Showing papers by "University of Duisburg-Essen published in 2010"

Improved Survival with Ipilimumab in Patients with Metastatic Melanoma.

Abstract: Background An improvement in overall survival among patients with metastatic melanoma has been an elusive goal. In this phase 3 study, ipilimumab — which blocks cytotoxic T-lymphocyte–associated antigen 4 to potentiate an antitumor T-cell response — administered with or without a glycoprotein 100 (gp100) peptide vaccine was compared with gp100 alone in patients with previously treated metastatic melanoma. Methods A total of 676 HLA-A*0201–positive patients with unresectable stage III or IV melanoma, whose disease had progressed while they were receiving therapy for metastatic disease, were randomly assigned, in a 3:1:1 ratio, to receive ipilimumab plus gp100 (403 patients), ipilimumab alone (137), or gp100 alone (136). Ipilimumab, at a dose of 3 mg per kilogram of body weight, was administered with or without gp100 every 3 weeks for up to four treatments (induction). Eligible patients could receive reinduction therapy. The primary end point was overall survival. Results The median overall survival was 10.0 months among patients receiving ipilimumab plus gp100, as compared with 6.4 months among patients receiving gp100 alone (hazard ratio for death, 0.68; P<0.001). The median overall survival with ipilimumab alone was 10.1 months (hazard ratio for death in the comparison with gp100 alone, 0.66; P = 0.003). No difference in overall survival was detected between the ipilimumab groups (hazard ratio with ipilimumab plus gp100, 1.04; P = 0.76). Grade 3 or 4 immune-related adverse events occurred in 10 to 15% of patients treated with ipilimumab and in 3% treated with gp100 alone. There were 14 deaths related to the study drugs (2.1%), and 7 were associated with immune-related adverse events. Conclusions Ipilimumab, with or without a gp100 peptide vaccine, as compared with gp100 alone, improved overall survival in patients with previously treated metastatic melanoma. Adverse events can be severe, long-lasting, or both, but most are reversible with appropriate treatment. (Funded by Medarex and Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00094653.)

The biofilm matrix

Abstract: The microorganisms in biofilms live in a self-produced matrix of hydrated extracellular polymeric substances (EPS) that form their immediate environment. EPS are mainly polysaccharides, proteins, nucleic acids and lipids; they provide the mechanical stability of biofilms, mediate their adhesion to surfaces and form a cohesive, three-dimensional polymer network that interconnects and transiently immobilizes biofilm cells. In addition, the biofilm matrix acts as an external digestive system by keeping extracellular enzymes close to the cells, enabling them to metabolize dissolved, colloidal and solid biopolymers. Here we describe the functions, properties and constituents of the EPS matrix that make biofilms the most successful forms of life on earth.

Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index

Abstract: Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and similar to 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 x 10(-8)), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.

Toxicity of silver nanoparticles increases during storage because of slow dissolution under release of silver ions

Abstract: The dissolution of citrate-stabilized and poly(vinylpyrrolidone)-stabilized silver nanoparticles in water was studied by dialysis for up to 125 days at 5, 25, and 37 °C. The particles slowly dissolve into ions on a time scale of several days. However, in all cases, a limiting value of the released silver was observed, i.e., the particles did not completely dissolve. In some cases, the nanoparticles released up to 90% of their weight. Formal kinetic data were computed. Rate and degree of dissolution depended on the functionalization as well as on the storage temperature. The release of silver led to a considerably increased toxicity of silver nanoparticles which had been stored in dispersion for several weeks toward human mesenchymal stem cells due to the increased concentration of silver ions. Consequently, “aged” (i.e., immersed) silver nanoparticles are much more toxic to cells than freshly prepared silver nanoparticles.

OnabotulinumtoxinA for treatment of chronic migraine: Results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 2 trial

Abstract: Objectives: This is the first of a pair of studies designed to assess efficacy, safety and tolerability of onabotulinumtoxinA (BOTOX®) as headache prophylaxis in adults with chronic migraine.Methods: The Phase III REsearch Evaluating Migraine Prophylaxis Therapy 1 (PREEMPT 1) is a phase 3 study, with a 24-week, double-blind, parallel-group, placebo-controlled phase followed by a 32-week, open-label phase. Subjects were randomized (1:1) to injections every 12 weeks of onabotulinumtoxinA (155 U–195 U; n = 341) or placebo (n = 338) (two cycles). The primary endpoint was mean change from baseline in headache episode frequency at week 24.Results: No significant between-group difference for onabotulinumtoxinA versus placebo was observed for the primary endpoint, headache episodes (−5.2 vs. −5.3; p = 0.344). Large within-group decreases from baseline were observed for all efficacy variables. Significant between-group differences for onabotulinumtoxinA were observed for the secondary endpoints, headache days (p =...

