Novel Approach Identifies SNPs in SLC2A10 and KCNK9 with Evidence for Parent-of-Origin Effect on Body Mass Index.

The phenotypic effect of some single nucleotide polymorphisms (SNPs) depends on their parental origin. We present a novel approach to detect parent-of-origin effects (POEs) in genome-wide genotype data of unrelated individuals. The method exploits increased phenotypic variance in the heterozygous genotype group relative to the homozygous groups. We applied the method to >56,000 unrelated individuals to search for POEs influencing body mass index (BMI). Six lead SNPs were carried forward for replication in five family-based studies (of ∼4,000 trios). Two SNPs replicated: the paternal rs2471083-C allele (located near the imprinted KCNK9 gene) and the paternal rs3091869-T allele (located near the SLC2A10 gene) increased BMI equally (beta = 0.11 (SD), P<0.0027) compared to the respective maternal alleles. Real-time PCR experiments of lymphoblastoid cell lines from the CEPH families showed that expression of both genes was dependent on parental origin of the SNPs alleles (P<0.01). Our scheme opens new opportunities to exploit GWAS data of unrelated individuals to identify POEs and demonstrates that they play an important role in adult obesity.

Frequency, characterisation and therapies of fatigue after stroke.

Post-stroke objective or subjective fatigue occurs in around 50% of patients and is frequent (30%) even after minor strokes. It can last more than one year after the event, and is characterised by a different quality from usual fatigue and good response to rest. Associated risk factors include age, single patients, female, disability, depression, attentional impairment and sometimes posterior strokes, but also inactivity, overweight, alcohol and sleep apnoea syndrome. There are few therapy studies, but treatment may include low-intensity training, cognitive therapy, treatment of associated depression, wakefulness-promoting agents like modafinil, correction of risk factors and adaptation of activities.

Does altering inclination alter effectiveness of treadmill training for gait impairment after stroke? A randomized controlled trial.

Objective: To assess whether a downhill walking training programme is more effective than the same amount of training applied uphill in chronic stroke survivors. Design: Randomized, single-blind study. Setting: Outpatient rehabilitation service. Methods: Thirty-eight adults with hemiplegia from stroke lasting more than three months were randomly allocated to one of the two groups: 'UP' - 45 minutes of physical therapy + 30 minutes of treadmill with 5% ascending slope; and 'DOWN' - 45 minutes of physical therapy + 30 minutes of treadmill with 5% descending slope. Both groups were treated 5 times a week for six weeks. Patients were evaluated before treatment, at the end of treatment and after three months. Outcome measures: Primary outcome measure was the number of patients showing an improvement in 6-minute walking test (6MWT) greater than 50 m. Secondary outcome measures were: (1) number of patients showing a clinically relevant improvement of gait speed during 10-m walking test (10mWT); (2) number of patients showing an improvement in timed up and go (TUG) greater than minimal detectable change. Results: Both groups had a significant improvement after treatment and at follow-up. At the end of treatment, compared to UP group, more patients in the DOWN group showed clinically significant improvements in primary and secondary outcomes (16/19 patients for 6MWT, 11/19 patients for 10mWT and 9/19 patients for TUG compared with 3/19, 4/19 and 2/19 patients, respectively, P < 0.01). At follow-up, results were similar except for 10mWT. Conclusions: In chronic stroke patients, downhill treadmill training produces a bigger effect than uphill training.

Prevalence of low fat-free mass index and high and very high body fat mass index following lung transplantation.

