Branching dendrites with resonant membrane: a “sum-over-trips” approach

Dendrites form the major components of neurons. They are complex branching structures that receive and process thousands of synaptic inputs from other neurons. It is well known that dendritic morphology plays an important role in the function of dendrites. Another important contribution to the response characteristics of a single neuron comes from the intrinsic resonant properties of dendritic membrane. In this paper we combine the effects of dendritic branching and resonant membrane dynamics by generalising the “sum-over-trips” approach (Abbott et al. in Biol Cybernetics 66, 49–60 1991). To illustrate how this formalism can shed light on the role of architecture and resonances in determining neuronal output we consider dual recording and reconstruction data from a rat CA1 hippocampal pyramidal cell. Specifically we explore the way in which an Ih current contributes to a voltage overshoot at the soma

To respond or not to respond - a personal perspective of intestinal tolerance

For many years, the intestine was one of the poor relations of the immunology world, being a realm inhabited mostly by specialists and those interested in unusual phenomena. However, this has changed dramatically in recent years with the realization of how important the microbiota is in shaping immune function throughout the body, and almost every major immunology institution now includes the intestine as an area of interest. One of the most important aspects of the intestinal immune system is how it discriminates carefully between harmless and harmful antigens, in particular, its ability to generate active tolerance to materials such as commensal bacteria and food proteins. This phenomenon has been recognized for more than 100 years, and it is essential for preventing inflammatory disease in the intestine, but its basis remains enigmatic. Here, I discuss the progress that has been made in understanding oral tolerance during my 40 years in the field and highlight the topics that will be the focus of future research

Fertility, Living Arrangements, Care and Mobility

There are four main interconnecting themes around which the contributions in this book are based. This introductory chapter aims to establish the broad context for the chapters that follow by discussing each of the themes. It does so by setting these themes within the overarching demographic challenge of the twenty-first century – demographic ageing. Each chapter is introduced in the context of the specific theme to which it primarily relates and there is a summary of the data sets used by the contributors to illustrate the wide range of cross-sectional and longitudinal data analysed

ICON 2019: International Scientific Tendinopathy Symposium Consensus: Clinical Terminology

© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.Background Persistent tendon pain that impairs function has inconsistent medical terms that can influence choice of treatment.1 When a person is told they have tendinopathy by clinician A or tendinitis by clinician B, they might feel confused or be alarmed at receiving what they might perceive as two different diagnoses. This may lead to loss of confidence in their health professional and likely adds to uncertainty if they were to search for information about their condition. Clear and uniform terminology also assists inter-professional communication. Inconsistency in terminology for painful tendon disorders is a problem at numerous anatomical sites. Historically, the term ‘tendinitis’ was first used to describe tendon pain, thickening and impaired function (online supplementary figure S1). The term ‘tendinosis’ has also been used in a small number of publications, some of which were very influential.2 3 Subsequently, ‘tendinopathy’ emerged as the most common term for persistent tendon pain.4 5 To our knowledge, experts (clinicians and researchers) or patients have never engaged in a formal process to discuss the terminology we use. We believe that health professionals have not yet agreed on the appropriate terminology for painful tendon conditions.Peer reviewedFinal Accepted Versio

Wiskott-Aldrich syndrome protein deficiency in innate immune cells leads to mucosal immune dysregulation and colitis in mice

BACKGROUND & AIMS: Immunodeficiency and autoimmune sequelae, including colitis, develop in patients and mice deficient in Wiskott-Aldrich Syndrome protein (WASP), a hematopoietic-specific intracellular signaling molecule that regulates the actin cytoskeleton. Development of colitis in WASP-deficient mice requires lymphocytes; transfer of T cells is sufficient to induce colitis in immunodeficient mice. We investigated the interactions between innate and adaptive immune cells in mucosal regulation during development of T-cell-mediated colitis in mice with WASP-deficient cells of the innate immune system. METHODS: Naïve and/or regulatory CD4(+) T cells were transferred from 129 SvEv mice into RAG-2 deficient (RAG-2 KO) mice or mice lacking WASP and RAG-2 (WRDKO). Animals were observed for the development of colitis; effector and regulatory functions of innate immune and T cells were analyzed with in vivo and in vitro assays. RESULTS: Transfer of unfractionated CD4(+) T cells induced severe colitis in WRDKO, but not RAG-2 KO, mice. Naïve wild-type T cells had higher levels of effector activity and regulatory T cells had reduced suppressive function when transferred into WRDKO mice compared to RAG-2 KO mice. Regulatory T-cell proliferation, generation, and maintenance of FoxP3 expression were reduced in WRDKO recipients, and associated with reduced numbers of CD103(+) tolerogenic dendritic cells and levels of interleukin (IL)-10. Administration of IL-10 prevented induction of colitis following transfer of T cells into WRDKO mice. CONCLUSIONS: Defective interactions between WASP-deficient innate immune cells and normal T cells disrupt mucosal regulation, potentially by altering the functions of tolerogenic dendritic cells, production of IL-10, and homeostasis of regulatory T cells

Achieving consensus on priority items for paediatric palliative care outcome measurement: Results from a modified Delphi survey, engagement with a children’s research involvement group and expert item generation

