2,220 research outputs found
The Recognition of Hypothalamo-Neurohypophysial Functions by Developing T Cells
Neuropeptide signals and specific neuropeptide receptors have been described in the
thymus supporting the concept of a close dialogue between the neuroendocrine and the
immune systems at the level of early T-cell differentiation. In this paper, we review
recent data about neurohypophysial (NHP)-related peptides detected in the thymus
from different species. We suggest that we are dealing in fact with other member(s) of
the NHP hormone family, which seems to exert its activity locally through a novel
model of cell-to-cell signaling, that of cryptocrine communication. This model involves
exchange of signals between thymic epithelial cells and developing thymocytes. The
NHP-related peptides have been shown to trigger thymocyte proliferation and could
induce immune tolerance of this highly conserved neuroendocrine family
Physical and psychological paths toward less severe fibromyalgia: A structural equation model
The authors gratefully acknowledge all the participants for their
collaboration and enthusiasm. We thank the assistant researchers
involved in this study and all the members of the Physical Activity
for HEaLth Promotion (PA-HELP; CTS-1018) research group.Supplementary data associated with this article can be found, in
the online version, at https://doi.org/10.1016/j.rehab.2019.06.017.Objectives: Previous research suggested isolated associations of physical and psychological factors with
fibromyalgia severity. Integration of physical and psychological, experienced and observed, modifiable
factors associated with fibromyalgia severity in a single model will reveal therapeutic paths toward less
severity of disease. We aimed to examine an encompassing model of determinants of fibromyalgia
severity.
Methods: This observational, population-based cross-sectional study included 569 people with
fibromyalgia. An integrative model of fibromyalgia severity was tested by using structural equation
modelling. This model included 8 factors: resilience, catastrophizing, active lifestyle, declarative
memory, subjective fitness, objective fitness, psychological distress, and physical fatigue.
Results: Two core paths were associated with reduced fibromyalgia severity: 1) a psychological path
connecting high resilience and low catastrophizing with low distress and 2) a physical path, connecting a
more active lifestyle (directly and via high objective and subjective physical fitness) with low fatigue.
Additional interconnecting paths especially suggested a connection from the psychological to physical
path. Our model explained 83% of the fibromyalgia severity.
Conclusions: The present model integrated the complexity of mutually influencing factors of fibromyalgia
severity, which may help to better understand the disease. It emphasised the importance of: 1) physical
factors and psychological factors and their interconnections, 2) patients’ experiences and clinical
measurements, and 3) positive and negative signs such as physical fitness and distress. Future
longitudinal and experimental research should aim at testing the causal direction of the associations in
the model as well as the clinical implications suggested by the model. For instance, to reduce fatigue,
exercise should enhance not only objective fitness but also fitness-related perceptions. Reducing distress
and fatigue seems crucial for lowering fibromyalgia severity.This work was supported by the Spanish Ministry of Economy and Competitiveness [I+D+i DEP2010-15639, I+D+I DEP2013-40908, I+D+I PSI2015-65241-R, and BES-2014-067612] and the Spanish Ministry of Education [FPU15/00002]. This study was funded in part by the University of Granada, Plan Propio de Investigación 2016, Excellence actions: Units of Excellence; Unit of Excellence on Exercise and Health (UCEES), and the Junta de Andalucía, Consejería de Conocimiento, Investigación y Universidades and European Regional Development Fund (ref. SOMM17/6107/UGR) and University of Jaén, Plan de Apoyo a la Investigación 2017-2019 [EI_SEJ07_2017]. The funders did not have any role in the study design, data collection and analyses, decision to publish, or preparation of the manuscript
Neurohypophysial Receptor Gene Expression by Thymic T Cell Subsets and Thymic T Cell Lymphoma Cell Lines
Abstract
Neurohypophysial oxytocin (OT) and vasopressin (VP) genes are
transcribed in thymic epithelium, while immature T lymphocytes express
functional neurohypophysial receptors. Neurohypophysial receptors belong
to the G protein-linked seven-transmembrane receptor superfamily and are encoded
by four distinct genes, OTR, V1R, V2R
and V3R. The objective of this study was to
identify the nature of neurohypophysial receptor in thymic T cell subsets purified by
