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Find video protocols related to scientific articles indexed in Pubmed.
EIF4G1 is neither a strong nor a common risk factor for Parkinson's disease: evidence from large European cohorts.
J. Med. Genet.
PUBLISHED: 11-05-2014
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Missense mutations in the eukaryotic translation initiation factor 4-? 1 (EIF4G1) gene have previously been implicated in familial Parkinson's disease (PD). A large PD family with autosomal-dominant segregation showed a heterozygous missense mutation and additional patients were found to have unique sequence variants that have not been observed in controls. Subsequent studies have reported contradictory findings.
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Discovery of a biomarker and lead small molecules to target r(GGGGCC)-associated defects in c9FTD/ALS.
Neuron
PUBLISHED: 08-14-2014
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A repeat expansion in C9ORF72 causes frontotemporal dementia and amyotrophic lateral sclerosis (c9FTD/ALS). RNA of the expanded repeat (r(GGGGCC)exp) forms nuclear foci or undergoes repeat-associated non-ATG (RAN) translation, producing "c9RAN proteins." Since neutralizing r(GGGGCC)exp could inhibit these potentially toxic events, we sought to identify small-molecule binders of r(GGGGCC)exp. Chemical and enzymatic probing of r(GGGGCC)8 indicate that it adopts a hairpin structure in equilibrium with a quadruplex structure. Using this model, bioactive small molecules targeting r(GGGGCC)exp were designed and found to significantly inhibit RAN translation and foci formation in cultured cells expressing r(GGGGCC)66 and neurons transdifferentiated from fibroblasts of repeat expansion carriers. Finally, we show that poly(GP) c9RAN proteins are specifically detected in c9ALS patient cerebrospinal fluid. Our findings highlight r(GGGGCC)exp-binding small molecules as a possible c9FTD/ALS therapeutic and suggest that c9RAN proteins could potentially serve as a pharmacodynamic biomarker to assess efficacy of therapies that target r(GGGGCC)exp.
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Modulation of the age at onset in spinocerebellar ataxia by CAG tracts in various genes.
Brain
PUBLISHED: 06-26-2014
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Polyglutamine-coding (CAG)n repeat expansions in seven different genes cause spinocerebellar ataxias. Although the size of the expansion is negatively correlated with age at onset, it accounts for only 50-70% of its variability. To find other factors involved in this variability, we performed a regression analysis in 1255 affected individuals with identified expansions (spinocerebellar ataxia types 1, 2, 3, 6 and 7), recruited through the European Consortium on Spinocerebellar Ataxias, to determine whether age at onset is influenced by the size of the normal allele in eight causal (CAG)n-containing genes (ATXN1-3, 6-7, 17, ATN1 and HTT). We confirmed the negative effect of the expanded allele and detected threshold effects reflected by a quadratic association between age at onset and CAG size in spinocerebellar ataxia types 1, 3 and 6. We also evidenced an interaction between the expanded and normal alleles in trans in individuals with spinocerebellar ataxia types 1, 6 and 7. Except for individuals with spinocerebellar ataxia type 1, age at onset was also influenced by other (CAG)n-containing genes: ATXN7 in spinocerebellar ataxia type 2; ATXN2, ATN1 and HTT in spinocerebellar ataxia type 3; ATXN1 and ATXN3 in spinocerebellar ataxia type 6; and ATXN3 and TBP in spinocerebellar ataxia type 7. This suggests that there are biological relationships among these genes. The results were partially replicated in four independent populations representing 460 Caucasians and 216 Asian samples; the differences are possibly explained by ethnic or geographical differences. As the variability in age at onset is not completely explained by the effects of the causative and modifier sister genes, other genetic or environmental factors must also play a role in these diseases.
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Greenness and allergies: evidence of differential associations in two areas in Germany.
J Epidemiol Community Health
PUBLISHED: 05-26-2014
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Positive greenness effects on health are increasingly reported, although studies on allergic outcomes remain limited and conflicting. We examined whether residential greenness is associated with childhood doctor diagnosed allergic rhinitis, eyes and nose symptoms and aeroallergen sensitisation using two combined birth cohorts (GINIplus and LISAplus) followed from birth to 10 years in northern and southern Germany (Ntotal=5803).
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The risks of methodology aversion in drug regulation.
Nat Rev Drug Discov
PUBLISHED: 05-01-2014
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Decisions made by drug regulatory agencies require a high level of expertise in statistical methodologies. Without urgent efforts to enhance the level of such expertise in European regulatory agencies, there is a risk that they will not be able to meet emerging challenges such as quantitative modelling of benefit–risk profiles, wider use of innovative trial designs and greater public transparency of clinical trial data.
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One-year evaluation of two hybrid composites placed in a randomized-controlled clinical trial.
