Novel genetic markers associate with atrial fibrillation risk in Europeans and Japanese

OBJECTIVES This study sought to identify nonredundant atrial fibrillation (AF) genetic susceptibility signals and examine their cumulative relations with AF risk. BACKGROUND AF-associated loci span broad genomic regions that may contain multiple susceptibility signals. Whether multiple signals exist at AF loci has not been systematically explored. METHODS We performed association testing conditioned on the most significant, independently associated genetic markers at 9 established AF loci using 2 complementary techniques in 64,683 individuals of European ancestry (3,869 incident and 3,302 prevalent AF cases). Genetic risk scores were created and tested for association with AF in Europeans and an independent sample of 11,309 individuals of Japanese ancestry (7,916 prevalent AF cases). RESULTS We observed at least 4 distinct AF susceptibility signals on chromosome 4q25 upstream of PITX2, but not at the remaining 8 AF loci. A multilocus score comprised 12 genetic markers demonstrated an estimated 5-fold gradient in AF risk. We observed a similar spectrum of risk associated with these markers in Japanese. Regions containing AF signals on chromosome 4q25 displayed a greater degree of evolutionary conservation than the remainder of the locus, suggesting that they may tag regulatory elements. CONCLUSIONS The chromosome 4q25 AF locus is architecturally complex and harbors at least 4 AF susceptibility signals in individuals of European ancestry. Similar polygenic AF susceptibility exists between Europeans and Japanese. Future work is necessary to identify causal variants, determine mechanisms by which associated loci predispose to AF, and explore whether AF susceptibility signals classify individuals at risk for AF and related morbidity.

Characterization of functioning in multiple sclerosis using the ICF

The objective of this study was to explore whether it is possible to describe based on the International Classification of Functioning, Disability and Health (ICF) relevant aspects of functioning and disability affected in multiple sclerosis (MS) as well as environmental factors relevant to persons with MS. The specific aim was to identify most relevant 'Body functions', 'Body structures', 'Activities and participation', as well as 'Environmental factors' in patients with MS using the ICF. Additionally, different MS forms were compared with respect to the identified problems. A multi-centre study was conducted in an empirical cross-sectional design. Data from 205 individuals with MS were collected in rehabilitation centres: disease related data, socio-demographic data, single interviews based on the Extended ICF Checklist and a patient questionnaire including ratings on general health and functioning status, Beck Depression Inventory II (BDI-II) and Comorbidity Questionnaire (SCQ). The 129 ICF categories identified represent a comprehensive classification of functioning in MS from the clinical perspective. Differences between MS forms were observed for several ICF categories, EDSS, general health and functioning status, but not for BDI and SCQ. The study showed that it is possible to describe based on the ICF the spectrum in functioning and disability affected in MS as well as environmental factors relevant to persons with MS.

The Combination of Interferon-Beta and HMG-CoA Reductase Inhibition in Multiple Sclerosis: Enthusiasm Lost too Soon?

Recent studies support the notion that statins, widely prescribed cholesterol-lowering agents, may target key elements in the immunological cascade leading to inflammation and tissue damage in the pathogenesis of multiple sclerosis (MS). Compelling experimental and observational clinical studies highlighted the possibility that statins may also exert immunomodulatory synergy with approved MS drugs, resulting in several randomized clinical trials testing statins in combination with interferon-beta (IFN-?). Some data, however, suggest that this particular combination may not be clinically beneficial, and might actually have a negative effect on the disease course in some patients with MS. In this regard, a small North American trial indicated that atorvastatin administered in combination with IFN-? may increase disease activity in relapsing-remitting MS. Although other trials did not confirm this finding, the enthusiasm for studies with statins dwindled. This review aims to provide a comprehensive overview of the completed clinical trials and reports of the interim analyses evaluating the combination of IFN-? and statins in MS. Moreover, we try to address the evident question whether usage of this combination routinely requires caution, since the number of IFN-?-treated MS patients receiving statins for lowering of cholesterol is expected to grow.

Lymphangiogenesis is upregulated in kidneys of patients with multiple myeloma

Neolymphangiogenesis has recently been demonstrated in transplanted kidneys as well as in chronic interstitial nephritis and IgA nephropathy. However, its significance in kidney disease remains to be defined and a systematic study of renal lymphangiogenesis is warranted. We investigated patients with multiple myeloma (MM) presenting in the great majority with acute renal insufficiency. Controls were allograft kidney donors and patients with renal insufficiency due to acute renal failure (ARF). Lymph vessel length density (LVD) was quantified immunohistochemically by means of antipodoplanin staining followed by computer-assisted stereology. The mean LVD in kidneys of patients with MM (23.19 mm(-2)) was higher when compared with allograft donors (7.42 mm(-2), P = 0.0003) and patients with ARF (6.78 mm(-2), P = 0.0002). The higher LVD was significantly associated with interstitial inflammation, and the newly formed lymph vessels were accompanied by diffuse and nodular interstitial infiltrates composed mainly of CD20(+) B cells and CD27(+) plasma cells. The infiltrates in patients with MM also displayed a higher expression of the B-cell chemoattractant CXCL13. These results demonstrate for the first time that lymphangiogenesis is a prominent feature in MM kidneys and that it is associated with a significant accumulation of macrophages, CD20(+) and CD27(+) B lymphocytes. Further studies should clarify whether these changes represent a beneficial or detrimental factor in the progression of the myeloma-related kidney damage.

