ASTRAL Score Predicts 5-Year Dependence and Mortality in Acute Ischemic Stroke.

BACKGROUND AND PURPOSE: The ASTRAL score was externally validated showing remarkable consistency on 3-month outcome prognosis in patients with acute ischemic stroke. The present study aimed to evaluate ASTRAL score's prognostic accuracy to predict 5-year outcome. METHODS: All consecutive patients with acute ischemic stroke registered in the Athens Stroke Registry between January 1, 1998, and December 31, 2010, were included. Patients were excluded if admitted >24 hours after symptom onset or if any ASTRAL score component was missing. End points were 5-year unfavorable functional outcome, defined as modified Rankin Scale 3 to 6, and 5-year mortality. For each outcome, the area under the receiver operating characteristics curve was calculated; also, a multivariate Cox proportional hazards analysis was performed to investigate whether the ASTRAL score was an independent predictor of outcome. The Kaplan-Meier product limit method was used to estimate the probability of 5-year survival for each ASTRAL score quartile. RESULTS: The area under the receiver operating characteristics curve of the score to predict 5-year unfavorable functional outcome was 0.89, 95% confidence interval 0.88 to 0.91. In multivariate Cox proportional hazards analysis, the ASTRAL score was independently associated with 5-year unfavorable functional outcome (hazard ratio, 1.09; 95% confidence interval, 1.08-1.10). The area under the receiver operating characteristics curve for the ASTRAL score's discriminatory power to predict 5-year mortality was 0.81 (95% confidence interval, 0.78-0.83). In multivariate analysis, the ASTRAL score was independently associated with 5-year mortality (hazard ratio, 1.09, 95% confidence interval, 1.08-1.10). During the 5-year follow-up, the probability of survival was significantly lower with increasing ASTRAL score quartiles (log-rank test <0.001). CONCLUSIONS: The ASTRAL score reliably predicts 5-year functional outcome and mortality in patients with acute ischemic stroke.

Molecular role of Cx37 in advanced atherosclerosis: a micro-array study.

Recently, we showed that connexin37 (Cx37) protects against early atherosclerotic lesion development by regulating monocyte adhesion. The expression of this gap junction protein is altered in mouse and human atherosclerotic lesions; it is increased in macrophages newly recruited to the lesions and disappears from the endothelium of advanced plaques. To obtain more insight into the molecular role of Cx37 in advanced atherosclerosis, we used micro-array analysis for gene expression profiling in aortas of ApoE(-/-) and Cx37(-/-)ApoE(-/-) mice before and after 18 weeks of cholesterol-rich diet. Out of >15,000 genes, 106 genes were significantly differentially expressed in young mice before diet (P-value of <0.05, fold change of >0.7 or <-0.7, and intensity value >2.2 times background). Ingenuity pathway analysis (IPA) revealed differences in genes involved in cell-to-cell signaling and interaction, cellular compromise and nutritional disease. In addition, we identified 100 genes that were significantly perturbed after the cholesterol-rich diet. Similar to the analysis on 10-week-old mice, IPA revealed differences in genes involved in cell-to-cell signaling and interaction as well as to immuno-inflammatory disease. Furthermore, we found important changes in genes involved in vascular calcification and matrix degradation, some of which were confirmed at protein level by (immuno-)histochemistry. In conclusion, we suggest that Cx37 deficiency alters the global differential gene expression profiles in young mice towards a pro-inflammatory phenotype, which are then further influenced in advanced atherosclerosis. The results provide new insights into the significance of Cx37 in plaque calcification.

Autosis is a Na+,K+-ATPase-regulated form of cell death triggered by autophagy-inducing peptides, starvation, and hypoxia-ischemia.

A long-standing controversy is whether autophagy is a bona fide cause of mammalian cell death. We used a cell-penetrating autophagy-inducing peptide, Tat-Beclin 1, derived from the autophagy protein Beclin 1, to investigate whether high levels of autophagy result in cell death by autophagy. Here we show that Tat-Beclin 1 induces dose-dependent death that is blocked by pharmacological or genetic inhibition of autophagy, but not of apoptosis or necroptosis. This death, termed "autosis," has unique morphological features, including increased autophagosomes/autolysosomes and nuclear convolution at early stages, and focal swelling of the perinuclear space at late stages. We also observed autotic death in cells during stress conditions, including in a subpopulation of nutrient-starved cells in vitro and in hippocampal neurons of neonatal rats subjected to cerebral hypoxia-ischemia in vivo. A chemical screen of ~5,000 known bioactive compounds revealed that cardiac glycosides, antagonists of Na(+),K(+)-ATPase, inhibit autotic cell death in vitro and in vivo. Furthermore, genetic knockdown of the Na(+),K(+)-ATPase α1 subunit blocks peptide and starvation-induced autosis in vitro. Thus, we have identified a unique form of autophagy-dependent cell death, a Food and Drug Administration-approved class of compounds that inhibit such death, and a crucial role for Na(+),K(+)-ATPase in its regulation. These findings have implications for understanding how cells die during certain stress conditions and how such cell death might be prevented.

