Voxelwise assessment of the regional distribution of damage in the brains of patients with multiple sclerosis and fatigue

BACKGROUND AND PURPOSE: Fatigue affects up to 90% of patients with MS. We assessed the regional distribution of lesions and atrophy of the normal-appearing WM and GM in patients with RRMS with fatigue compared with HC and patients with similar characteristics, but without fatigue. MATERIALS AND METHODS: From 14 patients with RRMS without fatigue, 10 with RRMS with fatigue, and 14 HC, we acquired brain dual-echo and high-resolution T1-weighted scans. Voxel-wise distributions of GM, WM damage, and T2 lesions were compared between patients with fatigued and nonfatigued MS by using SPM5 software. We report results at P < .05, FWE corrected. RESULTS: T2 lesion distribution and regional WM atrophy did not differ between patients with fatigued and nonfatigued MS. Compared with HC, patients with MS had significant WM atrophy in the posterior part of the corpus callosum and significant GM atrophy of the left superior frontal sulcus, left precentral gyrus, posterior cingulate cortex, right thalamus, and left middle frontal gyrus. No additional areas of atrophy were found in patients with nonfatigued MS compared with HC, whereas patients with fatigued MS also had atrophy of the left central sulcus. Atrophy in the left central sulcus and the precentral gyrus was more severe in patients with fatigued versus nonfatigued MS. In patients with MS, significant correlations were found between fatigue severity and GM atrophy in the left precentral gyrus (r = −0.73, P < .0001 uncorrected). CONCLUSIONS: Atrophy of the primary sensorimotor area is likely to contribute to MS-related fatigue

Cognitive Functions and White Matter Tract Damage in Amyotrophic Lateral Sclerosis: A Diffusion Tensor Tractography Study

BACKGROUND AND PURPOSE: ALS is predominantly a disease of the motor system, but cognitive and behavioral symptoms also are observed. DT MR imaging is sensitive to microstructural changes occurring in WM tracts of patients with ALS. In this study, we investigated the association between cognitive functions and extramotor WM tract abnormalities in ALS patients. MATERIALS AND METHODS: DT MR imaging was obtained from 16 nondemented patients with ALS and 15 healthy controls. Patients with ALS underwent a neuropsychologic and behavioral evaluation. DT tractography was used to asses the integrity of the CST, corpus callosum, and the major long-range association tracts. The relationship between DT MR imaging metrics and cognitive functions was tested by using linear model analyses, adjusting for age and clinical disability. RESULTS: Eleven patients (69%) scored below the fifth percentile in at least 1 cognitive test, and 2 of them had a mild executive impairment. Performances at tests assessing attention and executive functions correlated with DT MR imaging metrics of the corpus callosum, CST, and long association WM tracts bilaterally, including the cingulum, inferior longitudinal, inferior fronto-occipital, and uncinate fasciculi. Verbal learning and memory test scores were associated with fornix DT MR imaging values, whereas visual-spatial abilities correlated with left uncinate fractional anisotropy. CONCLUSIONS: WM tract degeneration is associated with neuropsychologic deficits in patients with ALS. DT tractography holds promise to gain insight into the role of the brain WM network abnormalities in the development of cognitive impairment in patients with ALS

Functional MR Imaging Correlates of Neuropsychological Impairment in Primary-Progressive Multiple Sclerosis

BACKGROUND AND PURPOSE: Cognitive deficits affect ≤30% of patients with PPMS. We investigated the functional correlates of cognitive network dysfunction in patients with PPMS and their correlation with the extent of structural MR imaging damage. MATERIALS AND METHODS: From 16 right-handed patients with PPMS and 17 matched controls, structural and fMRIs (during the performance of the 2-back task) were acquired. Neuropsychological tests exploring memory, attention, and frontal lobe cognitive domains were administered. T2 LL, NBV, and CC areas were measured. RESULTS: Six patients with PPMS were CI. Structural MR imaging measures did not differ between patients who were CI and those who were CP. Compared with patients who were CI, patients who were CP had increased activations of the left caudate nucleus, PFC, and inferior parietal lobule. Compared with controls and patients who were CP, patients who were CI had increased activations of the SII, cerebellum, and insula. Compared with controls, they also had increased activations of the right precentral gyrus and a reduced recruitment of the left PFC. In patients with PPMS, a decreased composite cognitive score correlated with increased activity of the cerebellum, insula, and SII, as well as decreased PFC activity. T2 LL correlated with decreased PFC recruitment and increased SII recruitment. CONCLUSIONS: In PPMS, an increased recruitment of cognitive-related networks might represent a functional reserve with the potential to limit the severity of cognitive impairment. The accumulation of T2 lesions and the consequent exhaustion of frontal lobe plasticity might contribute to cognitive impairment in PPMS

Management of oxygen saturation monitoring in preterm newborns in the NICU: the Italian picture