Towards an assessment of multiple ecosystem processes and services via functional traits

Abstract: Managing ecosystems to ensure the provision of multiple ecosystem services is a key challenge for applied ecology. Functional traits are receiving increasing attention as the main ecological attributes by which different organisms and biological communities influence ecosystem services through their effects on underlying ecosystem processes. Here we synthesize concepts and empirical evidence on linkages between functional traits and ecosystem services across different trophic levels. Most of the 247 studies reviewed considered plants and soil invertebrates, but quantitative trait–service associations have been documented for a range of organisms and ecosystems, illustrating the wide applicability of the trait approach. Within each trophic level, specific processes are affected by a combination of traits while particular key traits are simultaneously involved in the control of multiple processes. These multiple associations between traits and ecosystem processes can help to identify predictable trait–service clusters that depend on several trophic levels, such as clusters of traits of plants and soil organisms that underlie nutrient cycling, herbivory, and fodder and fibre production. We propose that the assessment of trait–service clusters will represent a crucial step in ecosystem service monitoring and in balancing the delivery of multiple, and sometimes conflicting, services in ecosystem management.

Conical intersection dynamics of the primary photoisomerization event in vision

Abstract: The primary photochemical event in vision, isomerization of the 11-cis chromophore in rhodopsin to the all-trans form, is one of the fastest natural photochemical processes known, taking less than a millionth of a millionth of a second. The molecular details of reactions of such rapidity are a stiff challenge to experimenters, but Polli et al. now report the characterization of the reaction using ultrafast optical spectroscopy with sub-20-femtosecond time resolution and spectral coverage from the visible to the near infrared. The data confirm that rhodopsin's extreme reactivity results from a molecular funnel mechanism that involves a 'conical intersection' between the potential energy surfaces of the starting and product molecules. Chemical reactions are usually described in terms of the movement of nuclei between the potential energy surfaces of ground and excited electronic states. Crossings known as conical intersections permit efficient transitions between the surfaces. It is shown here that ultrafast optical spectroscopy, with sub-20-fs time resolution and spectral coverage from the visible to the near-infrared, can map the isomerization of rhodopsin with sufficient resolution to shown that a conical intersection is important in this crucial event in vision. Ever since the conversion of the 11-cis retinal chromophore to its all-trans form in rhodopsin was identified as the primary photochemical event in vision1, experimentalists and theoreticians have tried to unravel the molecular details of this process. The high quantum yield of 0.65 (ref. 2), the production of the primary ground-state rhodopsin photoproduct within a mere 200 fs (refs 3–7), and the storage of considerable energy in the first stable bathorhodopsin intermediate8 all suggest an unusually fast and efficient photoactivated one-way reaction9. Rhodopsin's unique reactivity is generally attributed to a conical intersection between the potential energy surfaces of the ground and excited electronic states10,11 enabling the efficient and ultrafast conversion of photon energy into chemical energy12,13,14,15,16. But obtaining direct experimental evidence for the involvement of a conical intersection is challenging: the energy gap between the electronic states of the reacting molecule changes significantly over an ultrashort timescale, which calls for observational methods that combine high temporal resolution with a broad spectral observation window. Here we show that ultrafast optical spectroscopy with sub-20-fs time resolution and spectral coverage from the visible to the near-infrared allows us to follow the dynamics leading to the conical intersection in rhodopsin isomerization. We track coherent wave-packet motion from the photoexcited Franck–Condon region to the photoproduct by monitoring the loss of reactant emission and the subsequent appearance of photoproduct absorption, and find excellent agreement between the experimental observations and molecular dynamics calculations that involve a true electronic state crossing. Taken together, these findings constitute the most compelling evidence to date for the existence and importance of conical intersections in visual photochemistry.

