34 research outputs found
Mechanisms, models and biomarkers in amyotrophic lateral sclerosis
The last 30 years have seen a major advance in the understanding of the clinical and pathological heterogeneity of amyotrophic lateral sclerosis (ALS), and its overlap with frontotemporal dementia. Multiple, seemingly disparate biochemical pathways converge on a common clinical syndrome characterized by progressive loss of upper and lower motor neurons. Pathogenic themes in ALS include excitotoxicity, oxidative stress, mitochondrial dysfunction, neuroinflammation, altered energy metabolism, and most recently RNA mis-processing. The transgenic rodent, overexpressing mutant superoxide dismutase-1, is now only one of several models of ALS pathogenesis. The nematode, fruit fly and zebrafish all offer fresh insight, and the development of induced pluripotent stem cell-derived motor neurons holds promise for the screening of candidate therapeutics. The lack of useful biomarkers in ALS contributes to diagnostic delay, and the inability to stratify patients by prognosis may be an important factor in the failure of therapeutic trials. Biomarkers sensitive to disease activity might lessen reliance on clinical measures and survival as trial endpoints and reduce study length. Emerging proteomic markers of neuronal loss and glial activity in cerebrospinal fluid, a cortical signature derived from advanced structural and functional MRI, and the development of more sensitive measurements of lower motor neuron physiology are leading a new phase of biomarker-driven therapeutic discovery
Spatially heterogeneous ages in glassy dynamics
We construct a framework for the study of fluctuations in the nonequilibrium
relaxation of glassy systems with and without quenched disorder. We study two
types of two-time local correlators with the aim of characterizing the
heterogeneous evolution: in one case we average the local correlators over
histories of the thermal noise, in the other case we simply coarse-grain the
local correlators. We explain why the former describe the fingerprint of
quenched disorder when it exists, while the latter are linked to noise-induced
mesoscopic fluctuations. We predict constraints on the pdfs of the fluctuations
of the coarse-grained quantities. We show that locally defined correlations and
responses are connected by a generalized local out-of-equilibrium
fluctuation-dissipation relation. We argue that large-size heterogeneities in
the age of the system survive in the long-time limit. The invariance of the
theory under reparametrizations of time underlies these results. We relate the
pdfs of local coarse-grained quantities and the theory of dynamic random
manifolds. We define a two-time dependent correlation length from the spatial
decay of the fluctuations in the two-time local functions. We present numerical
tests performed on disordered spin models in finite and infinite dimensions.
Finally, we explain how these ideas can be applied to the analysis of the
dynamics of other glassy systems that can be either spin models without
disorder or atomic and molecular glassy systems.Comment: 47 pages, 60 Fig
Novel Loci for Adiponectin Levels and Their Influence on Type 2 Diabetes and Metabolic Traits : A Multi-Ethnic Meta-Analysis of 45,891 Individuals
J. Kaprio, S. Ripatti ja M.-L. Lokki työryhmien jäseniä.Peer reviewe
Pharmacologic interventions for fatigue in cancer and transplantation: a meta-analysis
Background Our objective was to determine whether, compared with control interventions, pharmacologic interventions reduce the severity of fatigue in patients with cancer or recipients of hematopoietic stem-cell transplantation (HSCT). Methods For a systematic review, we searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, CINAHL, and PSYCHINFO for randomized trials of systemic pharmacologic interventions for the management of fatigue in patients with cancer or recipients of HSCT. Two authors independently identified studies and abstracted data. Methodologic quality was assessed using the Cochrane Risk of Bias tool. The primary outcome was fatigue severity measured using various fatigue scales. Data were synthesized using random-effects models. Results In the 117 included trials (19,819 patients), the pharmacologic agents used were erythropoietins (n = 31), stimulants (n = 19), L-carnitine (n = 6), corticosteroids (n = 5), antidepressants (n = 5), appetite stimulants (n = 3), and other agents (n = 48). Fatigue was significantly reduced with erythropoietin [standardized mean difference (SMD): –0.52; 95% confidence interval (CI): –0.89 to –0.14] and with methylphenidate (SMD: –0.36; 95% CI: –0.56 to –0.15); modafinil (or armodafinil) and corticosteroids were not effective. Conclusions Erythropoietin and methylphenidate significantly reduced fatigue severity in patients with cancer and in recipients of HSCT. Concerns about the safety of those agents might limit their usefulness. Future research should identify effective interventions for fatigue that have minimal adverse effects