1,075 research outputs found
Pilot study of the safety and effect of adalimumab on pain, physical function, and musculoskeletal disease in mucopolysaccharidosis types I and II.
Mucopolysaccharidosis I and II are lysosomal storage disorders that, despite treatment with hematopoietic cell transplantation (HCT) and/or enzyme replacement therapy (ERT), continue to cause significant skeletal abnormalities leading to pain, stiffness, physical dysfunction, and short stature. Tumor necrosis factor - alpha (TNF-α) is elevated in individuals with MPS I and II and associated with pain and physical dysfunction. Therefore, we evaluated the safety and effects of the TNF-α inhibitor adalimumab in patients with MPS I and II in a 32-week, randomized, double blind, placebo-controlled, crossover study of adalimumab at a dose of 20 mg (weight 15-<30 kg) or 40 mg (weight ≥ 30 kg) administered subcutaneously every other week or saline placebo for 16 weeks. Participants were evaluated at baseline, week 16, and week 32 with the Children's Health Questionnaire - Parent Form 50 (CHQ-PF50), the Pediatric Pain Questionnaire (PPQ), range-of-motion (ROM) measurements, anthropometry, six-minute walk test (6MWT), hand dynamometer, and laboratory evaluations for safety. The primary outcome was safety and primary efficacy outcome was bodily pain (BP) measured by the CHQ-PF50. Two subjects, one with MPS I and one with MPS II, completed the study. Adalimumab was well tolerated and there were no serious adverse events. Standardized BP scores for age and gender were higher (i.e. less pain) at the end of the treatment versus placebo phase for both subjects. Subject #1 became unblinded during treatment due to skin erythema. Behavior measured by both CHQ-PF50 and parental report improved during treatment compared to placebo in both subjects. ROM improved by > 5° in seven of eight joints in Subject #1 and five of eight joints in Subject #2 (range 7.0° to 52.8°). There was no change in the PPQ, 6MWT, or hand dynamometer. Data from this small pilot study suggest that treatment with adalimumab is safe, tolerable, and may improve ROM, physical function, and possibly pain, in children with MPS I or II. However, additional clinical trials are needed before this therapy should be recommended as part of clinical care
The formation and disintegration of magnetic bright points observed by Sunrise/IMaX
The evolution of the physical parameters of magnetic bright points (MBPs)
located in the quiet Sun (mainly in the interwork) during their lifetime is
studied. First we concentrate on the detailed description of the magnetic field
evolution of three MBPs. This reveals that individual features follow
different, generally complex, and rather dynamic scenarios of evolution. Next
we apply statistical methods on roughly 200 observed MBP evolutionary tracks.
MBPs are found to be formed by the strengthening of an equipartition field
patch, which initially exhibits a moderate downflow. During the evolution,
strong downdrafts with an average velocity of 2.4 km/s set in. These flows,
taken together with the concurrent strengthening of the field, suggest that we
are witnessing the occurrence of convective collapses in these features,
although only 30% of them reach kG field strengths. This fraction might turn
out to be larger when the new 4 m class solar telescopes are operational as
observations of MBPs with current state of the art instrumentation could still
be suffering from resolution limitations. Finally, when the bright point
disappears (although the magnetic field often continues to exist) the magnetic
field strength has dropped to the equipartition level and is generally somewhat
weaker than at the beginning of the MBP's evolution. Noteworthy is that in
about 10% of the cases we observe in the vicinity of the downflows small-scale
strong (exceeding 2 km/s) intergranular upflows related spatially and
temporally to these downflows.Comment: 19 pages, 13 figures; final version published in "The Astrophysical
Journal
Landscape of MS patient cohorts and registries: recommendations for maximizing impact
BACKGROUND: There is a growing number of cohorts and registries collecting phenotypic and genotypic data from groups of multiple sclerosis patients. Improved awareness and better coordination of these efforts is needed.