Language lateralization in early and late bilinguals using an international vocabulary

In lateralized Lexical Decision Tasks (LDT), accuracy is commonly higher and reaction times are commonly faster for right visual field (RVF) than left visual field (LVF) presentations. This visual field differences are thought to demonstrate the left hemisphere's dominance for language. Unfortunately, different tasks and words are used between studies and languages making direct comparisons difficult. For example, high frequency words show a performance advantage over low frequency words. Moreover, demographic variables impact on lateralized behavior such as language knowledge (one versus several, early acquired versus late acquired). We here aim to alleviate some of these obstacles by presenting results from a lateralized LDT for which we selected words between 4 and 6 letters used in five different languages, i.e. English, French, German, Dutch and Italian. In this first study using these words, we compared performance of right- and left-handed students being either early or late bilinguals (acquired before or after the age of 6 years) from a French-speaking University in Switzerland. Results showed a left hemispheric advantage (accuracy, reaction times) for all groups, with a trend for early as compared to late bilinguals to be less accurate and taking longer in lexical decisions. These results show that the current words result in solid visual field differences, and do so irrespective of how many languages are spoken. While early bilinguals might experience a slight performance disadvantage, it was not affecting visual field differences.

The value of serum procalcitonin level for differentiation of infectious from noninfectious causes of fever after orthopaedic surgery.

BACKGROUND: Early diagnosis of postoperative orthopaedic infections is important in order to rapidly initiate adequate antimicrobial therapy. There are currently no reliable diagnostic markers to differentiate infectious from noninfectious causes of postoperative fever. We investigated the value of the serum procalcitonin level in febrile patients after orthopaedic surgery. METHODS: We prospectively evaluated 103 consecutive patients with new onset of fever within ten days after orthopaedic surgery. Fever episodes were classified by two independent investigators who were blinded to procalcitonin results as infectious or noninfectious origin. White blood-cell count, C-reactive protein level, and procalcitonin level were assessed on days 0, 1, and 3 of the postoperative fever. RESULTS: Infection was diagnosed in forty-five (44%) of 103 patients and involved the respiratory tract (eighteen patients), urinary tract (eighteen), joints (four), surgical site (two), bloodstream (two), and soft tissues (one). Unlike C-reactive protein levels and white blood-cell counts, procalcitonin values were significantly higher in patients with infection compared with patients without infection on the day of fever onset (p = 0.04), day 1 (p = 0.07), and day 3 (p = 0.003). Receiver-operating characteristics demonstrated that procalcitonin had the highest diagnostic accuracy, with a value of 0.62, 0.62, and 0.71 on days 0, 1, and 3, respectively. In a multivariate logistic regression analysis, procalcitonin was a significant predictor for postoperative infection on days 0, 1, and 3 of fever with an odds ratio of 2.3 (95% confidence interval, 1.1 to 4.4), 2.3 (95% confidence interval, 1.1 to 5.2), and 3.3 (95% confidence interval, 1.2 to 9.0), respectively. CONCLUSIONS: Serum procalcitonin is a helpful diagnostic marker supporting clinical and microbiological findings for more reliable differentiation of infectious from noninfectious causes of fever after orthopaedic surgery.

Dual-wavelength digital holographic microscopy with sub-nanometer axial accuracy

We present dual-wavelength Digital Holographic Microscopy (DHM) measurements on a certified 8.9 nm high Chromium thin step sample and demonstrate sub-nanometer axial accuracy. We introduce a modified DHM Reference Calibrated Hologram (RCH) reconstruction algorithm taking into account amplitude contributions. By combining this with a temporal averaging procedure and a specific dual-wavelength DHM arrangement, it is shown that specimen topography can be measured with an accuracy, defined as the axial standard deviation, reduced to at least 0.9 nm. Indeed, it is reported that averaging each of the two wavefronts recorded with real-time dual-wavelength DHM can provide up to 30% spatial noise reduction for the given configuration, thanks to their non-correlated nature. ©2008 COPYRIGHT SPIE

Automated auditory mismatch negativity paradigm improves coma prognostic accuracy after cardiac arrest and therapeutic hypothermia.

