The yield of long-term electrocardiographic recordings in refractory focal epilepsy

OBJECTIVE: To determine the incidence of clinically relevant arrhythmias in refractory focal epilepsy and to assess the potential of postictal arrhythmias as risk markers for sudden unexpected death in epilepsy (SUDEP). METHODS: We recruited people with refractory focal epilepsy without signs of ictal asystole and who had at least one focal seizure per month and implanted a loop recorder with 2-year follow-up. The devices automatically record arrhythmias. Subjects and caregivers were instructed to make additional peri-ictal recordings. Clinically relevant arrhythmias were defined as asystole ≥ 6 seconds; atrial fibrillation 200 bpm and duration > 30 seconds; persistent sinus bradycardia < 40 bpm while awake; and second- or third-degree atrioventricular block and ventricular tachycardia/fibrillation. We performed 12-lead electrocardiography (ECG) and tilt table testing to identify non-seizure-related causes of asystole. RESULTS: We included 49 people and accumulated 1060 months of monitoring. A total of 16 474 seizures were reported, of which 4679 were captured on ECG. No clinically relevant arrhythmias were identified. Three people had a total of 18 short-lasting (<6 seconds) periods of asystole, resulting in an incidence of 2.91 events per 1000 patient-months. None of these coincided with a reported seizure; one was explained by micturition syncope. Other non-clinically relevant arrhythmias included paroxysmal atrial fibrillation (n = 2), supraventricular tachycardia (n = 1), and sinus tachycardia with a right bundle branch block configuration (n = 1). SIGNIFICANCE: We found no clinically relevant arrhythmias in people with refractory focal epilepsy during long-term follow-up. The absence of postictal arrhythmias does not support the use of loop recorders in people at high SUDEP risk

Syncope diagnosis at referral to a tertiary syncope unit: an in-depth analysis of the fast II

OBJECTIVE: A substantial number of patients with a transient loss of consciousness (T-LOC) are referred to a tertiary syncope unit without a diagnosis. This study investigates the final diagnoses reached in patients who, on referral, were undiagnosed or inaccurately diagnosed in secondary care. METHODS: This study is an in-depth analysis of the recently published Fainting Assessment Study II, a prospective cohort study in a tertiary syncope unit. The diagnosis at the tertiary syncope unit was established after history taking (phase 1), following autonomic function tests (phase 2), and confirming after critical follow-up of 1.5-2 years, with the adjudicated diagnosis (phase 3) by a multidisciplinary committee. Diagnoses suggested by the referring physician were considered the phase 0 diagnosis. We determined the accuracy of the phase 0 diagnosis by comparing this with the phase 3 diagnosis. RESULTS: 51% (134/264) of patients had no diagnosis upon referral (phase 0), the remaining 49% (130/264) carried a diagnosis, but 80% (104/130) considered their condition unexplained. Of the patients undiagnosed at referral, three major causes of T-LOC were revealed: reflex syncope (69%), initial orthostatic hypotension (20%) and psychogenic pseudosyncope (13%) (sum > 100% due to cases with multiple causes). Referral diagnoses were either inaccurate or incomplete in 65% of the patients and were mainly altered at tertiary care assessment to reflex syncope, initial orthostatic hypotension or psychogenic pseudosyncope. A diagnosis of cardiac syncope at referral proved wrong in 17/18 patients. CONCLUSIONS: Syncope patients diagnosed or undiagnosed in primary and secondary care and referred to a syncope unit mostly suffer from reflex syncope, initial orthostatic hypotension or psychogenic pseudosyncope. These causes of T-LOC do not necessarily require ancillary tests, but can be diagnosed by careful history-taking. Besides access to a network of specialized syncope units, simple interventions, such as guideline-based structured evaluation, proper risk-stratification and critical follow-up may reduce diagnostic delay and improve diagnostic accuracy for syncope