The aim of this study was to determine the prevalence of low fat-free mass index (FFMI) and high and very high body fat mass index (BFMI) after lung transplantation (LTR). A total of 37 LTR patients were assessed prior to and at 1 month, 1 year and 2 years for FFM and compared to 37 matched volunteers (VOL). FFM was calculated by the Geneva equation and normalized for height (kg/m(2)). Subjects were classified as FFMI "low", <or=17.4 in men and <or=15.0 in women; BFMI "high", 5.2-8.1 in men and 8.3-11.7 in women; or "very high" >8.2 kg/m(2) in men and >11.8 kg/m(2) in women. In 23 M/14 F, body mass index (BMI) was 22.3+/-4.4 and 20.1+/-4.9 kg/m(2), respectively. The prevalence of low FFMI was 80% at 1 month and 33% at 2 years after LTR. Prevalence of very high BFMI increased and was higher in patients than VOL after LTR. The prevalence of low FFMI was high prior to and remained important 2 years after LTR, whereas BFMI was lower prior to and higher 2 years after LTR.

Acute multivessel revascularization improves 1-year outcome in ST-elevation myocardial infarction: a nationwide study cohort from the AMIS Plus registry.

BACKGROUND: The optimal strategy for percutaneous coronary intervention (PCI) of ST-segment elevation myocardial infarction (STEMI) in multi-vessel disease (MVD), i.e., multi-vessel PCI (MV-PCI) vs. PCI of the infarct-related artery only (IRA-PCI), still remains unknown. METHODS: Patients of the AMIS Plus registry admitted with an acute coronary syndrome were contacted after a median of 378 days (interquartile range 371-409). The primary end-point was all-cause death. The secondary end-point included all major adverse cardiovascular and cerebrovascular events (MACCE) including death, re-infarction, re-hospitalization for cardiac causes, any cardiac re-intervention, and stroke. RESULTS: Between 2005 and 2012, 8330 STEMI patients were identified, of whom 1909 (24%) had MVD. Of these, 442 (23%) received MV-PCI and 1467 (77%) IRA-PCI. While all-cause mortality was similar in both groups (2.7% both, p>0.99), MACCE was significantly lower after MV-PCI vs. IRA-PCI (15.6% vs. 20.0%, p=0.038), mainly driven by lower rates of cardiac re-hospitalization and cardiac re-intervention. Patients undergoing MV-PCI with drug-eluting stents had lower rates of all-cause mortality (2.1% vs. 7.4%, p=0.026) and MACCE (14.1% vs. 25.9%, p=0.042) compared with those receiving bare metal stents (BMS). In multivariate analysis, MV-PCI (odds ratio, OR 0.69, 95% CI 0.51-0.93, p=0.017) and comorbidities (Charlson index ≥ 2; OR 1.42, 95% CI 1.05-1.92, p=0.025) were independent predictors for 1-year MACCE. CONCLUSION: In an unselected nationwide real-world cohort, an approach using immediate complete revascularization may be beneficial in STEMI patients with MVD regarding MACCE, specifically when drug-eluting stents are used, but not regarding mortality. This has to be tested in a randomized controlled trial.

Early mobilization out of bed after ischaemic stroke reduces severe complications but not cerebral blood flow: a randomized controlled pilot trial.

OBJECTIVE: To evaluate whether early mobilization after acute ischaemic stroke is better than delayed mobilization with regard to medical complications and if it is safe in relation to neurological function and cerebral blood flow. DESIGN: Randomized controlled pilot trial of early versus delayed mobilization out of bed with incidence of severe complications as the primary outcome. SETTING: Acute stroke unit in the neurology department of a University Hospital. PARTICIPANTS: Fifty patients after ischaemic stroke with a National Institutes of Health Stroke Scale (NIHSS) score >6 were recruited. INTERVENTION: All patients were treated with physiotherapy immediately after their admission. In the early protocol patients were mobilized out of bed after 52 hours, in the delayed protocol after seven days. RESULTS: Eight out of 50 randomized patients were excluded from the per-protocol analysis because of early transfer to other hospitals. There were 2 (8%) severe complications in the 25 early mobilization patients and 8 (47%) in the 17 delayed mobilization patients (P < 0.006). There were no differences in the total number of complications or in clinical outcome. In the 26 patients (62%) who underwent serial transcranial Doppler ultrasonography, no blood flow differences were found. CONCLUSION: We found an apparent reduction in severe complications and no increase in total complications with an early mobilization protocol after acute ischaemic stroke. No influence on neurological three-month outcomes or on cerebral blood flow was seen. These results justify larger trials comparing mobilization protocols with possibly even faster mobilization out of bed than explored here.

