Defining Refractory Migraine: Results of the RHSIS Survey of American Headache Society Members

To gauge consensus regarding a proposed definition for refractory migraine proposed by Refractory Headache Special Interest Section, and where its use would be most appropriate. Background.— Headache experts have long recognized that a subgroup of headache sufferers remains refractory to treatment. Although different groups have proposed criteria to define refractory migraine, the definition remains controversial. The Refractory Headache Special Interest Section of the American Headache Society developed a definition through a consensus process, assisted by a literature review and initial membership survey. Design.— A 12-item questionnaire was distributed at the American Headache Society meeting in 2007 during a platform session and at the Refractory Headache Special Interest Section symposium. The same questionnaire was subsequently sent to all American Headache Society members via e-mail. A total of 151 responses from AHS members form the basis of this report. The survey instrument was designed using Survey Monkey. Frequencies and percentages of the survey were used to describe survey responses. Results.— American Headache Society members agreed that a definition for refractory migraine is needed (91%) that it should be added to the International Classification of Headache Disorders-2 (86%), and that refractory forms of non-migraine headache disorders should be defined (87%). Responders believed a refractory migraine definition would be of greatest value in selecting patients for clinical drug trials. The current refractory migraine definition requires a diagnosis of migraine, interference with function or quality of life despite modification of lifestyle factors, and adequate trials of acute and preventive medicines with established efficacy. The proposed criteria for the refractory migraine definition require failing 2 preventive medications to meet the threshold for failure. Although 42% of respondents agreed with the working definition of refractory migraine, 43% favored increasing the number to 3 (50%) or 4 (26%) preventive treatment failures. When respondents were asked if they felt that the proposed definition was appropriate to select patients for invasive procedures (patent foramen ovale repair or stimulators) only 44% agreed. Conclusions.— There is a consensus for a need for a definition for refractory migraine and that it should be added to the International Classification of Headache Disorder-2. There was also general agreement by the responders that refractory forms of non-migraine headache disorders should be defined.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72860/1/j.1526-4610.2009.01370.x.pd

Prevalence of suspected hypertrophic cardiomyopathy or left ventricular hypertrophy based on race and gender in teenagers using screening echocardiography

BACKGROUND:The goal of this study was to evaluate the prevalence of suspected hypertrophic cardiomyopathy (HCM) in a population of teenagers undergoing screening echocardiography for the detection of HCM.METHOD:The Anthony Bates Foundation performs screening echocardiography for the prevention of sudden death. A total of 2,066 students were studied between the ages of 13 to 19 years. Suspected HCM was defined as any wall thickness greater than or equal to] 15 mm. LVH was defined as wall thickness greater than or equal to] 13 mmRESULTS:Prevalence of suspected HCM was 0.7% (14/2066). After adjusting for hypertension (HTN), the total prevalence was 0.5% (8/1457). In a subgroup analysis, 551 teenagers with documented race and LV wall thickness were identified between the ages of 13 - 19 years. African American teenagers 6% (3/50)] had higher prevalence of suspected HCM 0.8% (4/501), OR 7.93, CI 1.72-36.49, p = 0.002]. After multivariate adjustment for age, gender, BMI and HTN (systolic BP >140 and diastolic BP of > 90), African American race remained independently associated with suspected HCM (OR 4.89, CI 1.24-39.62, p = 0.02).CONCLUSION:The prevalence of suspected HCM in young teenagers is approximately 0.2%. This prevalence appears to be higher in African Americans. However, due to small number of African Americans in our population, our result needs to be confirmed in larger trials.This item is part of the UA Faculty Publications collection. For more information this item or other items in the UA Campus Repository, contact the University of Arizona Libraries at [email protected]

Resting-State Quantitative Electroencephalography Reveals Increased Neurophysiologic Connectivity in Depression