OBJECTIVE: The purpose of this report is to provide a global landscape of the major longitudinal MS patient data collection efforts and share recommendations for increasing their impact.
METHODS: A workshop that included over 50 MS research and clinical experts from both academia and industry was convened to evaluate how current and future MS cohorts could be better used to provide answers to urgent questions about progressive MS.
RESULTS: The landscape analysis revealed a significant number of largely uncoordinated parallel studies. Strategic oversight and direction is needed to streamline and leverage existing and future efforts. A number of recommendations for enhancing these efforts were developed.
CONCLUSIONS: Better coordination, increased leverage of evolving technology, cohort designs that focus on the most important unanswered questions, improved access, and more sustained funding will be needed to close the gaps in our understanding of progressive MS and accelerate the development of effective therapies
When grassroots innovation movements encounter mainstream institutions: implications for models of inclusive innovation
Grassroots innovation movements (GIMs) can be regarded as initiators or advocates of alternative pathways of innovation. Sometimes these movements engage with more established science, technology and innovation (STI) institutions and development agencies in pursuit of their goals. In this paper, we argue that an important aspect to encounters between GIMs and mainstream STI institutions is the negotiation of different framings of grassroots innovation and development of policy models for inclusive innovation. These encounters can result in two different modes of engagement by GIMs; what we call insertion and mobilization. We illustrate and discuss these interrelated notions of framings and modes of engagement by drawing on three case studies of GIMs: the Social Technologies Network in Brazil, and the Honey Bee Network and People's Science Movements in India. The cases highlight that inclusion in the context of GIMs is not an unproblematic, smooth endeavour, and involves diverse interpretations and framings, which shape what and who gets included or excluded. Within the context of increasing policy interest, the analysis of encounters between GIMs and STI institutions can offer important lessons for the design of models of inclusive innovation and development
Energy landscapes, ideal glasses, and their equation of state
Using the inherent structure formalism originally proposed by Stillinger and
Weber [Phys. Rev. A 25, 978 (1982)], we generalize the thermodynamics of an
energy landscape that has an ideal glass transition and derive the consequences
for its equation of state. In doing so, we identify a separation of
configurational and vibrational contributions to the pressure that corresponds
with simulation studies performed in the inherent structure formalism. We
develop an elementary model of landscapes appropriate to simple liquids which
is based on the scaling properties of the soft-sphere potential complemented
with a mean-field attraction. The resulting equation of state provides an
accurate representation of simulation data for the Lennard-Jones fluid,
suggesting the usefulness of a landscape-based formulation of supercooled
liquid thermodynamics. Finally, we consider the implications of both the
general theory and the model with respect to the so-called Sastry density and
the ideal glass transition. Our analysis shows that a quantitative connection
can be made between properties of the landscape and a simulation-determined
Sastry density, and it emphasizes the distinction between an ideal glass
transition and a Kauzmann equal-entropy condition.Comment: 11 pages, 3 figure
Multiplex giant magnetoresistive biosensor microarrays identify interferon-associated autoantibodies in systemic lupus erythematosus.
High titer, class-switched autoantibodies are a hallmark of systemic lupus erythematosus (SLE). Dysregulation of the interferon (IFN) pathway is observed in individuals with active SLE, although the association of specific autoantibodies with chemokine score, a combined measurement of three IFN-regulated chemokines, is not known. To identify autoantibodies associated with chemokine score, we developed giant magnetoresistive (GMR) biosensor microarrays, which allow the parallel measurement of multiple serum antibodies to autoantigens and peptides. We used the microarrays to analyze serum samples from SLE patients and found individuals with high chemokine scores had significantly greater reactivity to 13 autoantigens than individuals with low chemokine scores. Our findings demonstrate that multiple autoantibodies, including antibodies to U1-70K and modified histone H2B tails, are associated with IFN dysregulation in SLE. Further, they show the microarrays are capable of identifying autoantibodies associated with relevant clinical manifestations of SLE, with potential for use as biomarkers in clinical practice
Anger and aggression in borderline personality disorder and attention deficithyperactivity disorder – does stress matter?