Review of Lodox Statscan in the detection of peripheral skeletal fractures in multiple injury patients

As part of the primary survey, polytrauma patients in our emergency department are examined using the new 'Lodox Statscan' (LS) digital low-radiation imaging device. The LS provides full-body anterior and lateral views based on enhanced linear slot-scanning technology, in accordance with the recommended Advanced Trauma Life Support (ATLS) Guidelines. This study's objectives were to establish whether LS appropriately rules out peripheral bone injuries and to examine whether LS imaging provides adequate information for the preoperative planning of such lesions.

Impact of non-steroidal anti-inflammatory drugs (NSAIDs) on cardiovascular outcomes in patients with stable atherothrombosis or multiple risk factors

We aimed to assess whether the use of non-steroidal anti-inflammatory drugs (NSAIDs) is associated with an increased risk of cardiovascular (CV) events in stable patients with established atherothrombosis or multiple risk factors.

Functional Imaging of Pheochromocytoma with Ga-DOTATOC and C-HED in a Genetically Defined Rat Model of Multiple Endocrine Neoplasia

Rats affected by the MENX multitumor syndrome develop pheochromocytoma (100%). Pheochromocytomas are uncommon tumors and animal models are scarce, hence the interest in MENX rats to identify and preclinically evaluate novel targeted therapies. A prerequisite for such studies is a sensitive and noninvasive detection of MENXassociated pheochromocytoma. We performed positron emission tomography (PET) to determine whether rat pheochromocytomas are detected by tracers used in clinical practice, such as 68Ga-DOTATOC (somatostatin analogue) or (11)C-Hydroxyephedrine (HED), a norepinephrine analogue. We analyzed four affected and three unaffected rats. The PET scan findings were correlated to histopathology and immunophenotype of the tumors, their proliferative index, and the expression of genes coding for somatostatin receptors or the norepinephrine transporter. We observed that mean 68Ga-DOTATOC standard uptake value (SUV) in adrenals of affected animals was 23.3 ± 3.9, significantly higher than in control rats (15.4 ± 7.9; P = .03). The increase in mean tumor-to-liver ratio of (11)C-HED in the MENX-affected animals (1.6 ± 0.5) compared to controls (0.7 ± 0.1) was even more significant (P = .0016). In a unique animal model, functional imaging depicting two pathways important in pheochromocytoma biology discriminated affected animals from controls, thus providing the basis for future preclinical work with MENX rats.

Drug hypersensitivity: flare-up reactions, cross-reactivity and multiple drug hypersensitivity

In drug hypersensitivity, change of drug treatment and continuation with a new drug may result in reappearance of drug hypersensitivity symptoms. This is not uncommon in patients with chronic infections requiring continued and long-lasting antibiotic treatments. For the clinician, the question arises whether these symptoms are due to cross-reactivity, are due to a new sensitization or are a reflection of a multiple drug hypersensitivity syndrome. Based on the p-i concept (pharmacological interaction with immune receptors), we propose that the efficient stimulation of T cells by a drug is the sum of drug-T-cell receptor affinity and readiness of the T cell to react, and therefore not constant. It heavily depends on the state of underlying immune activation. Consequently, drug hypersensitivity diseases, which go along with massive immune stimulations and often high serum cytokine values, are themselves risk factors for further drug hypersensitivity. The immune stimulation during drug hypersensitivity may, similar to generalized virus infections, lower the threshold of T-cell reactivity to drugs and cause rapid appearance of drug hypersensitivity symptoms to the second drug. We call the second hypersensitivity reaction a "flare-up" reaction; this is clinically important, as in most cases the second drug may be tolerated again, if the cofactors are missing. Moreover, the second treatment is often too short to cause a relevant sensitization.