OnabotulinumtoxinA for Treatment of Chronic Migraine: Pooled Results From the Double-Blind, Randomized, Placebo-Controlled Phases of the PREEMPT Clinical Program

Abstract: (Headache 2010;50:921-936) Objective.— To assess the efficacy, safety, and tolerability of onabotulinumtoxinA (BOTOX®) as headache prophylaxis in adults with chronic migraine. Background.— Chronic migraine is a prevalent, disabling, and undertreated neurological disorder. Few preventive treatments have been investigated and none is specifically indicated for chronic migraine. Methods.— The 2 multicenter, pivotal trials in the PREEMPT: Phase 3 REsearch Evaluating Migraine Prophylaxis Therapy clinical program each included a 24-week randomized, double-blind phase followed by a 32-week open-label phase (ClinicalTrials.gov identifiers NCT00156910, NCT00168428). Qualified patients were randomized (1:1) to onabotulinumtoxinA (155-195 U) or placebo injections every 12 weeks. Study visits occurred every 4 weeks. These studies were identical in design (eg, inclusion/exclusion criteria, randomization, visits, double-blind phase, open-label phase, safety assessments, treatment), with the only exception being the designation of the primary and secondary endpoints. Therefore, the predefined pooling of the results was justified and performed to provide a complete overview of between-group differences in efficacy, safety, and tolerability that may not have been evident in individual studies. The primary endpoint for the pooled analysis was mean change from baseline in frequency of headache days at 24 weeks. Secondary endpoints were mean change from baseline to week 24 in frequency of migraine/probable migraine days, frequency of moderate/severe headache days, total cumulative hours of headache on headache days, frequency of headache episodes, frequency of migraine/probable migraine episodes, frequency of acute headache pain medication intakes, and the proportion of patients with severe (≥60) Headache Impact Test-6 score at week 24. Results of the pooled analyses of the 2 PREEMPT double-blind phases are presented. Results.— A total of 1384 adults were randomized to onabotulinumtoxinA (n = 688) or placebo (n = 696). Pooled analyses demonstrated a large mean decrease from baseline in frequency of headache days, with statistically significant between-group differences favoring onabotulinumtoxinA over placebo at week 24 (−8.4 vs −6.6; P < .001) and at all other time points. Significant differences favoring onabotulinumtoxinA were also observed for all secondary efficacy variables at all time points, with the exception of frequency of acute headache pain medication intakes. Adverse events occurred in 62.4% of onabotulinumtoxinA patients and 51.7% of placebo patients. Most patients reported adverse events that were mild to moderate in severity and few discontinued (onabotulinumtoxinA, 3.8%; placebo, 1.2%) due to adverse events. No unexpected treatment-related adverse events were identified. Conclusions.— The pooled PREEMPT results demonstrate that onabotulinumtoxinA is an effective prophylactic treatment for chronic migraine. OnabotulinumtoxinA resulted in significant improvements compared with placebo in multiple headache symptom measures, and significantly reduced headache-related disability and improved functioning, vitality, and overall health-related quality of life. Repeat treatments with onabotulinumtoxinA were safe and well tolerated.

Penetration of Drugs through the Blood-Cerebrospinal Fluid/Blood-Brain Barrier for Treatment of Central Nervous System Infections

Abstract: The entry of anti-infectives into the central nervous system (CNS) depends on the compartment studied, molecular size, electric charge, lipophilicity, plasma protein binding, affinity to active transport systems at the blood-brain/blood-cerebrospinal fluid (CSF) barrier, and host factors such as meningeal inflammation and CSF flow. Since concentrations in microdialysates and abscesses are not frequently available for humans, this review focuses on drug CSF concentrations. The ideal compound to treat CNS infections is of small molecular size, is moderately lipophilic, has a low level of plasma protein binding, has a volume of distribution of around 1 liter/kg, and is not a strong ligand of an efflux pump at the blood-brain or blood-CSF barrier. When several equally active compounds are available, a drug which comes close to these physicochemical and pharmacokinetic properties should be preferred. Several anti-infectives (e.g., isoniazid, pyrazinamide, linezolid, metronidazole, fluconazole, and some fluoroquinolones) reach a CSF-to-serum ratio of the areas under the curves close to 1.0 and, therefore, are extremely valuable for the treatment of CNS infections. In many cases, however, pharmacokinetics have to be balanced against in vitro activity. Direct injection of drugs, which do not readily penetrate into the CNS, into the ventricular or lumbar CSF is indicated when other effective therapeutic options are unavailable.