PURPOSE: EEG and somatosensory evoked potential are highly predictive of poor outcome after cardiac arrest; their accuracy for good recovery is however low. We evaluated whether addition of an automated mismatch negativity-based auditory discrimination paradigm (ADP) to EEG and somatosensory evoked potential improves prediction of awakening. METHODS: EEG and ADP were prospectively recorded in 30 adults during therapeutic hypothermia and in normothermia. We studied the progression of auditory discrimination on single-trial multivariate analyses from therapeutic hypothermia to normothermia, and its correlation to outcome at 3 months, assessed with cerebral performance categories. RESULTS: At 3 months, 18 of 30 patients (60%) survived; 5 had severe neurologic impairment (cerebral performance categories = 3) and 13 had good recovery (cerebral performance categories = 1-2). All 10 subjects showing improvements of auditory discrimination from therapeutic hypothermia to normothermia regained consciousness: ADP was 100% predictive for awakening. The addition of ADP significantly improved mortality prediction (area under the curve, 0.77 for standard model including clinical examination, EEG, somatosensory evoked potential, versus 0.86 after adding ADP, P = 0.02). CONCLUSIONS: This automated ADP significantly improves early coma prognostic accuracy after cardiac arrest and therapeutic hypothermia. The progression of auditory discrimination is strongly predictive of favorable recovery and appears complementary to existing prognosticators of poor outcome. Before routine implementation, validation on larger cohorts is warranted.

Mutation identification by direct comparison of whole-genome sequencing data from mutant and wild-type individuals using k-mers.

Genes underlying mutant phenotypes can be isolated by combining marker discovery, genetic mapping and resequencing, but a more straightforward strategy for mapping mutations would be the direct comparison of mutant and wild-type genomes. Applying such an approach, however, is hampered by the need for reference sequences and by mutational loads that confound the unambiguous identification of causal mutations. Here we introduce NIKS (needle in the k-stack), a reference-free algorithm based on comparing k-mers in whole-genome sequencing data for precise discovery of homozygous mutations. We applied NIKS to eight mutants induced in nonreference rice cultivars and to two mutants of the nonmodel species Arabis alpina. In both species, comparing pooled F2 individuals selected for mutant phenotypes revealed small sets of mutations including the causal changes. Moreover, comparing M3 seedlings of two allelic mutants unambiguously identified the causal gene. Thus, for any species amenable to mutagenesis, NIKS enables forward genetics without requiring segregating populations, genetic maps and reference sequences.

Estimation du débit de filtration glomérulaire par la formule DFG = K x T/Pcr [Estimation of glomerular filtration rate by the formula GFR = K x T/Pc].

BACKGROUND: Creatinine clearance is the most common method used to assess glomerular filtration rate (GFR). In children, GFR can also be estimated without urine collection, using the formula GFR (mL/min x 1.73 m2) = K x height [cm]/Pcr [mumol/L]), where Pcr represents the plasma creatinine concentration. K is usually calculated using creatinine clearance (Ccr) as an index of GFR. The aim of the present study was to evaluate the reliability of the formula, using the standard UV/P inulin clearance to calculate K. METHODS: Clearance data obtained in 200 patients (1 month to 23 years) during the years 1988-1994 were used to calculate the factor K as a function of age. Forty-four additional patients were studied prospectively in conditions of either hydropenia or water diuresis in order to evaluate the possible variation of K as a function of urine flow rate. RESULTS: When GFR was estimated by the standard inulin clearance, the calculated values of K was 39 (infants less than 6 months), 44 (1-2 years) and 47 (2-12 years). The correlation between the values of GFR, as estimated by the formula, and the values measured by the standard clearance of inulin was highly significant; the scatter of individual values was however substantial. When K was calculated using Ccr, the formula overestimated Cin at all urine flow rates. When calculated from Ccr, K varied as a function of urine flow rate (K = 50 at urine flow rates of 3.5 and K = 64 at urine flow rates of 8.5 mL/min x 1.73 m2). When calculated from Cin, in the same conditions, K remained constant with a value of 50. CONCLUSIONS: The formula GFR = K x H/Pcr can be used to estimate GFR. The scatter of values precludes however the use of the formula to estimate GFR in pathophysiological studies. The formula should only be used when K is calculated from Cin, and the plasma creatinine concentration is measured in well defined conditions of hydration.

Genes mirror geography within Europe.