immunomagnetic selection, as well as in murine thymic lymphoma cell lines RL12-NP
and BW5147. OTR is transcribed in all thymic T cell subsets and T cell lines, while
V3R transcription is restricted to CD4+ CD8+ and CD8+ thymic cells. Neither V1R nor
V2R transcripts are detected in any kind of T cells. The OTR protein was identified by
immunocytochemistry on thymocytes freshly isolated from C57BL/6 mice. In murine fetal
thymic organ cultures, a specific OTR antagonist does not modify the percentage of T
cell subsets, but increases late T cell apoptosis further evidencing the involvement of
OT/OTR signaling in the control of T cell proliferation and survival. According to these
data, OTR and V3R are differentially expressed during T cell ontogeny. Moreover, the
restriction of OTR transcription to T cell lines derived from thymic lymphomas may be
important in the context of T cell leukemia pathogenesis and treatment
Formation of ultrathin Ni germanides : solid-phase reaction, morphology and texture
The solid-phase reaction of ultrathin (<= 10 nm) Ni films with different Ge substrates (single-crystalline (100), polycrystalline, and amorphous) was studied. As thickness goes down, thin film texture becomes a dominant factor in both the film's phase formation and morphological evolution. As a consequence, certain metastable microstructures are epitaxially stabilized on crystalline substrates, such as the epsilon-Ni5Ge3 phase or a strained NiGe crystal structure on the single-crystalline substrates. Similarly, the destabilizing effect of axiotaxial texture on the film's morphology becomes more pronounced as film thicknesses become smaller. These effects are contrasted by the evolution of germanide films on amorphous substrates, on which neither epitaxy nor axiotaxy can form, i.e. none of the (de) stabilizing effects of texture are observed. The crystallization of such amorphous substrates however, drives the film breakup
Objective and subjective measures of physical functioning in women with fibromyalgia: what type of measure is associated most clearly with subjective well-being?
To find modifiable factors that are related to subjective well-being would be valuable for improving
interventions in fibromyalgia. Physical activity, sedentary behaviour, and physical fitness may represent potential
areas to optimize treatment regimens. In fibromyalgia, there is a discordance between clinical observations and
patient-reported outcomes (objective and subjective assessments). Therefore, the present study aims at analyzing
the associations of objective and subjective evaluations of physical activity, sedentary behaviour, and physical
fitness with subjective well-being and determine if and how objective and subjective associations differ In the most conservative multivariate analysis, we found independent associations of the objective
measures of physical activity with positive affect and life satisfaction and sedentary behaviour with
positive affect. No such relationship was seen with subjective measures of the same behaviours.
Moreover, we observed that objective and subjective physical fitness evaluations were independent of
each other related to subjective well-being. Independent associations of the objectivemeasures (but not the subjective assessments) of physical
activity with positive affect and life satisfaction, and of sedentary behaviour with positive affect were observed.
However, objective measures and subjective appraisals of physical fitness appear to be independently related to
well-being,which should be consideredwhen developing physical exercise interventions for fibromyalgiaThis work was supported by the Spanish Ministry of Economy and
Competitiveness [I+D+i DEP2010-15639, I+D+I DEP2013-
40908, and BES-2014–067612]; the Spanish Ministry of Education
[FPU15/00002]. This study has been partially funded by the
University of Granada, Plan Propio de Investigación 2016,
Excellence actions: Units of Excellence; Unit of Excellence on
Exercise and Health (UCEES), and by the Junta de Andalucía,
Consejería de Conocimiento, Investigación y Universidades and
European Regional Development Fund (ERDF), ref. SOMM17/6107/
UGR. This research was supported (in part) by the Intramural
Research program of the NIH, National Institute of Nursing
Research
New low-stress PECVD poly-SiGe layers for MEMS