The Pipeline Embolization Device for the Intracranial Treatment of Aneurysms Trial

Abstract: BACKGROUND AND PURPOSE: Endoluminal reconstruction with flow diverting devices represents a novel constructive technique for the treatment of cerebral aneurysms. We present the results of the first prospective multicenter trial of a flow-diverting construct for the treatment of intracranial aneurysms. MATERIALS AND METHODS: Patients with unruptured aneurysms that were wide-necked (>4 mm), had unfavorable dome/neck ratios ( RESULTS: Thirty-one patients with 31 intracranial aneurysms (6 men; 42–76 years of age; average age, 54.6 years) were treated during the study period. Twenty-eight aneurysms arose from the ICA (5 cavernous, 15 parophthalmic, 4 superior hypophyseal, and 4 posterior communicating segments), 1 from the MCA, 1 from the vertebral artery, and 1 from the vertebrobasilar junction. Mean aneurysm size was 11.5 mm, and mean neck size was 5.8 mm. Twelve (38.7%) aneurysms had failed (or recurred after) a previous endovascular treatment. PED placement was technically successful in 30 of 31 patients (96.8%). Most aneurysms were treated with either 1 (n = 18) or 2 (n = 11) PEDs. Fifteen aneurysms (48.4%) were treated with a PED alone, while 16 were treated with both PED and embolization coils. Two patients experienced major periprocedural stroke. Follow-up angiography demonstrated complete aneurysm occlusion in 28 (93.3%) of the 30 patients who underwent angiographic follow-up. No significant in-construct stenosis (≥50%) was identified at follow-up angiography. CONCLUSIONS: Intracranial aneurysm treatment with the PED is technically feasible and can be achieved with a safety profile analogous to that reported for stent-supported coil embolization. PED treatment elicited a very high rate (93%) of complete angiographic occlusion at 6 months in a population of the most challenging anatomic subtypes of cerebral aneurysms.

The Nature of Nanotechnology

Abstract: Chapter 2 defines the expressions “Nanoscience” and “Nanotechnology” on a strictly scientific base. Various examples are used to illustrate the development from a scientific discovery via an engineering step to a final technology. “Molecular Motors and Machines”, “Molecular Switches” as well as “Single Electron Memories” are examples that are still exclusively objects of basic research, whereas “Drug Delivery” already reached the status of Nanoengineering. The “Gene Chip” is used as an example that is still object of research in basic nanoscience, but at the same time is already of interest in the nanoengineering step and has partially even reached the technology status. “Hyperthermia” and “Gas Sensors” have left the field of fundamental research and have developed to engineering as well as to technology. Chapter 2 closes with some examples belonging to the field of “Technology on the Nanoscale” which is, however, often but wrongly called “Nanotechnology”. Keywords: molecular motors and switches; singleelectron memories; drug delivery; gene chips; gas sensors

Giant solid-state barocaloric effect in the Ni-Mn-In magnetic shape-memory alloy

Abstract: The search for materials showing large caloric effects close to room temperature has become a challenge in modern materials physics and it is expected that such a class of materials will provide a way to renew present cooling devices that are based on the vapour compression of hazardous gases. Up to now, the most promising materials are giant magnetocaloric materials. The discovery of materials showing a giant magnetocaloric effect at temperatures close to ambient has opened up the possibility of using them for refrigeration. As caloric effects refer to the isothermal entropy change achieved by application of an external field, several caloric effects can take place on tuning different external parameters such as pressure and electric field. Indeed the occurrence of large electrocaloric and elastocaloric effects has recently been reported. Here we show that the application of a moderate hydrostatic pressure to a magnetic shape-memory alloy gives rise to a caloric effect with a magnitude that is comparable to the giant magnetocaloric effect reported in this class of materials. We anticipate that similar barocaloric effects will occur in many giant-magnetocaloric materials undergoing magnetostructural transitions involving a volume change.

Genetic evidence implicates the immune system and cholesterol metabolism in the aetiology of Alzheimer's disease.

Abstract: Background 1Late Onset Alzheimer's disease (LOAD) is the leading cause of dementia. Recent large genome-wide association studies (GWAS) identified the first strongly supported LOAD susceptibility genes since the discovery of the involvement of APOE in the early 1990s. We have now exploited these GWAS datasets to uncover key LOAD pathophysiological processes. Methodology We applied a recently developed tool for mining GWAS data for biologically meaningful information to a LOAD GWAS dataset. The principal findings were then tested in an independent GWAS dataset. Principal Findings We found a significant overrepresentation of association signals in pathways related to cholesterol metabolism and the immune response in both of the two largest genome-wide association studies for LOAD. Significance Processes related to cholesterol metabolism and the innate immune response have previously been implicated by pathological and epidemiological studies of Alzheimer's disease, but it has been unclear whether those findings reflected primary aetiological events or consequences of the disease process. Our independent evidence from two large studies now demonstrates that these processes are aetiologically relevant, and suggests that they may be suitable targets for novel and existing therapeutic approaches.