Background: Although many studies emphasize the importance of using oxygen saturation (SpO2) targets in the NICUs, there is a wide variability in used saturation ranges among centers. Primary aim was to draw a representative picture on how the management of oxygen monitoring is performed in the Italian NICUs. Second aim was to identify healthcare-professionals related factors associated with oxygen targeting in the preterm population. Methods: Cross-sectional study with data collection via an electronic survey form. A questionnaire containing pre-piloted and open questions on monitoring and management of the SpO2 was administered to neonatologists across the network of the Italian Society of Neonatology. The questions focused on: the infrastructure, specific training, healthcare professionals and patients-related factors. The results of the survey were anonymously collected, summarized and analyzed. Results: Out of 378 questionnaires, 93 were correctly filled. Thirty-six different SpO2 ranges were observed. Centers using written standard operating procedures on oxygen management and SpO2 monitoring maintained a correct average range of SpO2 90–95%, avoided hyperoxia and reconsidered saturation targets in relation to comorbidities. 39.8% of responders disabled alarms during neonatal care. One center used biomarkers for complete monitoring of neonatal oxygenation status. Conclusions: There is considerable variation in SpO2 targets for preterm infants in the Italian NICUs. Standard operating procedures and specific training for health care personnel are the main factors playing a role for the correct maintenance of the recommended oxygen targets in preterms

Extracellular sphingosine-1-phosphate : a novel actor in human glioblastoma stem cell survival

Glioblastomas are the most frequent and aggressive intracranial neoplasms in humans, and despite advances and the introduction of the alkylating agent temozolomide in therapy have improved patient survival, resistance mechanisms limit benefits. Recent studies support that glioblastoma stem-like cells (GSCs), a cell subpopulation within the tumour, are involved in the aberrant expansion and therapy resistance properties of glioblastomas, through still unclear mechanisms. Emerging evidence suggests that sphingosine-1-phosphate (S1P) a potent onco-promoter able to act as extracellular signal, favours malignant and chemoresistance properties in GSCs. Notwithstanding, the origin of S1P in the GSC environment remains unknown. We investigated S1P metabolism, release, and role in cell survival properties of GSCs isolated from either U87-MG cell line or a primary culture of human glioblastoma. We show that both GSC models, grown as neurospheres and expressing GSC markers, are resistant to temozolomide, despite not expressing the DNA repair protein MGMT, a major contributor to temozolomide-resistance. Pulse experiments with labelled sphingosine revealed that both GSC types are able to rapidly phosphorylate the long-chain base, and that the newly produced S1P is efficiently degraded. Of relevance, we found that S1P was present in GSC extracellular medium, its level being significantly higher than in U87-MG cells, and that the extracellular/intracellular ratio of S1P was about ten-fold higher in GSCs. The activity of sphingosine kinases was undetectable in GSC media, suggesting that mechanisms of S1P transport to the extracellular environment are constitutive in GSCs. In addition we found that an inhibitor of S1P biosynthesis made GSCs sensitive to temozolomide (TMZ), and that exogenous S1P reverted this effect, thus involving extracellular S1P as a GSC survival signal in TMZ resistance. Altogether our data implicate for the first time GSCs as a pivotal source of extracellular S1P, which might act as an autocrine/paracrine signal contributing to their malignant properties

RNA Structural Dynamics As Captured by Molecular Simulations: A Comprehensive Overview

With both catalytic and genetic functions, ribonucleic acid (RNA) is perhaps the most pluripotent chemical species in molecular biology, and its functions are intimately linked to its structure and dynamics. Computer simulations, and in particular atomistic molecular dynamics (MD), allow structural dynamics of biomolecular systems to be investigated with unprecedented temporal and spatial resolution. We here provide a comprehensive overview of the fast-developing field of MD simulations of RNA molecules. We begin with an in-depth, evaluatory coverage of the most fundamental methodological challenges that set the basis for the future development of the field, in particular, the current developments and inherent physical limitations of the atomistic force fields and the recent advances in a broad spectrum of enhanced sampling methods. We also survey the closely related field of coarse-grained modeling of RNA systems. After dealing with the methodological aspects, we provide an exhaustive overview of the available RNA simulation literature, ranging from studies of the smallest RNA oligonucleotides to investigations of the entire ribosome. Our review encompasses tetranucleotides, tetraloops, a number of small RNA motifs, A-helix RNA, kissing-loop complexes, the TAR RNA element, the decoding center and other important regions of the ribosome, as well as assorted others systems. Extended sections are devoted to RNA-ion interactions, ribozymes, riboswitches, and protein/RNA complexes. Our overview is written for as broad of an audience as possible, aiming to provide a much-needed interdisciplinary bridge between computation and experiment, together with a perspective on the future of the field

Cause of Death and Predictors of All-Cause Mortality in Anticoagulated Patients With Nonvalvular Atrial Fibrillation : Data From ROCKET AF