Functional properties of multiple isoforms of human divalent metal-ion transporter 1 (DMT1)

DMT1 (divalent metal-ion transporter 1) is a widely expressed metal-ion transporter that is vital for intestinal iron absorption and iron utilization by most cell types throughout the body, including erythroid precursors. Mutations in DMT1 cause severe microcytic anaemia in animal models. Four DMT1 isoforms that differ in their N- and C-termini arise from mRNA transcripts that vary both at their 5'-ends (starting in exon 1A or exon 1B) and at their 3'-ends giving rise to mRNAs containing (+) or lacking (-) the 3'-IRE (iron-responsive element) and resulting in altered C-terminal coding sequences. To determine whether these variations result in functional differences between isoforms, we explored the functional properties of each isoform using the voltage clamp and radiotracer assays in cRNA-injected Xenopus oocytes. 1A/IRE+-DMT1 mediated Fe2+-evoked currents that were saturable (K(0.5)(Fe) approximately 1-2 microM), temperature-dependent (Q10 approximately 2), H+-dependent (K(0.5)(H) approximately 1 muM) and voltage-dependent. 1A/IRE+-DMT1 exhibited the provisional substrate profile (ranked on currents) Cd2+, Co2+, Fe2+, Mn2+>Ni2+, V3+>>Pb2+. Zn2+ also evoked large currents; however, the zinc-evoked current was accounted for by H+ and Cl- conductances and was not associated with significant Zn2+ transport. 1B/IRE+-DMT1 exhibited the same substrate profile, Fe2+ affinity and dependence on the H+ electrochemical gradient. Each isoform mediated 55Fe2+ uptake and Fe2+-evoked currents at low extracellular pH. Whereas iron transport activity varied markedly between the four isoforms, the activity for each correlated with the density of anti-DMT1 immunostaining in the plasma membrane, and the turnover rate of the Fe2+ transport cycle did not differ between isoforms. Therefore all four isoforms of human DMT1 function as metal-ion transporters of equivalent efficiency. Our results reveal that the N- and C-terminal sequence variations among the DMT1 isoforms do not alter DMT1 functional properties. We therefore propose that these variations serve as tissue-specific signals or cues to direct DMT1 to the appropriate subcellular compartments (e.g. in erythroid cells) or the plasma membrane (e.g. in intestine).

The IKK inhibitor BMS-345541 affects multiple mitotic cell cycle transitions

The IkappaB kinase (IKK) complex controls processes such as inflammation, immune responses, cell survival and the proliferation of both normal and tumor cells. By activating NFkappaB, the IKK complex contributes to G1/S transition and first evidence has been presented that IKKalpha also regulates entry into mitosis. At what stage IKK is required and whether IKK also contributes to progression through mitosis and cytokinesis, however, has not yet been determined. In this study, we use BMS-345541, a potent allosteric small molecule inhibitor of IKK, to inhibit IKK specifically during G2 and during mitosis. We show that BMS-345541 affects several mitotic cell cycle transitions, including mitotic entry, prometaphase to anaphase progression and cytokinesis. Adding BMS-345541 to the cells released from arrest in S-phase blocked the activation of Aurora A, B and C, Cdk1 activation and histone H3 phosphorylation. Additionally, treatment of the mitotic cells with BMS-345541 resulted in precocious cyclin B1 and securin degradation, defective chromosome separation and improper cytokinesis. BMS-345541 was also found to override the spindle checkpoint in nocodazole-arrested cells. In vitro kinase assays using BMS-345541 indicate that these effects are not primarily due to a direct inhibitory effect of BMS-345541 on mitotic kinases such as Cdk1, Aurora A or B, Plk1 or NEK2. This study points towards a new potential role of IKK in cell cycle progression. Since deregulation of the cell cycle is one of the hallmarks of tumor formation and progression, the newly discovered level of BMS-345541 function could be useful for cell cycle control studies and may provide valuable clues for the design of future therapeutics.

Anti-myelin antibodies in clinically isolated syndrome indicate the risk of multiple sclerosis in a Swiss cohort

OBJECTIVES: In patients with a clinically isolated syndrome (CIS), the time interval to convert to clinically definite multiple sclerosis (CDMS) is highly variable. Individual and geographical prognostic factors remain to be determined. Whether anti-myelin antibodies may predict the risk of conversion to CDMS in Swiss CIS patients of the canton Berne was the subject of the study. METHODS: Anti-myelin oligodendrocyte glycoprotein and anti-myelin basic protein antibodies were determined prospectively in patients admitted to our department. RESULTS: After a mean follow-up of 12 months, none of nine antibody-negative, but 22 of 30 antibody-positive patients had progressed to CDMS. Beta-Interferon treatment delayed the time to conversion from a mean of 7.4 to 10.9 months. CONCLUSIONS: In a Swiss cohort, antibody-negative CIS patients have a favorable short-term prognosis, and antibody-positive patients benefit from early treatment.