Understanding the genetic structure of human populations is of fundamental interest to medical, forensic and anthropological sciences. Advances in high-throughput genotyping technology have markedly improved our understanding of global patterns of human genetic variation and suggest the potential to use large samples to uncover variation among closely spaced populations. Here we characterize genetic variation in a sample of 3,000 European individuals genotyped at over half a million variable DNA sites in the human genome. Despite low average levels of genetic differentiation among Europeans, we find a close correspondence between genetic and geographic distances; indeed, a geographical map of Europe arises naturally as an efficient two-dimensional summary of genetic variation in Europeans. The results emphasize that when mapping the genetic basis of a disease phenotype, spurious associations can arise if genetic structure is not properly accounted for. In addition, the results are relevant to the prospects of genetic ancestry testing; an individual's DNA can be used to infer their geographic origin with surprising accuracy-often to within a few hundred kilometres.

Temporal changes in mRNA expression of the brain nutrient transporters in the lithium-pilocarpine model of epilepsy in the immature and adult rat.

The lithium-pilocarpine model mimics most features of human temporal lobe epilepsy. Following our prior studies of cerebral metabolic changes, here we explored the expression of transporters for glucose (GLUT1 and GLUT3) and monocarboxylates (MCT1 and MCT2) during and after status epilepticus (SE) induced by lithium-pilocarpine in PN10, PN21, and adult rats. In situ hybridization was used to study the expression of transporter mRNAs during the acute phase (1, 4, 12 and 24h of SE), the latent phase, and the early and late chronic phases. During SE, GLUT1 expression was increased throughout the brain between 1 and 12h of SE, more strongly in adult rats; GLUT3 increased only transiently, at 1 and 4h of SE and mainly in PN10 rats; MCT1 was increased at all ages but 5-10-fold more in adult than in immature rats; MCT2 expression increased mainly in adult rats. At all ages, MCT1 and MCT2 up-regulation was limited to the circuit of seizures while GLUT1 and GLUT3 changes were more widespread. During the latent and chronic phases, the expression of nutrient transporters was normal in PN10 rats. In PN21 rats, GLUT1 was up-regulated in all brain regions. In contrast, in adult rats GLUT1 expression was down-regulated in the piriform cortex, hilus and CA1 as a result of extensive neuronal death. The changes in nutrient transporter expression reported here further support previous findings in other experimental models demonstrating rapid transcriptional responses to marked changes in cerebral energetic/glucose demand.

Avoiding crimes of obedience: A comparative study of the autobiographies of M. K. Gandhi, N. Mandela and M. L. King

This research aims to provide a contribution towards understanding how and why certain people can display disobedience behaviors, to overcome unjust situations, and withstand persecutions deployed by authority. The paper presents a hermeneutic content analysis of the autobiographical speeches and texts of Gandhi, M. L. King and Mandela. Our results show that parents' value orientation, experience of injustice during childhood and exploration of alternative viewpoints during adolescence play a crucial role in structuring prosocial disobedience. Findings show also that social responsibility and ingroup communication are important conditions for facing persecutions without dropping original goals.

Forced diuresis improves the diagnostic accuracy of 18F-FDG PET in abdominopelvic malignancies.

Our aim was to evaluate the role of forced diuresis in improving the diagnostic accuracy of abdominopelvic (18)F-FDG PET. METHODS: Thirty-two patients were enrolled. Besides the presence of known intravesical tumors or undefined renal lesions on the initial PET scan, the inclusion criterion was the appearance of indeterminate or equivocal (18)F-FDG foci that extended along the course of the urinary tract and could not confidently be separated from urinary activity. For each patient, a second abdominopelvic PET study was performed after intravenous injection of 0.5 mg of furosemide per kilogram of body weight (maximum, 40 mg) coupled with parenteral infusion of physiologic saline. RESULTS: Forced diuresis coupled with parenteral hydration eliminated any significant (18)F-FDG activity from the lower urinary tract in 31 (97%) of 32 patients after the bladder had been voided 3 successive times. Twelve intravesical lesions were visualized with outstanding clarity, whereas radiologic suspicion of locally recurrent bladder tumors was ruled out in 3 patients. Among 14 indeterminate or equivocal extravesical foci, 7 were deemed of no clinical value because they disappeared after furosemide challenge, whereas 7 persisting foci were proven to be true-positive PET findings. The performance of (18)F-FDG PET in characterizing 3 renal-space-occupying lesions could not be improved by our protocol. CONCLUSION: Furosemide challenge has the potential to noninvasively resolve the inherent (18)F-FDG contrast handicap in the lower urinary tract.