the message to the participant population, and creating a nonjudgmental environment. Results: Sixty women asked to wear the Actigraph GT1M returned the accelerometer, and 57 of them provided sufficient data for analysis (at least 10 hours a day for a minimum of 4 days) resulting in 95% adherence to the protocol. Participants wore the accelerometers for an average of 5.98 days and 13.15 hours per day. Conclusions: The high accelerometer monitoring adherence among this group of economically disadvantaged women demonstrates that collection of high-quality, objective physical data from disadvantaged populations in field-based research is possible

Nonmyeloablative regimen preserves "niches" allowing for peripheral expansion of donor T-cells

AbstractT-cell recovery following myeloablative preparatory regimens and cord blood transplantation in adult patients gen erally occurs between 1 and 3 years following allogeneic bone marrow transplantation. T-cell reconstitution may involve thymic education of donor-derived precursors or peripheral expansion of mature T-cells transferred in the graft. We measured quantitative and qualitative immunologic reconstitution, T-cell receptor spectratyping, and T-cell receptor excision circle (TREC) levels in adult recipients of umbilical cord blood transplants following a novel nonmyeloablative regimen. These results were compared to previously published results of similar patients receiving a myeloablative regimen and cord blood stem cells. With small numbers of patients treated so far, T-cells (CD3+) reached normal levels in adults 6 to 12 months following nonmyeloablative transplantation compared with 24 months in adults receiving a myeloablative regimen. At 12 months after transplantation, the numbers of phenotypically naive (CD45RA) T-cells were higher in those receiving the nonmyeloablative regimen. The T-cell repertoire in cord blood recipients treated with a nonmyeloablative regimen was markedly more diverse and robust compared with the repertoire in those receiving the myeloablative regimen at similar time points. TRECs (which are generated within the thymus and identify new thymic emigrants and those that have not divided) were detected 12 months after transplantation in the nonmyeloablative recipients, whereas TRECs were not detected in adults until 18 to 24 months in those receiving myeloablative regimens. Thus, in adults receiving a nonmyeloablative preparatory regimen, the quantitative and qualitative recovery of T-cells occurs through rapid peripheral expansion. The ability of patients receiving a nonmyeloablative regimen to recover within a few months suggests that the peripheral niches in which T-cells can proliferate are preserved in these patients compared to those receiving ablative regimens. Moreover, the presence of TREC-positive cells within 1 year suggests that thymic recovery is likewise accelerated in non myeloablative compared to myeloablative regimens.Biol Blood Marrow Transplant 2002;8(5):249-56

Identification of a dna methylation episignature in the 22q11.2 deletion syndrome

The 22q11.2 deletion syndrome (22q11.2DS) is the most common genomic disorder in humans and is the result of a recurrent 1.5 to 2.5 Mb deletion, encompassing approximately 20–40 genes, respectively. The clinical presentation of the typical deletion includes: Velocardiofacial, Di George, Opitz G/BBB and Conotruncalanomaly face syndromes. Atypical deletions (proximal, distal or nested) are rare and characterized mainly by normal phenotype or mild intellectual disability and variable clinical features. The pathogenetic mechanisms underlying this disorder are not completely understood. Because the 22q11.2 region harbours genes coding for transcriptional factors and chromatin remodelers, in this study, we performed analysis of genome‐wide DNA methylation of peripheral blood from 49 patients with 22q11.2DS using the Illumina Infinium Methylation EPIC bead chip arrays. This cohort comprises 43 typical, 2 proximal and 4 distal deletions. We demonstrated the evidence of a unique and highly specific episignature in all typical and proximal 22q11.2DS. The sensitivity and specificity of this signature was further confirmed by comparing it to over 1500 patients with other neurodevelopmental disorders with known episignatures. Mapping the 22q11.2DS DNA methylation episignature provides both novel insights into the molecular pathogenesis of this disorder and an effective tool in the molecular diagnosis of 22q11.2DS