Boundedness in the Higher-Dimensional Parabolic-Parabolic Chemotaxis System with Logistic Source

Abstract: We consider nonnegative solutions of the Neumann boundary value problem for the chemotaxis system in a smooth bounded convex domain Ω ⊂ ℝ n , n ≥ 1, where τ > 0, χ ∈ ℝ and f is a smooth function generalizing the logistic source It is shown that if μ is sufficiently large then for all sufficiently smooth initial data the problem possesses a unique global-in-time classical solution that is bounded in Ω × (0, ∞). Known results, asserting boundedness under the additional restriction n ≤ 2, are thereby extended to arbitrary space dimensions.

A new unit root test with two structural breaks in level and slope at unknown time

Abstract: In this paper, we propose a new augmented Dickey–Fuller-type test for unit roots which accounts for two structural breaks We consider two different specifications: (a) two breaks in the level of a trending data series and (b) two breaks in the level and slope of a trending data series The breaks whose time of occurrence is assumed to be unknown are modeled as innovational outliers and thus take effect gradually Using Monte Carlo simulations, we show that our proposed test has correct size, stable power, and identifies the structural breaks accurately

Macrophage Expression of Hypoxia-Inducible Factor-1α Suppresses T-Cell Function and Promotes Tumor Progression

Abstract: T cells can inhibit tumor growth, but their function in the tumor microenvironment is often suppressed. Many solid tumors exhibit abundant macrophage infiltration and low oxygen tension, yet how hypoxic conditions may affect innate immune cells and their impact on tumor progression is poorly understood. Targeted deletion of the hypoxia responsive transcription factor HIF-1α in macrophages in a progressive murine model of breast cancer resulted in reduced tumor growth, although VEGF-A and vascularization was unchanged. Tumor associated macrophages can suppress tumor infiltrating T cells by several mechanisms, and we found that hypoxia powerfully augmented macrophage-mediated T cell suppression in vitro in a manner dependent on macrophage expression of HIF-1α. Our findings link the innate immune hypoxic response to tumor progression through induction of T cell suppression in the tumor microenvironment.

From pathogenesis to treatment of chronic lymphocytic leukaemia

Abstract: Chronic lymphocytic leukaemia (CLL) has several unique features that distinguish it from other cancers. Most CLL tumour cells are inert and arrested in G0/G1 of the cell cycle and there is only a small proliferative compartment; however, the progressive accumulation of malignant cells will ultimately lead to symptomatic disease. Pathogenic mechanisms have been elucidated that involve multiple external (for example, microenvironmental stimuli and antigenic drive) and internal (genetic and epigenetic) events that are crucial in the transformation, progression and evolution of CLL. Our growing understanding of CLL biology is allowing the translation of targets and biological classifiers into clinical practice.

Silent and Apparent Cerebral Ischemia After Percutaneous Transfemoral Aortic Valve Implantation A Diffusion-Weighted Magnetic Resonance Imaging Study

Abstract: Background— The risk of stroke after transfemoral aortic valve implantation (TAVI) due to dislodgement and subsequent embolization of debris from aortic arch atheroma or from the calcified valve itself ranges between 2% and 10%. The rate of clinically silent cerebral ischemia is unknown but may be even higher. Methods and Results— Thirty-two patients who underwent TAVI with the use of a balloon-expandable (n=22) or self-expandable (n=10) stent valve prosthesis were included in this descriptive study and compared with a historical control group of 21 patients undergoing open surgical aortic valve replacement. Periprocedural apparent and silent cerebral ischemia was assessed by neurological testing and serial cerebral diffusion-weighted magnetic resonance imaging at baseline, at 3.4 (2.5 to 4.4) days after the procedure, and at 3 months. TAVI was successful in all patients. After the procedure, new foci of restricted diffusion on cerebral diffusion-weighted magnetic resonance imaging were found in 27 of 32 ...