Symptoms of Major Depressive Disorder (MDD) are hypothesized to arise from dysfunction in brain networks linking the limbic system and cortical regions. Alterations in brain functional cortical connectivity in resting-state networks have been detected with functional imaging techniques, but neurophysiologic connectivity measures have not been systematically examined. We used weighted network analysis to examine resting state functional connectivity as measured by quantitative electroencephalographic (qEEG) coherence in 121 unmedicated subjects with MDD and 37 healthy controls. Subjects with MDD had significantly higher overall coherence as compared to controls in the delta (0.5–4 Hz), theta (4–8 Hz), alpha (8–12 Hz), and beta (12–20 Hz) frequency bands. The frontopolar region contained the greatest number of “hub nodes” (surface recording locations) with high connectivity. MDD subjects expressed higher theta and alpha coherence primarily in longer distance connections between frontopolar and temporal or parietooccipital regions, and higher beta coherence primarily in connections within and between electrodes overlying the dorsolateral prefrontal cortical (DLPFC) or temporal regions. Nearest centroid analysis indicated that MDD subjects were best characterized by six alpha band connections primarily involving the prefrontal region. The present findings indicate a loss of selectivity in resting functional connectivity in MDD. The overall greater coherence observed in depressed subjects establishes a new context for the interpretation of previous studies showing differences in frontal alpha power and synchrony between subjects with MDD and normal controls. These results can inform the development of qEEG state and trait biomarkers for MDD

Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018.

Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field

Prediction of second neurological attack in patients with clinically isolated syndrome using support vector machines

The aim of this study is to predict the conversion from clinically isolated syndrome to clinically definite multiple sclerosis using support vector machines. The two groups of converters and non-converters are classified using features that were calculated from baseline data of 73 patients. The data consists of standard magnetic resonance images, binary lesion masks, and clinical and demographic information. 15 features were calculated and all combinations of them were iteratively tested for their predictive capacity using polynomial kernels and radial basis functions with leave-one-out cross-validation. The accuracy of this prediction is up to 86.4% with a sensitivity and specificity in the same range indicating that this is a feasible approach for the prediction of a second clinical attack in patients with clinically isolated syndromes, and that the chosen features are appropriate. The two features gender and location of onset lesions have been used in all feature combinations leading to a high accuracy suggesting that they are highly predictive. However, it is necessary to add supporting features to maximise the accuracy. © 2013 IEEE

Genetic determinants of risk in pulmonary arterial hypertension: international genome-wide association studies and meta-analysis

Background Rare genetic variants cause pulmonary arterial hypertension, but the contribution of common genetic variation to disease risk and natural history is poorly characterised. We tested for genome-wide association for pulmonary arterial hypertension in large international cohorts and assessed the contribution of associated regions to outcomes. Methods We did two separate genome-wide association studies (GWAS) and a meta-analysis of pulmonary arterial hypertension. These GWAS used data from four international case-control studies across 11744 individuals with European ancestry (including 2085 patients). One GWAS used genotypes from 5895 whole-genome sequences and the other GWAS used genotyping array data from an additional 5849 individuals. Cross-validation of loci reaching genome-wide significance was sought by meta-analysis. Conditional analysis corrected for the most significant variants at each locus was used to resolve signals for multiple associations. We functionally annotated associated variants and tested associations with duration of survival. All-cause mortality was the primary endpoint in survival analyses. Findings A locus near SOX17 (rs10103692, odds ratio 1·80 [95% CI 1·55–2·08], p=5·13×10– ¹⁵) and a second locus in HLA-DPA1 and HLA-DPB1 (collectively referred to as HLA-DPA1/DPB1 here; rs2856830, 1·56 [1·42–1·71], p=7·65×10– ²⁰) within the class II MHC region were associated with pulmonary arterial hypertension. The SOX17 locus had two independent signals associated with pulmonary arterial hypertension (rs13266183, 1·36 [1·25–1·48], p=1·69×10– ¹²; and rs10103692). Functional and epigenomic data indicate that the risk variants near SOX17 alter gene regulation via an enhancer active in endothelial cells. Pulmonary arterial hypertension risk variants determined haplotype-specific enhancer activity, and CRISPR-mediated inhibition of the enhancer reduced SOX17 expression. The HLA-DPA1/DPB1 rs2856830 genotype was strongly associated with survival. Median survival from diagnosis in patients with pulmonary arterial hypertension with the C/C homozygous genotype was double (13·50 years [95% CI 12·07 to >13·50]) that of those with the T/T genotype (6·97 years [6·02–8·05]), despite similar baseline disease severity. Interpretation This is the first study to report that common genetic variation at loci in an enhancer near SOX17 and in HLA-DPA1/DPB1 is associated with pulmonary arterial hypertension. Impairment of SOX17 function might be more common in pulmonary arterial hypertension than suggested by rare mutations in SOX17. Further studies are needed to confirm the association between HLA typing or rs2856830 genotyping and survival, and to determine whether HLA typing or rs2856830 genotyping improves risk stratification in clinical practice or trials. Funding UK NIHR, BHF, UK MRC, Dinosaur Trust, NIH/NHLBI, ERS, EMBO, Wellcome Trust, EU, AHA, ACClinPharm, Netherlands CVRI, Dutch Heart Foundation, Dutch Federation of UMC, Netherlands OHRD and RNAS, German DFG, German BMBF, APH Paris, INSERM, Université Paris-Sud, and French ANR