Interdependence, interaction, and relationships

Interdependence theory presents a logical analysis of the structure of interpersonal situations, offering a conceptual framework in which interdependence situations can be analyzed in terms of six dimensions. Specific situations present specific problems and opportunities, logically implying the relevance of specific motives and permitting their expression. Via the concept of transformation, the theory explains how interaction is shaped by broader considerations such as long-term goals and concern for a partner's welfare. The theory illuminates our understanding of social-cognitive processes that are of longstanding interest to psychologists such as cognition and affect, attribution, and self-presentation. The theory also explains adaptation to repeatedly encountered interdependence patterns, as well as the embodiment of such adaptations in interpersonal dispositions, relationship-specific motives, and social norms

Evaluating the Quality of Research into a Single Prognostic Biomarker: A Systematic Review and Meta-analysis of 83 Studies of C-Reactive Protein in Stable Coronary Artery Disease

Background Systematic evaluations of the quality of research on a single prognostic biomarker are rare. We sought to evaluate the quality of prognostic research evidence for the association of C-reactive protein (CRP) with fatal and nonfatal events among patients with stable coronary disease. Methods and Findings We searched MEDLINE (1966 to 2009) and EMBASE (1980 to 2009) and selected prospective studies of patients with stable coronary disease, reporting a relative risk for the association of CRP with death and nonfatal cardiovascular events. We included 83 studies, reporting 61,684 patients and 6,485 outcome events. No study reported a prespecified statistical analysis protocol; only two studies reported the time elapsed (in months or years) between initial presentation of symptomatic coronary disease and inclusion in the study. Studies reported a median of seven items (of 17) from the REMARK reporting guidelines, with no evidence of change over time. The pooled relative risk for the top versus bottom third of CRP distribution was 1.97 (95% confidence interval [CI] 1.78–2.17), with substantial heterogeneity (I2 = 79.5). Only 13 studies adjusted for conventional risk factors (age, sex, smoking, obesity, diabetes, and low-density lipoprotein [LDL] cholesterol) and these had a relative risk of 1.65 (95% CI 1.39–1.96), I2 = 33.7. Studies reported ten different ways of comparing CRP values, with weaker relative risks for those based on continuous measures. Adjusting for publication bias (for which there was strong evidence, Egger's p<0.001) using a validated method reduced the relative risk to 1.19 (95% CI 1.13–1.25). Only two studies reported a measure of discrimination (c-statistic). In 20 studies the detection rate for subsequent events could be calculated and was 31% for a 10% false positive rate, and the calculated pooled c-statistic was 0.61 (0.57–0.66). Conclusion Multiple types of reporting bias, and publication bias, make the magnitude of any independent association between CRP and prognosis among patients with stable coronary disease sufficiently uncertain that no clinical practice recommendations can be made. Publication of prespecified statistical analytic protocols and prospective registration of studies, among other measures, might help improve the quality of prognostic biomarker research

Recombination dynamics of a human Y-chromosomal palindrome:rapid GC-biased gene conversion, multi-kilobase conversion tracts, and rare inversions

The male-specific region of the human Y chromosome (MSY) includes eight large inverted repeats (palindromes) in which arm-to-arm similarity exceeds 99.9%, due to gene conversion activity. Here, we studied one of these palindromes, P6, in order to illuminate the dynamics of the gene conversion process. We genotyped ten paralogous sequence variants (PSVs) within the arms of P6 in 378 Y chromosomes whose evolutionary relationships within the SNP-defined Y phylogeny are known. This allowed the identification of 146 historical gene conversion events involving individual PSVs, occurring at a rate of 2.9-8.4×10(-4) events per generation. A consideration of the nature of nucleotide change and the ancestral state of each PSV showed that the conversion process was significantly biased towards the fixation of G or C nucleotides (GC-biased), and also towards the ancestral state. Determination of haplotypes by long-PCR allowed likely co-conversion of PSVs to be identified, and suggested that conversion tract lengths are large, with a mean of 2068 bp, and a maximum in excess of 9 kb. Despite the frequent formation of recombination intermediates implied by the rapid observed gene conversion activity, resolution via crossover is rare: only three inversions within P6 were detected in the sample. An analysis of chimpanzee and gorilla P6 orthologs showed that the ancestral state bias has existed in all three species, and comparison of human and chimpanzee sequences with the gorilla outgroup confirmed that GC bias of the conversion process has apparently been active in both the human and chimpanzee lineages

