Effect of Inhaled Xenon on Cerebral White Matter Damage in Comatose Survivors of Out-of-Hospital Cardiac Arrest: A Randomized Clinical Trial

IMPORTANCE: Evidence from preclinical models indicates that xenon gas can prevent the development of cerebral damage after acute global hypoxic-ischemic brain injury but, thus far, these putative neuroprotective properties have not been reported in human studies. OBJECTIVE: To determine the effect of inhaled xenon on ischemic white matter damage assessed with magnetic resonance imaging (MRI). DESIGN, SETTING, AND PARTICIPANTS: A randomized single-blind phase 2 clinical drug trial conducted between August 2009 and March 2015 at 2 multipurpose intensive care units in Finland. One hundred ten comatose patients (aged 24-76 years) who had experienced out-of-hospital cardiac arrest were randomized. INTERVENTIONS: Patients were randomly assigned to receive either inhaled xenon combined with hypothermia (33°C) for 24 hours (n = 55 in the xenon group) or hypothermia treatment alone (n = 55 in the control group). MAIN OUTCOMES AND MEASURES: The primary end point was cerebral white matter damage as evaluated by fractional anisotropy from diffusion tensor MRI scheduled to be performed between 36 and 52 hours after cardiac arrest. Secondary end points included neurological outcome assessed using the modified Rankin Scale (score 0 [no symptoms] through 6 [death]) and mortality at 6 months. RESULTS: Among the 110 randomized patients (mean age, 61.5 years; 80 men [72.7%]), all completed the study. There were MRI data from 97 patients (88.2%) a median of 53 hours (interquartile range [IQR], 47-64 hours) after cardiac arrest. The mean global fractional anisotropy values were 0.433 (SD, 0.028) in the xenon group and 0.419 (SD, 0.033) in the control group. The age-, sex-, and site-adjusted mean global fractional anisotropy value was 3.8% higher (95% CI, 1.1%-6.4%) in the xenon group (adjusted mean difference, 0.016 [95% CI, 0.005-0.027], P = .006). At 6 months, 75 patients (68.2%) were alive. Secondary end points at 6 months did not reveal statistically significant differences between the groups. In ordinal analysis of the modified Rankin Scale, the median (IQR) value was 1 (1-6) in the xenon group and 1 (0-6) in the control group (median difference, 0 [95% CI, 0-0]; P = .68). The 6-month mortality rate was 27.3% (15/55) in the xenon group and 34.5% (19/55) in the control group (adjusted hazard ratio, 0.49 [95% CI, 0.23-1.01]; P = .053). CONCLUSIONS AND RELEVANCE: Among comatose survivors of out-of-hospital cardiac arrest, inhaled xenon combined with hypothermia compared with hypothermia alone resulted in less white matter damage as measured by fractional anisotropy of diffusion tensor MRI. However, there was no statistically significant difference in neurological outcomes or mortality at 6 months. These preliminary findings require further evaluation in an adequately powered clinical trial designed to assess clinical outcomes associated with inhaled xenon among survivors of out-of-hospital cardiac arrest. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00879892

Degree of explanation

Partial explanations are everywhere. That is, explanations citing causes that explain some but not all of an effect are ubiquitous across science, and these in turn rely on the notion of degree of explanation. I argue that current accounts are seriously deficient. In particular, they do not incorporate adequately the way in which a cause’s explanatory importance varies with choice of explanandum. Using influential recent contrastive theories, I develop quantitative definitions that remedy this lacuna, and relate it to existing measures of degree of causation. Among other things, this reveals the precise role here of chance, as well as bearing on the relation between causal explanation and causation itself