Thick poly-SiGe layers, deposited by plasma-enhanced chemical vapor deposition (PECVD), are very promising structural layers for use in microaccelerometers, microgyroscopes or for thin-film encapsulation, especially for applications where the thermal budget is limited. In this work it is shown for the first time that these layers are an attractive alternative to low-pressure CVD (LPCVD) poly-Si or poly-SiGe because of their high growth rate (100-200 nm/min) and low deposition temperature (520/spl deg/C-590/spl deg/C). The combination of both of these features is impossible to achieve with either LPCVD SiGe (2-30 nm/min growth rate) or LPCVD poly-Si (annealing temperature higher than 900/spl deg/C to achieve structural layer having low tensile stress). Additional advantages are that no nucleation layer is needed (deposition directly on SiO/sub 2/ is possible) and that the as-deposited layers are polycrystalline. No stress or dopant activation anneal of the structural layer is needed since in situ phosphorus doping gives an as-deposited tensile stress down to 20 MPa, and a resistivity of 10 m/spl Omega/-cm to 30 m/spl Omega/-cm. With in situ boron doping, resistivities down to 0.6 m/spl Omega/-cm are possible. The use of these films as an encapsulation layer above an accelerometer is shown
Fatigue in Women with Fibromyalgia: A Gene-Physical Activity Interaction Study
Fatigue is a cardinal symptom in fibromyalgia. Fatigue is assumed to be the result of genetic susceptibility and environmental factors. We aimed at examining the role of genetic susceptibility for fatigue in southern Spanish women with fibromyalgia, by looking at single nucleotide polymorphisms in 34 fibromyalgia candidate-genes, at the interactions between genes, and at the gene-physical activity interactions. We extracted DNA from saliva of 276 fibromyalgia women to analyze gene-polymorphisms. Accelerometers registered physical activity and sedentary behavior. Fatigue was assessed with the Multidimensional Fatigue Inventory. Based on the Bonferroni's and False Discovery Rate values, we found that the genotype of the rs4453709 polymorphism (sodium channel protein type 9 subunit alpha, SCN9A, gene) was related to reduced motivation (AT carriers showed the highest reduced motivation) and reduced activity (AA carriers showed the lowest reduced activity). Carriers of the heterozygous genotype of the rs1801133 (methylene tetrahydrofolate reductase, MTHFR, gene) or rs4597545 (SCN9A gene) polymorphisms who were physically active reported lower scores on fatigue compared to their inactive counterparts. Highly sedentary carriers of the homozygous genotype of the rs7607967 polymorphism (AA/GG genotype; SCN9A gene) presented more reduced activity (a dimension of fatigue) than those with lower levels of sedentary behavior. Collectively, findings from the present study suggest that the contribution of genetics and gene-physical activity interaction to fatigue in fibromyalgia is modest
A novel method for predicting the budget impact of innovative medicines:validation study for oncolytics
Background High budget impact (BI) estimates of new drugs have led to decision-making challenges potentially resulting in restrictions in patient access. However, current BI predictions are rather inaccurate and short term. We therefore developed a new approach for BI prediction. Here, we describe the validation of our BI prediction approach using oncology drugs as a case study. Methods We used Dutch population-level data to estimate BI where BI is defined as list price multiplied by volume. We included drugs in the antineoplastic agents ATC category which the European Medicines Agency (EMA) considered a New Active Substance and received EMA marketing authorization (MA) between 2000 and 2017. A mixed-effects model was used for prediction and included tumor site, orphan, first in class or conditional approval designation as covariates. Data from 2000 to 2012 were the training set. BI was predicted monthly from 0 to 45 months after MA. Cross-validation was performed using a rolling forecasting origin with e|Ln(observed BI/predicted BI)| as outcome. Results The training set and validation set included 25 and 44 products, respectively. Mean error, composed of all validation outcomes, was 2.94 (median 1.57). Errors are higher with less available data and at more future predictions. Highest errors occur without any prior data. From 10 months onward, error remains constant. Conclusions The validation shows that the method can relatively accurately predict BI. For payers or policymakers, this approach can yield a valuable addition to current BI predictions due to its ease of use, independence of indications and ability to update predictions to the most recent data
Trastuzumab duocarmazine in locally advanced and metastatic solid tumours and HER2-expressing breast cancer: a phase 1 dose-escalation and dose-expansion study
