Recent studies have demonstrated that the skin of a normal adult human contains 10–20 billion resident memory T cells, including various helper, cytotoxic, and regulatory T cell subsets, that are ...poised to respond to environmental antigens. Using only autologous human tissues, we report that both in vitro and in vivo, resting epidermal Langerhan cells (LCs) selectively and specifically induced the activation and proliferation of skin resident regulatory T (Treg) cells, a minor subset of skin resident memory T cells. In the presence of foreign pathogen, however, the same LCs activated and induced proliferation of effector memory T (Tem) cells and limited Treg cells' activation. These underappreciated properties of LCs, namely maintenance of tolerance in normal skin, and activation of protective skin resident memory T cells upon infectious challenge, help clarify the role of LCs in skin.
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► Langerhans cells (LCs) directly interact with skin resident memory T cells ► LCs induce activation and proliferation of skin resident Treg cells at steady state ► LCs control the proliferation of skin-resident effector memory T cells at steady state ► During infection, LC induce the proliferation of skin resident effector memory T cells
Although lymphoma is a very heterogeneous group of biologically complex malignancies, tumor cells across all B cell lymphoma subtypes share a set of underlying traits that promote the development and ...sustain malignant B cells. One of these traits, the ability to evade apoptosis, is essential for lymphoma development. Alterations in the Bcl-2 family of proteins, the key regulators of apoptosis, is a hallmark of B cell lymphoma. Significant efforts have been made over the last 30 years to advance knowledge of the biology, molecular mechanisms, and therapeutic potential of targeting Bcl-2 family members. In this review, we will highlight the complexities of the Bcl-2 family, including our recent discovery of overexpression of the anti-apoptotic Bcl-2 family member Bcl-w in lymphomas, and describe recent advances in the field that include the development of inhibitors of anti-apoptotic Bcl-2 family members for the treatment of B cell lymphomas and their performance in clinical trials.
This study examined proficiency levels in fundamental motor skills (FMS) in children within Key Stage 1 and 2 of the English school system. Four hundred and ninety-two children aged 6–9 Years old ...(245 boys, 247 girls) from school Years Two (n = 130), Three (n = 154) and Four (n = 208) participated in this study. FMS for the run, jump, throw and catch were assessed using the Test of Gross Motor Development – 2. The proportion of children who achieved mastery or near mastery of the skills was determined. For the whole sample, 18.5% (n = 91) did not achieve mastery in any of the four skills. A similar proportion (18.7%, n = 92) achieved mastery in all four of the FMS examined in this study. The proportion of children achieving mastery of all four skills was lower for Year Two children (0%) compared to children in years Three (24%) and Four (25%). More boys (25.7%) achieved mastery in all four of the FMS compared to girls (11.7%). Individual behavioural components in skill performance were also examined. The results of the present study highlight that less than one-fifth of children aged 6–9 years old have mastered the four key FMS identified by the physical education (PE) curriculum despite having the developmental potential to become fundamentally competent by six years of age. Fostering positive trajectories of FMS development presents a challenge for PE specialists given the association between FMS mastery in childhood and physical activity, weight status and health.
Summary
Background
Faecal calprotectin decreases during exclusive enteral nutrition in children with active Crohn's disease. It is unknown how faecal calprotectin changes during food re‐introduction ...and the influence of maintenance enteral nutrition.
Aims
To study changes to faecal calprotectin during exclusive enteral nutrition and at food reintroduction, and explore associations with maintenance enteral nutrition.
Methods
Children with Crohn's disease were followed during exclusive enteral nutrition and during food‐reintroduction. Faecal calprotectin was measured before, at 33 and 54 days of exclusive enteral nutrition, and at 17, 52 and 72 days after food‐reintroduction. Maintenance enteral nutrition use was recorded with estimated weight food diaries. Data are presented with medians and Q1:Q3.
Results
Sixty‐six patients started exclusive enteral nutrition and 41 (62%) achieved clinical remission (weighted paediatric Crohn's disease activity index <12.5). Baseline faecal calprotectin (mg/kg) decreased after 4 and 8 weeks of exclusive enteral nutrition (Start: 1433 Q1: 946, Q3: 1820 vs 33 days: 844 314, 1438 vs 54 days: 453 165, 1100; P < .001). Within 17 days of food reintroduction, faecal calprotectin increased to 953 Q1: 519, Q3: 1611 and by 52 days to 1094 660, 1625 (both P < .02). Fifteen of 41 (37%) children in remission used maintenance enteral nutrition (333 kcal or 18% of energy intake). At 17 days of food reintroduction, faecal calprotectin was lower in maintenance enteral nutrition users than non‐users (651 Q1: 271, Q3: 1781 vs 1238 749, 2102, P = .049) and correlated inversely with maintenance enteral nutrition volume (rho: −0.573, P = .041), kcals (rho: −0.584, P = .036) and % energy intake (rho: −0.649, P = .016). Maintenance enteral nutrition use was not associated with longer periods of remission (P = .7). Faecal calprotectin at the end of exclusive enteral nutrition did not predict length of remission.