The feeling of fluent perception: A single experience from multiple asynchronous sources

Zeki and co-workers recently proposed that perception can best be described as locally distributed, asynchronous processes that each create a kind of microconsciousness, which condense into an experienced percept. The present article is aimed at extending this theory to metacognitive feelings. We present evidence that perceptual fluency-the subjective feeling of ease during perceptual processing-is based on speed of processing at different stages of the perceptual process. Specifically, detection of briefly presented stimuli was influenced by figure-ground contrast, but not by symmetry (Experiment 1) or the font (Experiment 2) of the stimuli. Conversely, discrimination of these stimuli was influenced by whether they were symmetric (Experiment 1) and by the font they were presented in (Experiment 2), but not by figure-ground contrast. Both tasks however were related with the subjective experience of fluency (Experiments 1 and 2). We conclude that subjective fluency is the conscious phenomenal correlate of different processing stages in visual perception.

The moderating role of personal mastery on the relationship between caregiving status and multiple dimensions of fatigue

OBJECTIVE: A substantial proportion of chronically-stressed spousal dementia caregivers report fatigue. The objective of this study was to examine whether personal mastery moderates the relationship between caregiving status (caregiver/non-caregiver) and multiple dimensions of fatigue. METHODS: Seventy-three elderly Alzheimer's caregivers and 41 elderly non-caregivers completed the Multidimensional Fatigue Symptom Inventory-Short Form (MFSI-SF) and questionnaires assessing mastery. RESULTS: Regression analyses indicated that global fatigue was significantly higher for caregivers (M = 38.0 +/- 21.0) compared to non-caregivers (M = 18.2 +/- 10.4). However, personal mastery moderated the relation between caregiving status and global fatigue (t = -2.03, df = 107, p = 0.045), such that for those with low mastery, caregivers' fatigue scores were 18.1 points higher than non-caregivers, and for those with high mastery, this difference was only 7.5 points. For specific dimensions of fatigue, mastery moderated the relations between caregiving status and both emotional (t = -2.01, df = 107, p = 0.047) and physical (t = -2.51, df = 107, p = 0.014) fatigue. Specifically, association between caregiving status and emotional fatigue was greater when mastery was low than when mastery was high. Caregiving status was significantly associated with physical fatigue when mastery was low, but not when mastery was high. Significant main effects were found between mastery and general fatigue and vigor. CONCLUSION: Given the proportion of fatigued caregivers and the impact fatigue has on health; these findings provide important information regarding mastery's relationship with fatigue and may inform interventions aiming to alleviate fatigue in caregivers. Copyright (c) 2009 John Wiley ; Sons, Ltd.

A comparison of the strength of biodiversity effects across multiple functions

In order to predict which ecosystem functions are most at risk from biodiversity loss, meta-analyses have generalised results from biodiversity experiments over different sites and ecosystem types. In contrast, comparing the strength of biodiversity effects across a large number of ecosystem processes measured in a single experiment permits more direct comparisons. Here, we present an analysis of 418 separate measures of 38 ecosystem processes. Overall, 45 % of processes were significantly affected by plant species richness, suggesting that, while diversity affects a large number of processes not all respond to biodiversity. We therefore compared the strength of plant diversity effects between different categories of ecosystem processes, grouping processes according to the year of measurement, their biogeochemical cycle, trophic level and compartment (above- or belowground) and according to whether they were measures of biodiversity or other ecosystem processes, biotic or abiotic and static or dynamic. Overall, and for several individual processes, we found that biodiversity effects became stronger over time. Measures of the carbon cycle were also affected more strongly by plant species richness than were the measures associated with the nitrogen cycle. Further, we found greater plant species richness effects on measures of biodiversity than on other processes. The differential effects of plant diversity on the various types of ecosystem processes indicate that future research and political effort should shift from a general debate about whether biodiversity loss impairs ecosystem functions to focussing on the specific functions of interest and ways to preserve them individually or in combination.

The Assessment of Multiple Processes Underlying the Attentional Blink: A Fixed - links Modeling Approach based on Behavioral and Electrophysiological Data

When observers are presented with two visual targets appearing in the same position in close temporal proximity, a marked reduction in detection performance of the second target has often been reported, the so-called attentional blink phenomenon. Several studies found a similar decrement of P300 amplitudes during the attentional blink period as observed with detection performances of the second target. However, whether the parallel courses of second target performances and corresponding P300 amplitudes resulted from the same underlying mechanisms remained unclear. The aim of our study was therefore to investigate whether the mechanisms underlying the AB can be assessed by fixed-links modeling and whether this kind of assessment would reveal the same or at least related processes in the behavioral and electrophysiological data. On both levels of observation three highly similar processes could be identified: an increasing, a decreasing and a u-shaped trend. Corresponding processes from the behavioral and electrophysiological data were substantially correlated, with the two u-shaped trends showing the strongest association with each other. Our results provide evidence for the assumption that the same mechanisms underlie attentional blink task performance at the electrophysiological and behavioral levels as assessed by fixed-links models.