Expression of MYC, IgM, As Well As Non-Germinal Centre B-Cell Like Immunophenotype and Positive Immunofish Index Predict a Worse Progression Free Survival and Overall Survival in a Series of 670 De Novo Diffuse Large B-Cell Lymphomas Included in Clinical Trials: A GELA Study of the 2003 Program

Introduction: Diffuse large B-cell lymphomas (DLBCL) represent a heterogeneous disease with variable clinical outcome. Identifying phenotypic biomarkers of tumor cells on paraffin sections that predict different clinical outcome remain an important goal that may also help to better understand the biology of this lymphoma. Differentiating non-germinal centre B-cell-like (non-GCB) from Germinal Centre B-cell-like (GCB) DLBCL according to Hans algorithm has been considered as an important immunohistochemical biomarker with prognostic value among patients treated with R-CHOP although not reproducibly found by all groups. Gene expression studies have also shown that IgM expression might be used as a surrogate for the GCB and ABC subtypes with a strong preferential expression of IgM in ABC DLBCL subtype. ImmunoFISH index based on the differential expression of MUM-1, FOXP1 by immunohistochemistry and on the BCL6 rearrangement by FISH has been previously reported (C Copie-Bergman, J Clin Oncol. 2009;27:5573-9) as prognostic in an homogeneous series of DLBCL treated with R-CHOP. In addition, oncogenic MYC protein overexpression by immunohistochemistry may represent an easy tool to identify the consequences of MYC deregulation in DLBCL. Our aim was to analyse by immunohistochemistry the prognostic relevance of MYC, IgM, GCB/nonGCB subtype and ImmunoFISH index in a large series of de novo DLBCL treated with Rituximab (R)-chemotherapy (anthracyclin based) included in the 2003 program of the Groupe d'Etude des Lymphomes de l'Adulte (GELA) trials. Methods: The 2003 program included patients with de novo CD20+ DLBCL enrolled in 6 different LNH-03 GELA trials (LNH-03-1B, -B, -3B, 39B, -6B, 7B) stratifying patients according to age and age-adjusted IPI. Tumor samples were analyzed by immunohistochemistry using CD10, BCL6, MUM1, FOXP1 (according to Barrans threshold), MYC, IgM antibodies on tissue microarrays and by FISH using BCL6 split signal DNA probes. Considering evaluable Hans score, 670 patients were included in the study with 237 (35.4%) receiving intensive R-ACVBP regimen and 433 (64.6%) R-CHOP/R-mini-CHOP. Results: 304 (45.4%) DLBCL were classified as GCB and 366 (54.6%) as non-GCB according to Hans algorithm. 337/567 cases (59.4%) were positive for the ImmunoFISH index (i.e. two out of the three markers positive: MUM1 protein positive, FOXP1 protein Variable or Strong, BCL6 rearrangement). Immunofish index was preferentially positive in the non-GCB subtype (81.3%) compared to the GCB subtype (31.2%), (p<0.001). IgM was recorded as positive in tumor cells in 351/637 (52.4%) DLBCL cases with a preferential expression in non-GCB 195 (53.3%) vs GCB subtype 100(32.9%), p<0.001). MYC was positive in 170/577 (29.5%) cases with a 40% cut-off and in 44/577 (14.2%) cases with a cut-off of 70%. There was no preferential expression of MYC among GCB or non-GCB subtype (p>0.4) for both cut-offs. Progression-free Survival (PFS) was significantly worse among patients with high IPI score (p<0.0001), IgM positive tumor (p<0.0001), MYC positive tumor with a 40% threshold (p<0.001), ImmunoFISH positive index (p<0.002), non-GCB DLBCL subtype (p<0.0001). Overall Survival (OS) was also significantly worse among patients with high IPI score (p<0.0001), IgM positive tumor (p=0.02), MYC positive tumor with a 40% threshold (p<0.01), ImmunoFISH positive index (p=0.02), non-GCB DLBCL subtype (p<0.0001). All significant parameters were included in a multivariate analysis using Cox Model and in addition to IPI, only the GCB/non-GCB subtype according to Hans algorithm predicted significantly a worse PFS among non-GCB subgroup (HR 1.9 [1.3-2.8] p=0.002) as well as a worse OS (HR 2.0 [1.3-3.2], p=0.003). This strong prognostic value of non-GCB subtyping was confirmed considering only patients treated with R- CHOP for PFS (HR 2.1 [1.4-3.3], p=0.001) and for OS (HR 2.3 [1.3-3.8], p=0.002). Conclusion: Our study on a large series of patients included in trials confirmed the relevance of immunohistochemistry as a useful tool to identify significant prognostic biomarkers for clinical use. We show here that IgM and MYC might be useful prognostic biomarkers. In addition, we confirmed in this series the prognostic value of the ImmunoFISH index. Above all, we fully validated the strong and independent prognostic value of the Hans algorithm, daily used by the pathologists to subtype DLBCL.