From limestone to catalysis: application of calcium compounds as homogeneous catalysts.

Abstract: 5. Hydrosilylation 3862 5.1. Alkene Hydrosilylation 3863 5.2. Ketone Hydrosilylation 3865 6. Alkene Hydrogenation 3866 7. Aldol-, Mannich-, and Michael-Type Reactions 3867 7.1. Enantioand Diastereoselective Conversions 3867 7.2. Remarks on Stereoselective Induction 3869 8. Miscellaneous Conversions 3869 9. Analogies between Yb2+ and Ca2+ Chemistry 3871 10. Conclusions and Perspectives 3872 11. References 3873

The trifunctional antibody catumaxomab for the treatment of malignant ascites due to epithelial cancer: Results of a prospective randomized phase II/III trial

Abstract: Malignant ascites is a common manifestation of advanced cancers, and treatment options are limited. The trifunctional antibody catumaxomab (anti-epithelial cell-adhesion molecule x anti-CD3) represents a targeted immunotherapy for the intraperitoneal (i.p.) treatment of malignant ascites secondary to epithelial cancers. In this phase II/III trial (EudraCT 2004-000723-15; NCT00836654), cancer patients (n = 258) with recurrent symptomatic malignant ascites resistant to conventional chemotherapy were randomized to paracentesis plus catumaxomab (catumaxomab) or paracentesis alone (control) and stratified by cancer type (129 ovarian and 129 nonovarian). Catumaxomab was administered as an i.p. infusion on Days 0, 3, 7 and 10 at doses of 10, 20, 50 and 150 μg, respectively. The primary efficacy endpoint was puncture-free survival. Secondary efficacy parameters included time to next paracentesis, ascites signs and symptoms and overall survival (OS). Puncture-free survival was significantly longer in the catumaxomab group (median 46 days) than the control group (median 11 days) (hazard ratio = 0.254: p < 0.0001) as was median time to next paracentesis (77 versus 13 days; p < 0.0001). In addition, catumaxomab patients had fewer signs and symptoms of ascites than control patients. OS showed a positive trend for the catumaxomab group and, in a prospectively planned analysis, was significantly prolonged in patients with gastric cancer (n = 66; 71 versus 44 days; p = 0.0313). Although adverse events associated with catumaxomab were frequent, they were manageable, generally reversible and mainly related to its immunologic mode of action. Catumaxomab showed a clear clinical benefit in patients with malignant ascites secondary to epithelial cancers, especially gastric cancer, with an acceptable safety profile.

Meta-Analysis of Genome-Wide Association Studies of Attention- Deficit/Hyperactivity Disorder

Abstract: Objective Although twin and family studies have shown attention-deficit/hyperactivity disorder (ADHD) to be highly heritable, genetic variants influencing the trait at a genome-wide significant level have yet to be identified. As prior genome-wide association studies (GWAS) have not yielded significant results, we conducted a meta-analysis of existing studies to boost statistical power. Method We used data from four projects: a) the Children's Hospital of Philadelphia (CHOP); b) phase I of the International Multicenter ADHD Genetics project (IMAGE); c) phase II of IMAGE (IMAGE II); and d) the Pfizer-funded study from the University of California, Los Angeles, Washington University, and Massachusetts General Hospital (PUWMa). The final sample size consisted of 2,064 trios, 896 cases, and 2,455 controls. For each study, we imputed HapMap single nucleotide polymorphisms, computed association test statistics and transformed them to z-scores, and then combined weighted z-scores in a meta-analysis. Results No genome-wide significant associations were found, although an analysis of candidate genes suggests that they may be involved in the disorder. Conclusions Given that ADHD is a highly heritable disorder, our negative results suggest that the effects of common ADHD risk variants must, individually, be very small or that other types of variants, e.g., rare ones, account for much of the disorder's heritability.

Common variants in KCNN3 are associated with lone atrial fibrillation

Abstract: Atrial fibrillation (AF) is the most common sustained arrhythmia. Previous studies have identified several genetic loci associated with typical AF. We sought to identify common genetic variants underlying lone AF. This condition affects a subset of individuals without overt heart disease and with an increased heritability of AF. We report a meta-analysis of genome-wide association studies conducted using 1,335 individuals with lone AF (cases) and 12,844 unaffected individuals (referents). Cases were obtained from the German AF Network, Heart and Vascular Health Study, the Atherosclerosis Risk in Communities Study, the Cleveland Clinic and Massachusetts General Hospital. We identified an association on chromosome 1q21 to lone AF (rs13376333, adjusted odds ratio = 1.56; P = 6.3 x 10(-12)), and we replicated this association in two independent cohorts with lone AF (overall combined odds ratio = 1.52, 95% CI 1.40-1.64; P = 1.83 x 10(-21)). rs13376333 is intronic to KCNN3, which encodes a potassium channel protein involved in atrial repolarization.