DNA Methylation of the ABO Promoter Underlies Loss of ABO Allelic Expression in a Significant Proportion of Leukemic Patients

Background: Loss of A, B and H antigens from the red blood cells of patients with myeloid malignancies is a frequent occurrence. Previously, we have reported alterations in ABH antigens on the red blood cells of 55% of patients with myeloid malignancies. Methodology/Principal Findings: To determine the underlying molecular mechanisms of this loss, we assessed ABO allelic expression in 21 patients with ABH antigen loss previously identified by flow cytometric analysis as well as an additional 7 patients detected with ABH antigen changes by serology. When assessing ABO mRNA allelic expression, 6/12 (50%) patients with ABH antigen loss detected by flow cytometry and 5/7 (71%) of the patients with ABH antigen loss detected by serology had a corresponding ABO mRNA allelic loss of expression. We examined the ABO locus for copy number and DNA methylation alterations in 21 patients, 11 with loss of expression of one or both ABO alleles, and 10 patients with no detectable allelic loss of ABO mRNA expression. No loss of heterozygosity (LOH) at the ABO locus was observed in these patients. However in 8/11 (73%) patients with loss of ABO allelic expression, the ABO promoter was methylated compared with 2/10 (20%) of patients with no ABO allelic expression loss (P = 0.03). Conclusions/Significance: We have found that loss of ABH antigens in patients with hematological malignancies is associated with a corresponding loss of ABO allelic expression in a significant proportion of patients. Loss of ABO allelic expression was strongly associated with DNA methylation of the ABO promoter.Tina Bianco-Miotto, Damian J. Hussey, Tanya K. Day, Denise S. O'Keefe and Alexander Dobrovi

Modulation of emotional appraisal by false physiological feedback during fMRI

BACKGROUND James and Lange proposed that emotions are the perception of physiological reactions. Two-level theories of emotion extend this model to suggest that cognitive interpretations of physiological changes shape self-reported emotions. Correspondingly false physiological feedback of evoked or tonic bodily responses can alter emotional attributions. Moreover, anxiety states are proposed to arise from detection of mismatch between actual and anticipated states of physiological arousal. However, the neural underpinnings of these phenomena previously have not been examined. METHODOLOGY/PRINCIPAL FINDINGS We undertook a functional brain imaging (fMRI) experiment to investigate how both primary and second-order levels of physiological (viscerosensory) representation impact on the processing of external emotional cues. 12 participants were scanned while judging face stimuli during both exercise and non-exercise conditions in the context of true and false auditory feedback of tonic heart rate. We observed that the perceived emotional intensity/salience of neutral faces was enhanced by false feedback of increased heart rate. Regional changes in neural activity corresponding to this behavioural interaction were observed within included right anterior insula, bilateral mid insula, and amygdala. In addition, right anterior insula activity was enhanced during by asynchronous relative to synchronous cardiac feedback even with no change in perceived or actual heart rate suggesting this region serves as a comparator to detect physiological mismatches. Finally, BOLD activity within right anterior insula and amygdala predicted the corresponding changes in perceived intensity ratings at both a group and an individual level. CONCLUSIONS/SIGNIFICANCE Our findings identify the neural substrates supporting behavioural effects of false physiological feedback, and highlight mechanisms that underlie subjective anxiety states, including the importance of the right anterior insula in guiding second-order "cognitive" representations of bodily arousal state