Safety of thrombolysis in stroke mimics: results from a multicenter cohort study.

BACKGROUND AND PURPOSE: Intravenous thrombolysis for acute ischemic stroke is beneficial within 4.5 hours of symptom onset, but the effect rapidly decreases over time, necessitating quick diagnostic in-hospital work-up. Initial time strain occasionally results in treatment of patients with an alternate diagnosis (stroke mimics). We investigated whether intravenous thrombolysis is safe in these patients. METHODS: In this multicenter observational cohort study containing 5581 consecutive patients treated with intravenous thrombolysis, we determined the frequency and the clinical characteristics of stroke mimics. For safety, we compared the symptomatic intracranial hemorrhage (European Cooperative Acute Stroke Study II [ECASS-II] definition) rate of stroke mimics with ischemic strokes. RESULTS: One hundred stroke mimics were identified, resulting in a frequency of 1.8% (95% confidence interval, 1.5-2.2). Patients with a stroke mimic were younger, more often female, and had fewer risk factors except smoking and previous stroke or transient ischemic attack. The symptomatic intracranial hemorrhage rate in stroke mimics was 1.0% (95% confidence interval, 0.0-5.0) compared with 7.9% (95% confidence interval, 7.2-8.7) in ischemic strokes. CONCLUSIONS: In experienced stroke centers, among patients treated with intravenous thrombolysis, only a few had a final diagnosis other than stroke. The complication rate in these stroke mimics was low.

The neuroanatomical model of post-stroke depression: towards a change of focus?

One third of all stroke survivors develop post-stroke depression (PSD). Depressive symptoms adversely affect rehabilitation and significantly increase risk of death in the post-stroke period. One of the theoretical views on the determinants of PSD focuses on psychosocial factors like disability and social support. Others emphasize biologic mechanisms such as disruption of biogenic amine neurotransmission and release of proinflammatory cytokines. The "lesion location" perspective attempts to establish a relationship between localization of stroke and occurrence of depression, but empirical results remain contradictory. These divergences are partly related to the fact that neuroimaging methods, unlike neuropathology, are not able to assess precisely the full extent of stroke-affected areas and do not specify the different types of vascular lesions. We provide here an overview of the known phenomenological profile and current pathogenic hypotheses of PSD and present neuropathological data challenging the classic "single-stroke"-based neuroanatomical model of PSD. We suggest that vascular burden due to the chronic accumulation of small macrovascular and microvascular lesions may be a crucial determinant of the development and evolution of PSD.