Playing with networks : How economists explain

Peer reviewe

The Explanatory Value of Abstracting Away from Idiosyncratic and Messy Detail

Some explanations are relatively abstract: they abstract away from the idiosyncratic or messy details of the case in hand. The received wisdom in philosophy is that this is a virtue for any explanation to possess. I argue that the apparent consensus on this point is illusory. When philosophers make this claim, they differ on which of four alternative varieties of abstractness they have in mind. What's more, for each variety of abstractness there are several alternative reasons to think that the variety of abstractness in question is a virtue. I identify the most promising reasons, and dismiss some others. The paper concludes by relating this discussion to the idea that explanations in biology, psychology and social science cannot be replaced by relatively micro explanations without loss of understanding.This work has received funding from the European Research Council under the European Union’s Seventh Framework Programme (FP7/2007-2013)/ERC Grant agreement no 284123.This is the author accepted manuscript. The final version is available from Springer via http://dx.doi.org/10.1007/s11098-015-0554-

Comparison of the Alzheimer's disease assessment scale cognitive subscale and the vascular dementia assessment scale in differentiating elderly individuals with different degrees of white matter changes : The Ladis study

Background/Aims: The Alzheimer's Disease Assessment Scale cognitive subscale (ADAS-cog) is a widely used rating instrument. The Vascular Dementia Assessment Scale cognitive subscale (VADAS-cog) includes additional tests reflecting mental speed and executive functions. The objective of this study was to compare the results of the two scales among subjects with various degrees of white matter hyperintensities (WMHs). Methods:In the multicentre, multinational Leukoaraiosis and Disability in the Elderly (LADIS) study, 616 non-disabled subjects between the ages of 65 and 84 were examined using MRI, the ADAS-cog and VADAS-cog. The WMH rating from the MRI divided the patients into groups of mild (n = 280), moderate (n = 187) and severe (n = 149) degrees of change. Results: Covariance analysis controlling for the effect of age and education revealed that the ADAS-cog differentiated only the mild and severe WMH groups, while the differences between all three groups were highly significant with the VADAS-cog. Conclusions:The VADAS-cog significantly differentiated between all the white matter groups. In comparison, the ADAS-cog differentiated only severe changes. Accordingly, the VADAS-cog may be a more sensitive endpoint in studies of patients with white matter load and vascular burden of the brain

The leukoaraiosis is more prevalent in the large artery atherosclerosis stroke subtype among Korean patients with ischemic stroke

<p>Abstract</p> <p>Background</p> <p>Several studies have suggested that the specific stroke subtype may influence the presence of leukoaraiosis in patients with ischemic stroke. We investigated the association between stroke subtype and leukoaraiosis in Korean patients with ischemic stroke by MRI.</p> <p>Methods</p> <p>There were 594 patients included in this study that were classified as large artery disease, lacune and cardioembolic stroke. For large-artery disease, the analysis focused on the intracranial or extracranial location of the stenosis, and the multiplicity of the stenotic lesions. Leukoaraiosis grading was performed according to the Atherosclerosis Risk in Communities Study.</p> <p>Results</p> <p>There was a significant association between leukoaraiosis and the stroke subtypes; the large-artery-disease group had a higher prevalence of leukoaraiosis than did the other groups (55.4% in the large-artery-disease group, 30.3% in the lacunar group and 14.3% in the cardioembolic group, P = 0.016 by chi-square test). On the multivariate linear regression analysis, age, the presence of hypertension, previous stroke and stroke subtype were independently associated with the presence of leukoaraiosis. In the sub analysis of the large-artery-disease group, the leukoaraiosis had a tendency to be more prevalent in the mixed and intracranial stenosis group than did the extracranial stenosis group (45.5% in the mixed group, 40.3% in the intracranial group and 26.9% in the extracranial group, P = 0.08 by chi-square test).</p> <p>Conclusion</p> <p>The association of leukoaraiosis with large-artery disease in this study might be due to the relatively high prevalence of intracranial occlusive lesions in Korean stroke patients compared to other ethnic groups.</p

Histomorphological study of the spinal growth plates from the convex side and the concave side in adolescent idiopathic scoliosis