Conclusions
The effect of exclusive enteral nutrition on faecal calprotectin is diminished early during food reintroduction. Maintenance enteral nutrition at ~18% of energy intake is associated with a lower faecal calprotectin at the early phase of food reintroduction but is ineffective in maintaining longer term remission.
(1) Background: This study sought to calibrate triaxial accelerometery, worn on both wrists, waist and both ankles, during children's physical activity (PA), with particular attention to object ...control motor skills performed at a fast and slow cadence, and to cross-validate the accelerometer cut-points derived from the calibration using an independent dataset. (2) Methods: Twenty boys (10.1 ±1.5 years) undertook seven, five-minute bouts of activity lying supine, standing, running (4.5kmph
) instep passing a football (fast and slow cadence), dribbling a football (fast and slow cadence), whilst wearing five GENEActiv accelerometers on their non-dominant and dominant wrists and ankles and waist. VO
was assessed concurrently using indirect calorimetry. ROC curve analysis was used to generate cut-points representing sedentary, light and moderate PA. The cut-points were then cross-validated using independent data from 30 children (9.4 ± 1.4 years), who had undertaken similar activities whilst wearing accelerometers and being assessed for VO
. (3) Results: GENEActiv monitors were able to discriminate sedentary activity to an excellent level irrespective of wear location. For moderate PA, discrimination of activity was considered good for monitors placed on the dominant wrist, waist, non-dominant and dominant ankles but fair for the non-dominant wrist. Applying the cut-points to the cross-validation sample indicated that cut-points validated in the calibration were able to successfully discriminate sedentary behaviour and moderate PA to an excellent standard and light PA to a fair standard. (4) Conclusions: Cut-points derived from this calibration demonstrate an excellent ability to discriminate children's sedentary behaviour and moderate intensity PA comprising motor skill activity.
The anti-inflammatory effect of exclusive enteral nutrition on the gut of children with Crohn's disease is rapidly lost after food reintroduction. This study assessed disease dietary triggers ...following successful treatment with exclusive enteral nutrition.
Nutrient intake, dietary patterns and dietary biomarkers in faeces (gluten immunogenic peptides, undigestible starch, short chain fatty acids) were assessed in 14 children with Crohn's disease during early food reintroduction, following exclusive enteral nutrition. Groups above (Group A) and below (Group B) the median levels of faecal calprotectin after food reintroduction were assigned for comparative analysis.
Intakes of fibre, gluten-containing cereals and red and processed meat were significantly higher in Group A than Group B; (median Q1, Q3, g/day; Fibre: 12.1 11.2, 19.9 vs. 9.9 7.6, 12.1, p = 0.03; Red and processed meat: 151 66.7, 190 vs. 63.3 21.7, 67, p = 0.02; gluten-containing cereals: 289 207, 402 vs. 203 61, 232, p = 0.035). A diet consisting of cereals and meat products was predictive (92% accuracy) of higher faecal calprotectin levels after food reintroduction. In faeces, butyrate levels, expressed as absolute concentration and relative abundance, were higher in Group A than Group B by 28.4 µmol/g (p = 0.015) and 6.4% (p = 0.008), respectively. Levels of gluten immunogenic peptide and starch in faeces did not differ between the two groups.
This pilot study identified potential dietary triggers of gut inflammation in children with Crohn's disease after food reintroduction following treatment with exclusive enteral nutrition.
Clinical trials.gov registration number: NCT02341248; Clinical trials.gov URL: https://clinicaltrials.gov/ct2/show/NCT02341248 (retrospectively registered).
The aim of this study was to investigate the relationship between weekday, weekend day and four-day physical activity (PA) behaviours and fundamental movement skills (FMS) in British preschool ...children from a low socio-economic status background using compositional data analysis (CoDA). One hundred and eighty-five preschool children aged 3–4 years provided objectively assessed PA and sedentary behaviour (SB) data (GENEActiv accelerometer) and FMS (TGMD-2). The association of 24-h movement behaviours with FMS was explored using CoDA and isotemporal substitution (R Core Team, 3.6.1). When data were considered compositionally (SB, light PA (LPA), moderate and vigorous PA (MVPA)) and adjusted for age, BMI and sex, the weekday-derived composition predicted total motor competence (r2 = 0.07), locomotor (r2 = 0.08) and object control skills (r2 = 0.09); the weekend day-derived composition predicted total motor competence (r2 = 0.03) and object control skills (r2 = 0.03), the 4-day-derived composition predicted total motor competence (r2 = 0.07), locomotor (r2 = 0.07) and object control skills (r2 = 0.06) (all p < 0.05). Reallocation of 5 min of LPA at the expense of any behaviour was associated with significant improvements in total motor competence, locomotor and object control skills; for weekend-derived behaviours, MVPA was preferential. Considering movement behaviours over different time periods is required to better understand the effect of the 24-h movement composition on FMS in preschool children.