Safety and functional outcome of thrombolysis in dissection-related ischemic stroke: a meta-analysis of individual patient data.

Background and Purpose-The safety and efficacy of thrombolysis in cervical artery dissection (CAD) are controversial. The aim of this meta-analysis was to pool all individual patient data and provide a valid estimate of safety and outcome of thrombolysis in CAD.Methods-We performed a systematic literature search on intravenous and intra-arterial thrombolysis in CAD. We calculated the rates of pooled symptomatic intracranial hemorrhage and mortality and indirectly compared them with matched controls from the Safe Implementation of Thrombolysis in Stroke-International Stroke Thrombolysis Register. We applied multivariate regression models to identify predictors of excellent (modified Rankin Scale=0 to 1) and favorable (modified Rankin Scale=0 to 2) outcome.Results-We obtained individual patient data of 180 patients from 14 retrospective series and 22 case reports. Patients were predominantly female (68%), with a mean +/- SD age of 46 +/- 11 years. Most patients presented with severe stroke (median National Institutes of Health Stroke Scale score=16). Treatment was intravenous thrombolysis in 67% and intra-arterial thrombolysis in 33%. Median follow-up was 3 months. The pooled symptomatic intracranial hemorrhage rate was 3.1% (95% CI, 1.3 to 7.2). Overall mortality was 8.1% (95% CI, 4.9 to 13.2), and 41.0% (95% CI, 31.4 to 51.4) had an excellent outcome. Stroke severity was a strong predictor of outcome. Overlapping confidence intervals of end points indicated no relevant differences with matched controls from the Safe Implementation of Thrombolysis in Stroke-International Stroke Thrombolysis Register.Conclusions-Safety and outcome of thrombolysis in patients with CAD-related stroke appear similar to those for stroke from all causes. Based on our findings, thrombolysis should not be withheld in patients with CAD. (Stroke. 2011;42:2515-2520.)

FTO genotype is associated with phenotypic variability of body mass index.

There is evidence across several species for genetic control of phenotypic variation of complex traits, such that the variance among phenotypes is genotype dependent. Understanding genetic control of variability is important in evolutionary biology, agricultural selection programmes and human medicine, yet for complex traits, no individual genetic variants associated with variance, as opposed to the mean, have been identified. Here we perform a meta-analysis of genome-wide association studies of phenotypic variation using ∼170,000 samples on height and body mass index (BMI) in human populations. We report evidence that the single nucleotide polymorphism (SNP) rs7202116 at the FTO gene locus, which is known to be associated with obesity (as measured by mean BMI for each rs7202116 genotype), is also associated with phenotypic variability. We show that the results are not due to scale effects or other artefacts, and find no other experiment-wise significant evidence for effects on variability, either at loci other than FTO for BMI or at any locus for height. The difference in variance for BMI among individuals with opposite homozygous genotypes at the FTO locus is approximately 7%, corresponding to a difference of ∼0.5 kilograms in the standard deviation of weight. Our results indicate that genetic variants can be discovered that are associated with variability, and that between-person variability in obesity can partly be explained by the genotype at the FTO locus. The results are consistent with reported FTO by environment interactions for BMI, possibly mediated by DNA methylation. Our BMI results for other SNPs and our height results for all SNPs suggest that most genetic variants, including those that influence mean height or mean BMI, are not associated with phenotypic variance, or that their effects on variability are too small to detect even with samples sizes greater than 100,000.

Vitamin d and stroke: promise for prevention and better outcome.