Functional traits as indicators of biodiversity response to land use changes across ecosystems and organisms

Abstract: Rigorous and widely applicable indicators of biodiversity are needed to monitor the responses of ecosystems to global change and design effective conservation schemes. Among the potential indicators of biodiversity, those based on the functional traits of species and communities are interesting because they can be generalized to similar habitats and can be assessed by relatively rapid field assessment across eco-regions. Functional traits, however, have as yet been rarely considered in current common monitoring schemes. Moreover, standardized procedures of trait measurement and analyses have almost exclusively been developed for plants but different approaches have been used for different groups of organisms. Here we review approaches using functional traits as biodiversity indicators focussing not on plants as usual but particularly on animal groups that are commonly considered in different biodiversity monitoring schemes (benthic invertebrates, collembolans, above ground insects and birds). Further, we introduce a new framework based on functional traits indices and illustrate it using case studies where the traits of these organisms can help monitoring the response of biodiversity to different land use change drivers. We propose and test standard procedures to integrate different components of functional traits into biodiversity monitoring schemes across trophic levels and disciplines. We suggest that the development of indicators using functional traits could complement, rather than replace, the existent biodiversity monitoring. In this way, the comparison of the effect of land use changes on biodiversity is facilitated and is expected to positively influence conservation management practices.

European Respiratory Society guidelines for the diagnosis and management of lymphangioleiomyomatosis

Abstract: Lymphangioleiomyomatosis (LAM) is a rare lung disease, which occurs sporadically or in association with the genetic disease tuberous sclerosis complex (TSC) 1, 2. Sporadic LAM affects ∼1 in 400,000 adult females; in TSC, LAM occurs in 30–40% of adult females 3, 4 and exceptionally in males and children 5, 6. Patients with LAM usually develop progressive dyspnoea and recurrent pneumothorax, chylous collections and occasional haemoptysis 1. Extra pulmonary lymphadenopathy and cystic masses of the axial lymphatics termed lymphangioleiomyomas can result in abdominal and pelvic lymphatic obstruction 7. LAM is often associated with angiomyolipoma in the kidneys 8, and an increased frequency of meningioma 9. LAM varies in clinical features and rate of progression: this together with an absence of clear prognostic factors results in patients being given conflicting information about prognosis. Diagnosis is made by tissue biopsy (generally from the lung but occasionally from lymph nodes or lymphangioleiomyomas) and/or a combination of history and high-resolution computed tomography scanning (HRCT). Pathological diagnosis relies on characteristic LAM cell morphology and positive immunoreactivity to smooth muscle actin and HMB-45 antibodies. Increasingly HRCT is used to diagnose LAM without resorting to lung biopsy; however a number of conditions with multiple pulmonary cysts can mimic LAM. As LAM is rare, there have been no controlled trials of its management. Supportive treatment includes management of airflow obstruction and hypoxaemia with bronchodilators and oxygen respectively, specific treatment for surgical or pleural complications including pneumo- and chylothorax, and interventional treatment of renal lesions 10, 11. As LAM is a disease of females and is thought to be accelerated by oestrogen, oophorectomy, tamoxifen, progesterone and gonadotropin-releasing hormone (GnRH) analogues have been used without evidence that they are effective. The recent finding of abnormalities in the TSC1/2 genes resulting …

The Curvelet Transform

Abstract: Multiresolution methods are deeply related to image processing, biological and computer vision, and scientific computing. The curvelet transform is a multiscale directional transform that allows an almost optimal nonadaptive sparse representation of objects with edges. It has generated increasing interest in the community of applied mathematics and signal processing over the years. In this article, we present a review on the curvelet transform, including its history beginning from wavelets, its logical relationship to other multiresolution multidirectional methods like contourlets and shearlets, its basic theory and discrete algorithm. Further, we consider recent applications in image/video processing, seismic exploration, fluid mechanics, simulation of partial different equations, and compressed sensing.