BACKGROUND: There is no validated outcome measure for use in children’s palliative care outside sub-Saharan Africa. Stakeholders must be involved in the development of such measures to ensure face and content validity. AIM: To gain expert stakeholder consensus on items for inclusion in a paediatric palliative care outcome measure to establish face and content validity. DESIGN: This study was conducted in two phases following Rothrock and COSMIN guidance on patient-reported outcome measure development. Phase 1: Three-round modified Delphi survey to establish consensus on priority items. Phase 2: Item generation meeting with key stakeholders to develop initial measure versions. A young person’s advisory group was also consulted on priority outcomes. SETTING AND PARTICIPANTS: Delphi survey: Parents and professionals with experience of caring for a child with a life-limiting condition. Young person’s advisory group: young people age 10–20 years. Item generation meeting: bereaved parents, academics and clinicians. RESULTS: Phase 1: Delphi survey (n = 82). Agreement increased from Kendall’s W = 0.17 to W = 0.61, indicating movement towards consensus. Agreement between professional and parent ranking was poor (Cohen’s kappa 0.13). Professionals prioritised physical symptoms, whereas parents prioritised psychosocial and practical concerns. Advisory group: Children (n = 22) prioritised items related to living a ‘normal life’ in addition to items prioritised by adult participants. Phase 2: Five age/developmental stage appropriate child and proxy-reported versions of C-POS, containing 13 items, were drafted. CONCLUSIONS: This study highlights the importance and feasibility of involving key stakeholders in PROM item generation, as important differences were found in the priority outcomes identified by children, parents and professionals

Duodenal carcinoma at the ligament of Treitz. A molecular and clinical perspective

Background There is very small occurrence of adenocarcinoma in the small bowel. We present a case of primary duodenal adenocarcinoma and discuss the findings of the case diagnostic modalities, current knowledge on the molecular biology behind small bowel neoplasms and treatment options. Case The patient had a history of iron deficiency anemia and occult bleeding with extensive workup consisting of upper endoscopy, colonoscopy, capsule endoscopy, upper gastrointestinal series with small bowel follow through and push enteroscopy. Due to persistent abdominal pain and iron deficiency anemia the patient underwent push enteroscopy which revealed adenocarcinoma of the duodenum. The patient underwent en-bloc duodenectomy which revealed T3N1M0 adenocarcinoma of the 4th portion of the duodenum. Conclusions Primary duodenal carcinoma, although rare should be considered in the differential diagnosis of occult gastrointestinal bleeding when evaluation of the lower and upper GI tract is unremarkable. We discuss the current evaluation and management of this small bowel neoplasm

Design and Administration of Patient-Centred Outcome Measures: The Perspectives of Children and Young People with Life-Limiting or Life-Threatening Conditions and Their Family Members

BACKGROUND: Self-reported health data from children with life-limiting conditions is rarely collected. To improve acceptability and feasibility of child and family-centred outcome measures for children, they need to be designed in a way that reflects preferences, priorities and abilities. OBJECTIVES: The aim was to identify preferences for patient-reported outcome measure design (recall period, response format, length, administration mode) to improve the feasibility, acceptability, comprehensibility and relevance of a child and family-centred outcome measure, among children with life-limiting conditions and their family members. METHOD: A semi-structured qualitative interview study seeking the perspectives of children with life-limiting conditions, their siblings and parents on measure design was conducted. Participants were purposively sampled and recruited from nine UK sites. Verbatim transcripts were analysed using framework analysis. RESULTS: A total of 79 participants were recruited: 39 children aged 5–17 years (26 living with a life-limiting condition; 13 healthy siblings) and 40 parents (of children aged 0–17 years). Children found a short recall period and a visually appealing measure with ten questions or fewer most acceptable. Children with life-limiting conditions were more familiar with using rating scales such as numeric and Likert than their healthy siblings. Children emphasised the importance of completing the measure alongside interactions with a healthcare professional to enable them to talk about their responses. While parents assumed that electronic completion methods would be most feasible and acceptable, a small number of children preferred paper. CONCLUSIONS: This study demonstrates that children with life-limiting conditions can engage in communicating preferences regarding the design of a patient-centred outcome measure. Where possible, children should be given the opportunity to participate in the measure development process to enhance acceptability and uptake in clinical practice. Results of this study should be considered in future research on outcome measure development in children

TGFβR signalling determines CD103⁺CD11b⁺ dendritic cell development in the intestine

CD103+CD11b+ dendritic cells (DCs) are unique to the intestine, but the factors governing their differentiation are unclear. Here we show that transforming growth factor receptor 1 (TGFβR1) has an indispensable, cell intrinsic role in the development of these cells. Deletion of Tgfbr1 results in markedly fewer intestinal CD103+CD11b+ DCs and a reciprocal increase in the CD103−CD11b+ dendritic cell subset. Transcriptional profiling identifies markers that define the CD103+CD11b+ DC lineage, including CD101, TREM1 and Siglec-F, and shows that the absence of CD103+CD11b+ DCs in CD11c-Cre.Tgfbr1fl/fl mice reflects defective differentiation from CD103−CD11b+ intermediaries, rather than an isolated loss of CD103 expression. The defect in CD103+CD11b+ DCs is accompanied by reduced generation of antigen-specific, inducible FoxP3+ regulatory T cells in vitro and in vivo, and by reduced numbers of endogenous Th17 cells in the intestinal mucosa. Thus, TGFβR1-mediated signalling may explain the tissue-specific development of these unique DCs