The role of vitamin D (VitD) has recently been expanded beyond bone homeostasis and regulation of calcium levels. VitD deficiency has been proposed as a new risk factor for cardiovascular disease, including stroke. Low 25(OH)VitD levels are very common among post-stroke patients, probably due to their limited mobility and decreased sunlight exposure along with a higher prevalence of malnutrition, and they have been associated with previous and incident cerebrovascular events. Contributing mechanisms have been linked to the association of VitD deficiency with the presence of hypertension, diabetes mellitus and atherosclerosis. Moreover, there is experimental evidence demonstrating that VitD exerts neuroprotective effects, such as stimulation of neurotrophic factors, quenching of oxidative hyperactivity and regulation of neuronal death, as well as antithrombotic properties. It is plausible that VitD supplementation could be a beneficial intervention for the prevention and/or treatment of cerebrovascular disease possibly by decreasing the aforementioned cerebrovascular risk factors and simultaneously by improving neurologic and cognitive functions, thereby reducing falls and fractures in post-stroke patients. However, study results are still conflicting and data from large, randomized clinical trials are needed to clarify these speculations.

Characteristics and early and long-term outcome in patients with acute ischemic stroke and low ejection fraction.

OBJECTIVES: We assessed the clinical characteristics of patients with acute ischemic stroke (AIS) with left ventricular ejection fraction (EF) ≤ 35% and investigated the association of low EF with early and long-term outcome. METHODS: A total of 2439 patients of the Acute Stroke Registry and Analysis of Lausanne (ASTRAL) were selected. Demographics, risk factors, pre-stroke treatment, and clinical, radiological and metabolic variables in patients with and without low EF were compared. Functional independence (modified Rankin Score ≤ 2) and mortality were recorded 1 week up to 12 months from admission. RESULTS: Low EF patients (n=119) were more commonly men, older, had higher rates of coronary artery disease and atrial fibrillation (AF), and more frequent pretreatment with anticoagulants, antiplatelets and antihypertensive agents. On admission, they presented with higher stroke severity and had lower values of systolic blood pressure, higher heart rate, and worse estimated glomerular filtration rate. Stroke-related disability and death rates were higher in low EF patients during follow-up (19.5% vs. 7.8% at 1 week, and 36.1% vs. 16.5% at 12 months). Increasing age, stroke severity, and AF were independent predictors of one-year mortality in these patients while prior use of statins had a favorable effect on early mortality. CONCLUSIONS: AIS in patients with low EF is associated with older age, cardiac comorbidities, and more severe clinical presentation. Low EF can identify a subset of AIS patients at high risk of early and long-term functional disability and mortality.

Development of a pediatric eosinophilic esophagitis activity index (ped-EEsAI): International experts propose dysphagia, whitish exudates on endoscopy , and intraepithelial eosinophili count as major items related to EoE activity

Background and Aims: The international EEsAI study group aims to develop, validate and evaluate the first pediatric EoE activity index (ped-EEsAI). We report on results of phase 1, which aims to generate candidate items. Methods: This study involves 3 phases: (1) item generation, (2) index derivation and testing on a first patient cohort, and (3) validation in a second cohort. In phase 1, item generation, weighting and reduction are achieved through a Delphi process with an international EoE expert group. The experts proposed and ranked candidate items on a 7-point Likert scale (0 = no, 6 = perfect relationship with EoE activity). Results: 23 international EoE experts proposed and ranked 39 items (20 clinical, 6 endoscopic, 8 histologic, 5 laboratory items). Rank order for clinical items: dysphagia related to food consistencies (median 5, range 2-6), severity of dysphagia (5, 3-6), frequency of dysphagia episodes (5, 3-6), regurgitation and vomiting (4, 2-5), response to dietary restrictions (4, 1-6); endoscopic items: whitish exudates (5, 3-6), furrowing (4, 3-6), corrugated rings (4, 2-6), linear shearing (4, 2-6), strictures (3, 2-6); histologic items: intraepithelial eosinophil count (5, 4-6), lamina propria fibrosis (3, 2-6), basal layer enlargement (3, 1-5); laboratory items: % blood eosinophils (3, 0-5). Conclusions: These items will now be reduced in further Delphi rounds, tested on a cohort of 100 pediatric EoE patients and validated in a second independent cohort, resulting in a robust, broadly accepted disease activity index for use in clinical trials and daily care.