Background: Trastuzumab duocarmazine is a novel HER2-targeting antibody-drug conjugate comprised of trastuzumab covalently bound to a linker drug containing duocarmycin. Preclinical studies showed promising antitumour activity in various models. In this first-in-human study, we assessed the safety and activity of trastuzumab duocarmazine in patients with advanced solid tumours. Methods: We did a phase 1 dose-escalation and dose-expansion study. The dose-escalation cohort comprised patients aged 18 years or older enrolled from three academic hospitals in Belgium, the Netherlands, and the UK with locally advanced or metastatic solid tumours with variable HER2 status who were refractory to standard cancer treatment. A separate cohort of patients were enrolled to the dose-expansion phase from 15 hospitals in Belgium, the Netherlands, Spain, and the UK. Dose-expansion cohorts included patients aged 18 years or older with breast, gastric, urothelial, or endometrial cancer with at least HER2 immunohistochemistry 1+ expression and measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST). Trastuzumab duocarmazine was administered intravenously on day 1 of each 3-week cycle. In the dose-escalation phase, trastuzumab duocarmazine was given at doses of 0.3 mg/kg to 2.4 mg/kg (3 + 3 design) until disease progression or unacceptable toxicity. The primary endpoint of the dose-escalation phase was to assess safety and ascertain the recommended phase 2 dose, which would be the dose used in the dose-expansion phase. The primary endpoint of the dose-expansion phase was the proportion of patients achieving an objective response (complete response or partial response), as assessed by the investigator using RECIST version 1.1. This ongoing study is registered with ClinicalTrials.gov, number NCT02277717, and is fully recruited. Findings: Between Oct 30, 2014, and April 2, 2018, 39 patients were enrolled and treated in the dose-escalation phase and 146 patients were enrolled and treated in the dose-expansion phase. One dose-limiting toxic effect (death from pneumonitis) occurred at the highest administered dose (2.4 mg/kg) in the dose-escalation phase. One further death occurred in the dose-escalation phase (1.5 mg/kg cohort) due to disease progression, which was attributed to general physical health decline. Grade 3-4 treatment-related adverse events reported more than once in the dose-escalation phase were keratitis (n=3) and fatigue (n=2). Based on all available data, the recommended phase 2 dose was set at 1.2 mg/kg. In the dose-expansion phase, treatment-related serious adverse events were reported in 16 (11%) of 146 patients, most commonly infusion-related reactions (two [1%]) and dyspnoea (two [1%]). The most common treatment-related adverse events (grades 1-4) were fatigue (48 [33%] of 146 patients), conjunctivitis (45 [31%]), and dry eye (45 [31%]). Most patients (104 [71%] of 146) had at least one ocular adverse event, with grade 3 events reported in ten (7%) of 146 patients. No patients died from treatment-related adverse events and four patients died due to disease progression, which were attributed to hepatic failure (n=1), upper gastrointestinal haemorrhage (n=1), neurological decompensation (n=1), and renal failure (n=1). In the breast cancer dose-expansion cohorts, 16 (33%, 95% CI 20.4-48.4) of 48 assessable patients with HER2-positive breast cancer achieved an objective response (all partial responses) according to RECIST. Nine (28%, 95% CI 13.8-46.8) of 32 patients with HER2-low, hormone receptor-positive breast cancer and six (40%, 16.3-67.6) of 15 patients with HER2-low, hormone receptor-negative breast cancer achieved an objective response (all partial responses). Partial responses were also observed in one (6%, 95% CI 0.2-30.2) of 16 patients with gastric cancer, four (25%, 7.3-52.4) of 16 patients with urothelial cancer, and five (39%, 13.9-68.4) of 13 patients with endometrial cancer. Interpretation: Trastuzumab duocarmazine shows notable clinical activity in heavily pretreated patients with HER2-expressing metastatic cancer, including HER2-positive trastuzumab emtansine-resistant and HER2-low breast cancer, with a manageable safety profile. Further investigation of trastuzumab duocarmazine for HER2-positive breast cancer is ongoing and trials for HER2-low breast cancer and other HER2-expressing cancers are in preparation. Copyright (C) 2019 Elsevier Ltd. All rights reserved
Measurement of the t t-bar production cross section in the dilepton channel in pp collisions at sqrt(s) = 7 TeV
The t t-bar production cross section (sigma[t t-bar]) is measured in
proton-proton collisions at sqrt(s) = 7 TeV in data collected by the CMS
experiment, corresponding to an integrated luminosity of 2.3 inverse
femtobarns. The measurement is performed in events with two leptons (electrons
or muons) in the final state, at least two jets identified as jets originating
from b quarks, and the presence of an imbalance in transverse momentum. The
measured value of sigma[t t-bar] for a top-quark mass of 172.5 GeV is 161.9 +/-
2.5 (stat.) +5.1/-5.0 (syst.) +/- 3.6(lumi.) pb, consistent with the prediction
of the standard model.Comment: Replaced with published version. Included journal reference and DO
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