BACKGROUND: The impact of stress on anger and aggression in Borderline Personality Disorder (BPD) and Attention Deficit Hyperactivity Disorder (ADHD) has not been thoroughly investigated. The goal of this study was to investigate different aspects of anger and aggression in patients with these disorders. METHODS: Twenty-nine unmedicated female BPD patients, 28 ADHD patients and 30 healthy controls (HC) completed self-reports measuring trait anger, aggression and emotion regulation capacities. A modified version of the Point Subtraction Aggression Paradigm and a state anger measurement were applied under resting and stress conditions. Stress was induced by the Mannheim Multicomponent Stress Test (MMST). RESULTS: Both patient groups scored significantly higher on all self-report measures compared to HCs. Compared to ADHD patients, BPD patients reported higher trait aggression and hostility, a stronger tendency to express anger when provoked and to direct anger inwardly. Furthermore, BPD patients exhibited higher state anger than HCs and ADHD patients under both conditions and showed a stress-dependent anger increase. At the behavioral level, no significant effects were found. In BPD patients, aggression and anger were positively correlated with emotion regulation deficits. CONCLUSIONS: Our findings suggest a significant impact of stress on self-perceived state anger in BPD patients but not on aggressive behavior towards others in females with BPD or ADHD. However, it appears to be pronounced inwardly directed anger which is of clinical importance in BPD patients. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s40479-017-0057-5) contains supplementary material, which is available to authorized users
INCIDENCE OF SYMPTOMATIC AND ASYMPTOMATIC \u3ci\u3ePLASMODIUM FALCIPARUM\u3c/i\u3e INFECTION FOLLOWING CURATIVE THERAPY IN ADULT RESIDENTS OF NORTHERN GHANA
Adult residents of holoendemic malaria regions in Africa have a naturally acquired immunity (NAI) to malaria that renders them more resistant to new infections, limits parasitemia, and reduces the frequency and severity of illness. Given such attributes, it is not clear how one might evaluate drug or vaccine efficacy in adults without serious confounding. To determine symptomatic and asymptomatic malaria attack rates in adults of northern Ghana, 197 men and women underwent curative therapy for any pre-existing malaria infections at the start of the high transmission (wet) season. They were monitored for first parasitemia and first clinical episode of infection by Plasmodium falciparum over a 20-week period (May–October 1996). The cumulative incidence of primary infection by P. falciparum was 0.98 and incidence density of infection was calculated to be 7.0 cases/person-year. Symptoms were reported by 19.5% of the individuals at the time of first recurrent parasitemia. Incidence of infection, parasite density, and the frequency of symptoms were comparable in males and females. The results suggest that NAI did not provide these adults with significant defense against rapid re-infection and suggest that this population-infection design could serve to demonstrate the efficacy of a drug or vaccine in preventing parasitemia
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Adenosine kinase inhibition selectively promotes rodent and porcine islet β-cell replication
Diabetes is a pathological condition characterized by relative insulin deficiency, persistent hyperglycemia, and, consequently, diffuse micro- and macrovascular disease. One therapeutic strategy is to amplify insulin-secretion capacity by increasing the number of the insulin-producing β cells without triggering a generalized proliferative response. Here, we present the development of a small-molecule screening platform for the identification of molecules that increase β-cell replication. Using this platform, we identify a class of compounds [adenosine kinase inhibitors (ADK-Is)] that promote replication of primary β cells in three species (mouse, rat, and pig). Furthermore, the replication effect of ADK-Is is cell type-selective: treatment of islet cell cultures with ADK-Is increases replication of β cells but not that of α cells, PP cells, or fibroblasts. Short-term in vivo treatment with an ADK-I also increases β-cell replication but not exocrine cell or hepatocyte replication. Therefore, we propose ADK inhibition as a strategy for the treatment of diabetes.Stem Cell and Regenerative Biolog
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