Modulation of emotional appraisal by false physiological feedback during fMRI

BACKGROUND James and Lange proposed that emotions are the perception of physiological reactions. Two-level theories of emotion extend this model to suggest that cognitive interpretations of physiological changes shape self-reported emotions. Correspondingly false physiological feedback of evoked or tonic bodily responses can alter emotional attributions. Moreover, anxiety states are proposed to arise from detection of mismatch between actual and anticipated states of physiological arousal. However, the neural underpinnings of these phenomena previously have not been examined. METHODOLOGY/PRINCIPAL FINDINGS We undertook a functional brain imaging (fMRI) experiment to investigate how both primary and second-order levels of physiological (viscerosensory) representation impact on the processing of external emotional cues. 12 participants were scanned while judging face stimuli during both exercise and non-exercise conditions in the context of true and false auditory feedback of tonic heart rate. We observed that the perceived emotional intensity/salience of neutral faces was enhanced by false feedback of increased heart rate. Regional changes in neural activity corresponding to this behavioural interaction were observed within included right anterior insula, bilateral mid insula, and amygdala. In addition, right anterior insula activity was enhanced during by asynchronous relative to synchronous cardiac feedback even with no change in perceived or actual heart rate suggesting this region serves as a comparator to detect physiological mismatches. Finally, BOLD activity within right anterior insula and amygdala predicted the corresponding changes in perceived intensity ratings at both a group and an individual level. CONCLUSIONS/SIGNIFICANCE Our findings identify the neural substrates supporting behavioural effects of false physiological feedback, and highlight mechanisms that underlie subjective anxiety states, including the importance of the right anterior insula in guiding second-order "cognitive" representations of bodily arousal state

Mechanisms underlying fatigue: a voxel-based morphometric study of chronic fatigue syndrome

BACKGROUND: Fatigue is a crucial sensation that triggers rest, yet its underlying neuronal mechanisms remain unclear. Intense long-term fatigue is a symptom of chronic fatigue syndrome, which is used as a model to study the mechanisms underlying fatigue. METHODS: Using magnetic resonance imaging, we conducted voxel-based morphometry of 16 patients and 49 age-matched healthy control subjects. RESULTS: We found that patients with chronic fatigue syndrome had reduced gray-matter volume in the bilateral prefrontal cortex. Within these areas, the volume reduction in the right prefrontal cortex paralleled the severity of the fatigue of the subjects. CONCLUSION: These results are consistent with previous reports of an abnormal distribution of acetyl-L-carnitine uptake, which is one of the biochemical markers of chronic fatigue syndrome, in the prefrontal cortex. Thus, the prefrontal cortex might be an important element of the neural system that regulates sensations of fatigue

The Phosphatomes of the Multicellular Myxobacteria Myxococcus xanthus and Sorangium cellulosum in Comparison with Other Prokaryotic Genomes

BACKGROUND: Analysis of the complete genomes from the multicellular myxobacteria Myxococcus xanthus and Sorangium cellulosum identified the highest number of eukaryotic-like protein kinases (ELKs) compared to all other genomes analyzed. High numbers of protein phosphatases (PPs) could therefore be anticipated, as reversible protein phosphorylation is a major regulation mechanism of fundamental biological processes. METHODOLOGY: Here we report an intensive analysis of the phosphatomes of M. xanthus and S. cellulosum in which we constructed phylogenetic trees to position these sequences relative to PPs from other prokaryotic organisms. PRINCIPAL FINDINGS: PREDOMINANT OBSERVATIONS WERE: (i) M. xanthus and S. cellulosum possess predominantly Ser/Thr PPs; (ii) S. cellulosum encodes the highest number of PP2c-type phosphatases so far reported for a prokaryotic organism; (iii) in contrast to M. xanthus only S. cellulosum encodes high numbers of SpoIIE-like PPs; (iv) there is a significant lack of synteny among M. xanthus and S. cellulosum, and (v) the degree of co-organization between kinase and phosphatase genes is extremely low in these myxobacterial genomes. CONCLUSIONS: We conclude that there has been a greater expansion of ELKs than PPs in multicellular myxobacteria