247 research outputs found
Validation of a score tool for measurement of histological severity in juvenile dermatomyositis and association with clinical severity of disease.
OBJECTIVES: To study muscle biopsy tissue from patients with juvenile dermatomyositis (JDM) in order to test the reliability of a score tool designed to quantify the severity of histological abnormalities when applied to biceps humeri in addition to quadriceps femoris. Additionally, to evaluate whether elements of the tool correlate with clinical measures of disease severity. METHODS: 55 patients with JDM with muscle biopsy tissue and clinical data available were included. Biopsy samples (33 quadriceps, 22 biceps) were prepared and stained using standardised protocols. A Latin square design was used by the International Juvenile Dermatomyositis Biopsy Consensus Group to score cases using our previously published score tool. Reliability was assessed by intraclass correlation coefficient (ICC) and scorer agreement (α) by assessing variation in scorers' ratings. Scores from the most reliable tool items correlated with clinical measures of disease activity at the time of biopsy. RESULTS: Inter- and intraobserver agreement was good or high for many tool items, including overall assessment of severity using a Visual Analogue Scale. The tool functioned equally well on biceps and quadriceps samples. A modified tool using the most reliable score items showed good correlation with measures of disease activity. CONCLUSIONS: The JDM biopsy score tool has high inter- and intraobserver agreement and can be used on both biceps and quadriceps muscle tissue. Importantly, the modified tool correlates well with clinical measures of disease activity. We propose that standardised assessment of muscle biopsy tissue should be considered in diagnostic investigation and clinical trials in JDM
What do you do for a living? Toward a more succinct definition of health services research
This commentary discusses the need for, and the advantages of, a more concise, revised definition of the field of health services research. It argues for a definition that includes not only the topics on which health services research focuses but also the goals of health services research. A number of condensed definitions are provided for consideration
Are mice good models for human neuromuscular disease? Comparing muscle excursions in walking between mice and humans
The mouse is one of the most widely used animal models to study neuromuscular diseases and test new therapeutic strategies. However, findings from successful pre-clinical studies using mouse models frequently fail to translate to humans due to various factors. Differences in muscle function between the two species could be crucial but often have been overlooked. The purpose of this study was to evaluate and compare muscle excursions in walking between mice and humans
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Age differences in brain activity during emotion processing: reflections of age-Related decline or increased emotion regulation?
Despite the fact that physical health and cognitive abilities decline with aging, the ability to regulate emotion remains stable and in some aspects improves across the adult life span. Older adults also show a positivity effect in their attention and memory, with diminished processing of negative stimuli relative to positive stimuli compared with younger adults. The current paper reviews functional magnetic resonance imaging studies investigating age-related differences in emotional processing and discusses how this evidence relates to two opposing theoretical accounts of older adultsâ positivity effect. The aging-brain model [Cacioppo et al. in: Social Neuroscience: Toward Understanding the Underpinnings of the Social Mind. New York, Oxford University Press, 2011] proposes that older adultsâ positivity effect is a consequence of age-related decline in the amygdala, whereas the cognitive control hypothesis [Kryla-Lighthall and Mather in: Handbook of Theories of Aging, ed 2. New York, Springer, 2009; Mather and Carstensen: Trends Cogn Sci 2005;9:496â502; Mather and Knight: Psychol Aging 2005;20:554â570] argues that the positivity effect is a result of older adultsâ greater focus on regulating emotion. Based on evidence for structural and functional preservation of the amygdala in older adults and findings that older adults show greater prefrontal cortex activity than younger adults while engaging in emotion-processing tasks, we argue that the cognitive control hypothesis is a more likely explanation for older adultsâ positivity effect than the aging-brain model
Periodic Emission from the Gamma-ray Binary 1FGL J1018.6-5856
Gamma-ray binaries are stellar systems containing a neutron star or black
hole with gamma-ray emission produced by an interaction between the components.
These systems are rare, even though binary evolution models predict dozens in
our Galaxy. A search for gamma-ray binaries with the Fermi Large Area Telescope
(LAT) shows that 1FGL J1018.6-5856 exhibits intensity and spectral modulation
with a 16.6 day period. We identified a variable X-ray counterpart, which shows
a sharp maximum coinciding with maximum gamma-ray emission, as well as an
O6V((f)) star optical counterpart and a radio counterpart that is also
apparently modulated on the orbital period. 1FGL J1018.6-5856 is thus a
gamma-ray binary, and its detection suggests the presence of other fainter
binaries in the Galaxy.Comment: Contact authors: R.H.D. Corbet, M. Kerr, C.C. Cheun
Degradation of GSPT1 causes TP53-independent cell death in leukemia whilst sparing normal hematopoietic stem cells
Targeted protein degradation is a rapidly advancing and expanding therapeutic approach. Drugs that degrade GSPT1 via the CRL4CRBN ubiquitin ligase are a new class of cancer therapy in active clinical development with evidence of activity against acute myeloid leukemia in early phase trials. However, other than activation of the integrated stress response, the downstream effects of GSPT1 degradation leading to cell death are largely undefined, and no murine models are available to study these agents. We identified the domains of GSPT1 essential for cell survival and show that GSPT1 degradation leads to impaired translation termination, activation of the integrated stress response pathway, and TP53-independent cell death. CRISPR-Cas9 screens implicated decreased translation initiation as protective to GSPT1 degradation, suggesting that cells with higher levels of translation are more susceptible to GSPT1 degradation. We defined two Crbn amino acids that prevent Gspt1 degradation in mice, generated a knock-in mouse with alteration of these residues, and demonstrated the efficacy of GSPT1-degrading drugs in vivo with relative sparing of numbers and function of long-term hematopoietic stem cells. Our results provide a mechanistic basis for the use of GSPT1 degraders for the treatment of cancer, including TP53-mutant AML
Subliminal versus supraliminal stimuli activate neural responses in anterior cingulate cortex, fusiform gyrus and insula:a meta-analysis of fMRI studies
Background: Non-conscious neural activation may underlie various psychological functions in health and disorder. However, the neural substrates of non-conscious processing have not been entirely elucidated. Examining the differential effects of arousing stimuli that are consciously, versus unconsciously perceived will improve our knowledge of neural circuitry involved in non-conscious perception. Here we conduct preliminary analyses of neural activation in studies that have used both subliminal and supraliminal presentation of the same stimulus. Methods: We use Activation Likelihood Estimation (ALE) to examine functional Magnetic Resonance Imaging (fMRI) studies that uniquely present the same stimuli subliminally and supraliminally to healthy participants during functional magnetic resonance imaging (fMRI). We included a total of 193 foci from 9 studies representing subliminal stimulation and 315 foci from 10 studies representing supraliminal stimulation. Results: The anterior cingulate cortex is significantly activated during both subliminal and supraliminal stimulus presentation. Subliminal stimuli are linked to significantly increased activation in the right fusiform gyrus and right insula. Supraliminal stimuli show significantly increased activation in the left rostral anterior cingulate. Conclusions: Non-conscious processing of arousing stimuli may involve primary visual areas and may also recruit the insula, a brain area involved in eventual interoceptive awareness. The anterior cingulate is perhaps a key brain region for the integration of conscious and non-conscious processing. These preliminary data provide candidate brain regions for further study in to the neural correlates of conscious experience
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