In this study, murine peritoneal macrophages from naïve lavage were found to generate four phospholipids that contain 12-hydroxyeicosatetraenoic acid (12-HETE). They comprise three plasmalogen and ...one diacyl phosphatidylethanolamines (PEs) (16:0p, 18:1p, 18:0p, and 18:0a at sn-1) and are absent in macrophages from 12/15-lipoxygenase (12/15-LOX)-deficient mice. They are generated acutely in response to calcium mobilization, are primarily cell-associated, and are detected on the outside of the plasma membrane. Levels of 12-HETE-PEs in naïve lavage are in a similar range to those of free 12-HETE (5.5 ± 0.2 ng or 18.5 ± 1.03 ng/lavage for esterified versus free, respectively). In healthy mice, 12/15-LOX-derived 12-HETE-PEs are found in the peritoneal cavity, peritoneal membrane, lymph node, and intestine, with a similar distribution to 12/15-LOX-derived 12-HETE. In vivo generation of 12-HETE-PEs occurs in a Th2-dependent model of murine lung inflammation associated with interleukin-4/interleukin-13 expression. In contrast, in Toll receptor-dependent peritonitis mediated either by live bacteria or bacterial products, 12-HETE-PEs are rapidly cleared during the acute phase then reappear during resolution. The human homolog, 18:0a/15-HETE-PE inhibited human monocyte generation of cytokines in response to lipopolysaccharide. In summary, a new family of lipid mediators generated by murine macrophages during Th2 inflammation are identified and structurally characterized. The studies suggest a new paradigm for lipids generated by 12/15-LOX in inflammation involving formation of esterified eicosanoids.
Geomorphological mapping is a well-established method for examining earth surface processes and landscape evolution in a range of environmental contexts. In glacial research, it provides crucial data ...for a wide range of process-oriented studies and palaeoglaciological reconstructions; in the latter case providing an essential geomorphological framework for establishing glacial chronologies. In recent decades, there have been significant developments in remote sensing and Geographical Information Systems (GIS), with a plethora of high-quality remotely-sensed datasets now (often freely) available. Most recently, the emergence of unmanned aerial vehicle (UAV) technology has allowed sub-decimetre scale aerial images and Digital Elevation Models (DEMs) to be obtained. Traditional field mapping methods still have an important role in glacial geomorphology, particularly in cirque glacier, valley glacier and icefield/ice-cap outlet settings. Field mapping is also used in ice sheet settings, but often takes the form of necessarily highly-selective ground-truthing of remote mapping. Given the increasing abundance of datasets and methods available for mapping, effective approaches are necessary to enable assimilation of data and ensure robustness. This paper provides a review and assessment of the various glacial geomorphological methods and datasets currently available, with a focus on their applicability in particular glacial settings. We distinguish two overarching ‘work streams’ that recognise the different approaches typically used in mapping landforms produced by ice masses of different sizes: (i) mapping of ice sheet geomorphological imprints using a combined remote sensing approach, with some field checking (where feasible); and (ii) mapping of alpine and plateau-style ice mass (cirque glacier, valley glacier, icefield and ice-cap) geomorphological imprints using remote sensing and considerable field mapping. Key challenges to accurate and robust geomorphological mapping are highlighted, often necessitating compromises and pragmatic solutions. The importance of combining multiple datasets and/or mapping approaches is emphasised, akin to multi-proxy approaches used in many Earth Science disciplines. Based on our review, we provide idealised frameworks and general recommendations to ensure best practice in future studies and aid in accuracy assessment, comparison, and integration of geomorphological data. These will be of particular value where geomorphological data are incorporated in large compilations and subsequently used for palaeoglaciological reconstructions. Finally, we stress that robust interpretations of glacial landforms and landscapes invariably requires additional chronological and/or sedimentological evidence, and that such data should ideally be collected as part of a holistic assessment of the overall glacier system.
Patient-reported quality of life (QOL) after salvage brachytherapy for radiorecurrent prostate cancer has not been well-characterized prospectively.
We examined 25 men who recurred after primary ...radiotherapy for prostate cancer and received MRI-guided salvage brachytherapy as part of a prospective Phase II study. These patients received prospectively a validated patient-reported QOL questionnaire to fill out at baseline, as well as 3, 15, and 27 months after re-irradiation to determine the degree of sexual, bowel, and urinary dysfunction (maximum dysfunction score=100).
On average, sexual function continued to decline with time, and patients had significantly worse sexual function scores at 27 months than baseline (p=0.01). Although bowel and urinary symptoms worsened acutely at 3 or 15 months, they showed on average some improvement by 27 months, and there were no significant differences between baseline and 27-month urinary or bowel scores. An interval to re-irradiation less than 4.5 years and prior brachytherapy were each associated significantly with the largest decrements in bowel function (p=0.035).
Similar to the patterns seen in the de novo setting, patients who receive salvage brachytherapy report a worsening of bowel and urinary symptoms followed by some improvement by 27 months, while sexual function steadily declines over time. Interval to re-irradiation and type of prior radiation received may be used to counsel and optimize selection of men for salvage brachytherapy with regard to QOL endpoints.
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