M. Kaste on työryhmän ROCKET AF Steering Comm jäsen.Background-Atrial fibrillation is associated with higher mortality. Identification of causes of death and contemporary risk factors for all-cause mortality may guide interventions. Methods and Results-In the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) study, patients with nonvalvular atrial fibrillation were randomized to rivaroxaban or dose-adjusted warfarin. Cox proportional hazards regression with backward elimination identified factors at randomization that were independently associated with all-cause mortality in the 14 171 participants in the intention-to-treat population. The median age was 73 years, and the mean CHADS(2) score was 3.5. Over 1.9 years of median follow-up, 1214 (8.6%) patients died. Kaplan-Meier mortality rates were 4.2% at 1 year and 8.9% at 2 years. The majority of classified deaths (1081) were cardiovascular (72%), whereas only 6% were nonhemorrhagic stroke or systemic embolism. No significant difference in all-cause mortality was observed between the rivaroxaban and warfarin arms (P=0.15). Heart failure (hazard ratio 1.51, 95% CI 1.33-1.70, P= 75 years (hazard ratio 1.69, 95% CI 1.51-1.90, P Conclusions-In a large population of patients anticoagulated for nonvalvular atrial fibrillation, approximate to 7 in 10 deaths were cardiovascular, whereasPeer reviewe

Baseline characteristics of patients in the reduction of events with darbepoetin alfa in heart failure trial (RED-HF)

&lt;p&gt;Aims: This report describes the baseline characteristics of patients in the Reduction of Events with Darbepoetin alfa in Heart Failure trial (RED-HF) which is testing the hypothesis that anaemia correction with darbepoetin alfa will reduce the composite endpoint of death from any cause or hospital admission for worsening heart failure, and improve other outcomes.&lt;/p&gt; &lt;p&gt;Methods and results: Key demographic, clinical, and laboratory findings, along with baseline treatment, are reported and compared with those of patients in other recent clinical trials in heart failure. Compared with other recent trials, RED-HF enrolled more elderly [mean age 70 (SD 11.4) years], female (41%), and black (9%) patients. RED-HF patients more often had diabetes (46%) and renal impairment (72% had an estimated glomerular filtration rate &#60;60 mL/min/1.73 m2). Patients in RED-HF had heart failure of longer duration [5.3 (5.4) years], worse NYHA class (35% II, 63% III, and 2% IV), and more signs of congestion. Mean EF was 30% (6.8%). RED-HF patients were well treated at randomization, and pharmacological therapy at baseline was broadly similar to that of other recent trials, taking account of study-specific inclusion/exclusion criteria. Median (interquartile range) haemoglobin at baseline was 112 (106–117) g/L.&lt;/p&gt; &lt;p&gt;Conclusion: The anaemic patients enrolled in RED-HF were older, moderately to markedly symptomatic, and had extensive co-morbidity.&lt;/p&gt

Clinical correlates of grey matter pathology in multiple sclerosis

Traditionally, multiple sclerosis has been viewed as a disease predominantly affecting white matter. However, this view has lately been subject to numerous changes, as new evidence of anatomical and histological changes as well as of molecular targets within the grey matter has arisen. This advance was driven mainly by novel imaging techniques, however, these have not yet been implemented in routine clinical practice. The changes in the grey matter are related to physical and cognitive disability seen in individuals with multiple sclerosis. Furthermore, damage to several grey matter structures can be associated with impairment of specific functions. Therefore, we conclude that grey matter damage - global and regional - has the potential to become a marker of disease activity, complementary to the currently used magnetic resonance markers (global brain atrophy and T2 hyperintense lesions). Furthermore, it may improve the prediction of the future disease course and response to therapy in individual patients and may also become a reliable additional surrogate marker of treatment effect

RNA motif search with data-driven element ordering

BACKGROUND: In this paper, we study the problem of RNA motif search in long genomic sequences. This approach uses a combination of sequence and structure constraints to uncover new distant homologs of known functional RNAs. The problem is NP-hard and is traditionally solved by backtracking algorithms. RESULTS: We have designed a new algorithm for RNA motif search and implemented a new motif search tool RNArobo. The tool enhances the RNAbob descriptor language, allowing insertions in helices, which enables better characterization of ribozymes and aptamers. A typical RNA motif consists of multiple elements and the running time of the algorithm is highly dependent on their ordering. By approaching the element ordering problem in a principled way, we demonstrate more than 100-fold speedup of the search for complex motifs compared to previously published tools. CONCLUSIONS: We have developed a new method for RNA motif search that allows for a significant speedup of the search of complex motifs that include pseudoknots. Such speed improvements are crucial at a time when the rate of DNA sequencing outpaces growth in computing. RNArobo is available at http://compbio.fmph.uniba.sk/rnarobo. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12859-016-1074-x) contains supplementary material, which is available to authorized users