Asymmetrical growth of the vertebrae has been implicated as one possible etiologic factor in the pathogenesis of adolescent idiopathic scoliosis. The longitudinal vertebral growth derives from the endochondral ossification of the vertebral growth plate. In the present study, the growth plates from the convex and concave side of the vertebrae were characterized by the method of histology and immunohistochemistry to evaluate the growth activity, cell proliferation, and apoptosis. Normal zoned architectures were observed in the convex side of the growth plate and disorganized architectures in the concave side. The histological grades were significantly different between the convex and the concave side of the growth plate in the apex vertebrae (P < 0.05). The histological difference was also found significant statistically between end vertebrae and apex vertebrae in the concave side of vertebral growth plates (P < 0.05). The proliferative potential indexes and apoptosis indexes of chondrocytes in the proliferative and hypertrophic zone in the convex side were significantly higher than that in the concave side in the apex vertebral growth plate (P < 0.05). There was a significant difference of the proliferative potential index (proliferating cell nuclear antigen, PCNA index) between convex side and concave side at the upper end vertebra (P < 0.05). The difference of the proliferative potential index and apoptosis index were found significant statistically in the concave side of the vertebral growth plate between end vertebrae and apex vertebrae (P < 0.05). The same result was also found for the apoptosis index (terminal deoxynucleotidyl transferase mediated deoxyuridine triphosphate biotin nick end labeling assay, TUNEL index) in the convex side of vertebral growth plate between end vertebrae and apex vertebrae (P < 0.05). Some correlation were found between radiographic measurements and proliferation and apoptosis indexes. The difference in histological grades and cellular activity between the convex and concave side indicated that the bilateral growth plate of the vertebrae in AIS patients have different growth kinetics which may affect the curve progression

Abstraction in ecology : reductionism and holism as complementary heuristics

In addition to their core explanatory and predictive assumptions, scientific models include simplifying assumptions, which function as idealizations, approximations, and abstractions. There are methods to investigate whether simplifying assumptions bias the results of models, such as robustness analyses. However, the equally important issue - the focus of this paper - has received less attention, namely, what are the methodological and epistemic strengths and limitations associated with different simplifying assumptions. I concentrate on one type of simplifying assumption, the use of mega parameters as abstractions in ecological models. First, I argue that there are two kinds of mega parameters qua abstractions, sufficient parameters and aggregative parameters, which have gone unnoticed in the literature. The two are associated with different heuristics, holism and reductionism, which many view as incompatible. Second, I will provide a different analysis of abstractions and the associated heuristics than previous authors. Reductionism and holism and the accompanying abstractions have different methodological and epistemic functions, strengths, and limitations, and the heuristics should be viewed as providing complementary research perspectives of cognitively limited beings. This is then, third, used as a premise to argue for epistemic and methodological pluralism in theoretical ecology. Finally, the presented taxonomy of abstractions is used to comment on the current debate whether mechanistic accounts of explanation are compatible with the use of abstractions. This debate has suffered from an abstract discussion of abstractions. With a better taxonomy of abstractions the debate can be resolved.Peer reviewe

Drift as a Force of Evolution: A Manipulationist Account

Can evolutionary theory be properly characterised as a “theory of forces”, like Newtonian mechanics? One common criticism to this claim concerns the possibility to conceive genetic drift as a causal process endowed by a specific magnitude and direction. In this article, we aim to offer an original response to this criticism by pointing out a connection between the notion of force and the notion of explanatory depth, as depicted in Hitchcock and Woodward’s manipulationist account of causal explanation. In a nutshell, our argument is that, since force-explanations can be consistently reframed as deep explanations and vice versa, and the notion of drift can be characterised in manipulationist terms as constitutively intervening in evolutionary deep explanations, then drift-explanations can be consistently reframed as force-explanations, and drift can be properly considered as a force of evolution. Insofar as similar considerations may be extended also to other evolutionary factors – chiefly selection –, our analysis offers an important support to the claim that evolutionary theory is a theory of forces.info:eu-repo/semantics/publishedVersio