Germline selection shapes human mitochondrial DNA diversity.

Approximately 2.4% of the human mitochondrial DNA (mtDNA) genome exhibits common homoplasmic genetic variation. We analyzed 12,975 whole-genome sequences to show that 45.1% of individuals from 1526 mother-offspring pairs harbor a mixed population of mtDNA (heteroplasmy), but the propensity for maternal transmission differs across the mitochondrial genome. Over one generation, we observed selection both for and against variants in specific genomic regions; known variants were more likely to be transmitted than previously unknown variants. However, new heteroplasmies were more likely to match the nuclear genetic ancestry as opposed to the ancestry of the mitochondrial genome on which the mutations occurred, validating our findings in 40,325 individuals. Thus, human mtDNA at the population level is shaped by selective forces within the female germ line under nuclear genetic control, which ensures consistency between the two independent genetic lineages.NIHR, Wellcome Trust, MRC, Genomics Englan

Defining Refractory Migraine and Refractory Chronic Migraine: Proposed Criteria From the Refractory Headache Special Interest Section of the American Headache Society

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/74368/1/j.1526-4610.2008.01132.x.pd

Intravascular Stem Cell Bioreactor for Prevention of Adverse Remodeling After Myocardial Infarction

Background Prevention of adverse remodeling after myocardial infarction (MI) is an important goal of stem cell therapy. Clinical trial results vary, however, and poor cell retention and survival after delivery likely limit the opportunity to exert beneficial effects. To overcome these limitations, we built an implantable intravascular bioreactor (IBR) designed to protect contained cells from washout, dilution, and immune attack while allowing sustained release of beneficial paracrine factors. Methods and Results IBRs were constructed using semipermeable membrane adhered to a clinical-grade catheter shaft. Mesenchymal stem cell (MSC) viability in and paracrine factor release from IBRs were assessed in vitro and IBR biocompatibility and immune protection confirmed in vivo. In a porcine anterior MI model, IBRs containing 25 million allogeneic MSCs (IBR-MSCs) were compared with IBRs containing media alone (IBR-Placebo; n=8 per group) with adverse remodeling assessed by magnetic resonance imaging. Four weeks after MI, IBR-MSCs had no significant change in end-diastolic volume (+0.33±4.32 mL; P=0.89), end-systolic volume (+2.14±4.13 mL; P=0.21), and left ventricular ejection fraction (-2.27±2.94; P=0.33) while IBR-Placebo had significant increases in end-diastolic volume (+10.37±3.84 mL; P=0.01) and ESV (+11.35±2.88 mL; P=0.01), and a significant decrease in left ventricular ejection fraction (-5.78±1.70; P=0.025). Eight weeks after MI, adherent pericarditis was present in 0 of 8 IBR-MSCs versus 4 of 8 IBR-Placebo (P=0.02), suggesting an anti-inflammatory effect. In a separate study, 25 million allogeneic pig MSCs directly injected in the peri-infarct zone 3 days after MI (n=6) showed no significant benefit in adverse remodeling at 4 weeks compared with IBR-MSCs. Conclusions MSCs deployed inside an implantable, removable, and potentially rechargeable bioreactor in a large animal model remain viable, are immunoprotected, and attenuate adverse remodeling 4 weeks after MI