B844: Checklist of the Vascular Plants of Maine Third Revision

This is the third revision of the Checklist of Vascular Plants of Maine. Like its predecessors, it lists all ferns and related plants, conifers, and flowering plants native and naturalized in Maine and records their county-level distribution in the state. The first Check- list (Ogden et al. 1948) was based on specimens in herbaria at the University of Maine (hereafter referred to as MAINE), Portland Society of Natural History, New England Botanical Club, Gray Herbarium of Harvard University, and the private collection of Glen D. Chamberlain of Presque Isle, Maine (now part of MAINE). Bean et al. (1966) revised the checklist to include additions to the flora and update the nomenclature to follow Fernald (1950). Richards et al. (1983) added many new state and county records in the second revision. The purpose of this revision is twofold. First, we have included many new county and state records. Since Richards et al. (1983) there has been considerable collecting in Maine, much of it directed at searching for new state and county records in relatively neglected regions of the state. Second, there have been numerous changes in the scientific names of Maine plants since Fernald (1950), the nomenclatural basis of Richards et al. (1983). We have largely followed Kartesz\u27s (1994) nomenclature (see Taxonomy and Nomenclature section). Recent work on rare plants and establishment of an official list of endangered and threatened plants in Maine (Dibble et al. 1989; Maine State Planning Office 1990) also motivate updating the known distribution and taxonomy of Maine\u27s flora.https://digitalcommons.library.umaine.edu/aes_bulletin/1121/thumbnail.jp

Making it easy to do the right thing in healthcare: Advancing improvement science education through accredited pan European higher education modules

Background: Numerous international policy drivers espouse the need to improve healthcare. The application of Improvement Science has the potential to restore the balance of healthcare and transform it to a more person-centred and quality improvement focussed system. However there is currently no accredited Improvement Science education offered routinely to healthcare students. This means that there are a huge number of healthcare professionals who do not have the conceptual or experiential skills to apply Improvement Science in everyday practise. Methods: This article describes how seven European Higher Education Institutions (HEIs) worked together to develop four evidence informed accredited inter-professional Improvement Science modules for under and postgraduate healthcare students. It outlines the way in which a Policy Delphi, a narrative literature review, a review of the competency and capability requirements for healthcare professionals to practise Improvement Science, and a mapping of current Improvement Science education informed the content of the modules. Results: A contemporary consensus definition of Healthcare Improvement Science was developed. The four Improvement Science modules that have been designed are outlined. A framework to evaluate the impact modules have in practise has been developed and piloted. Conclusion: The authors argue that there is a clear need to advance healthcare Improvement Science education through incorporating evidence based accredited modules into healthcare professional education. They suggest that if Improvement Science education, that incorporates work based learning, becomes a staple part of the curricula in inter-professional education then it has real promise to improve the delivery, quality and design of healthcare.Erasmus+ Life long Learning Programme

The Human Phenotype Ontology project:linking molecular biology and disease through phenotype data

The Human Phenotype Ontology (HPO) project, available at http://www.human-phenotype-ontology.org, provides a structured, comprehensive and well-defined set of 10,088 classes (terms) describing human phenotypic abnormalities and 13,326 subclass relations between the HPO classes. In addition we have developed logical definitions for 46% of all HPO classes using terms from ontologies for anatomy, cell types, function, embryology, pathology and other domains. This allows interoperability with several resources, especially those containing phenotype information on model organisms such as mouse and zebrafish. Here we describe the updated HPO database, which provides annotations of 7,278 human hereditary syndromes listed in OMIM, Orphanet and DECIPHER to classes of the HPO. Various meta-attributes such as frequency, references and negations are associated with each annotation. Several large-scale projects worldwide utilize the HPO for describing phenotype information in their datasets. We have therefore generated equivalence mappings to other phenotype vocabularies such as LDDB, Orphanet, MedDRA, UMLS and phenoDB, allowing integration of existing datasets and interoperability with multiple biomedical resources. We have created various ways to access the HPO database content using flat files, a MySQL database, and Web-based tools. All data and documentation on the HPO project can be found online