Dent Mater
PUBLISHED: 04-29-2014
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The aim of this prospective randomized-controlled clinical trial is to assess the long-term performance of two direct composite resins in posterior teeth. This study provides a survey of the one-year results.
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Prediction of the age at onset in spinocerebellar ataxia type 1, 2, 3 and 6.
J. Med. Genet.
PUBLISHED: 04-29-2014
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The most common spinocerebellar ataxias (SCA)--SCA1, SCA2, SCA3, and SCA6--are caused by (CAG)n repeat expansion. While the number of repeats of the coding (CAG)n expansions is correlated with the age at onset, there are no appropriate models that include both affected and preclinical carriers allowing for the prediction of age at onset.
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Respiratory diseases are associated with molar-incisor hypomineralizations.
Swiss Dent J
PUBLISHED: 03-28-2014
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The objective of our study was to evaluate the association of molar-incisor hypomineralizations (MIHs) with prospectively collected potential causative factors from the first 4 years of life, e.g. respiratory diseases, breastfeeding, maternal smoking and parental education. A total of 692 children (10 years old) from the GINI birth cohort study participated. The dental examination included the registration of enamel hypomineralizations (EHs) according to the EAPD criteria. Children with EH were sub-categorized into those with at least one EH (MIH/1), those with a minimum of one EH on at least one first permanent molar (MIH/2) and those with EH on at least one first permanent molar and a permanent incisor (MIH/3). All relationships between causative factors and caries or MIH were evaluated using simple and multiple logistic regression analyses. EHs were observed in 37.9% (MIH/1), 14.7% (MIH/2) and 9.2% (MIH/3) of all subjects. After adjustment for confounding factors, 10-year-old children with at least one episode of respiratory disease had a significantly higher risk (2.48 times, adjusted OR) for the development of MIH/3. In case of breastfeeding, a non-significant association was observed. None of the tested factors was associated with either MIH/1 or MIH/2. Early respiratory diseases seem to be directly or indirectly related to MIH/3 only. The role of (systemic) medications used for treatment of these diseases needs to be investigated in future studies.
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Sharing clinical trial data on patient level: Opportunities and challenges.
Biom J
PUBLISHED: 03-20-2014
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In recent months one of the most controversially discussed topics among regulatory agencies, the pharmaceutical industry, journal editors, and academia has been the sharing of patient-level clinical trial data. Several projects have been started such as the European Medicines Agency´s (EMA) "proactive publication of clinical trial data", the BMJ open data campaign, or the AllTrials initiative. The executive director of the EMA, Dr. Guido Rasi, has recently announced that clinical trial data on patient level will be published from 2014 onwards (although it has since been delayed). The EMA draft policy on proactive access to clinical trial data was published at the end of June 2013 and open for public consultation until the end of September 2013. These initiatives will change the landscape of drug development and publication of medical research. They provide unprecedented opportunities for research and research synthesis, but pose new challenges for regulatory authorities, sponsors, scientific journals, and the public. Besides these general aspects, data sharing also entails intricate biostatistical questions such as problems of multiplicity. An important issue in this respect is the interpretation of multiple statistical analyses, both prospective and retrospective. Expertise in biostatistics is needed to assess the interpretation of such multiple analyses, for example, in the context of regulatory decision-making by optimizing procedural guidance and sophisticated analysis methods.
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Self-rated health, nutritional intake and mortality in adult hospitalized patients.
Eur. J. Clin. Invest.
PUBLISHED: 03-01-2014
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In the general population, poor self-rated health (SRH) is associated with malnutrition; however, these associations have not been studied in hospitalized patients. We aimed to evaluate SRH, indicators of nutrition, nutritional status and their association with in-hospital mortality.
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Sanfilippo type A: new clinical manifestations and neuro-imaging findings in patients from the same family in Israel: a case report.
J Med Case Rep
PUBLISHED: 02-28-2014
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Sanfilippo syndrome type A (mucopolysaccharidosis IIIA - MPS IIIA) is an autosomal recessive lysosomal storage disorder caused by a deficiency in sulfamidase.
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A cross-sectional analysis of the effects of residential greenness on blood pressure in 10-year old children: results from the GINIplus and LISAplus studies.
BMC Public Health
PUBLISHED: 02-26-2014
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According to Ulrich's psychoevolutionary theory, contact with green environments mitigates stress by activating the parasympathetic system, (specifically, by decreasing blood pressure (BP)). Experimental studies have confirmed this biological effect. However, greenness effects on BP have not yet been explored using an observational study design. We assessed whether surrounding residential greenness is associated with BP in 10 year-old German children.
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Optical gating with organic building blocks. A quantitative model for the fluorescence modulation of photochromic perylene bisimide dithienylcyclopentene triads.
Sci Rep
PUBLISHED: 02-20-2014
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We investigated the capability of molecular triads, consisting of two strong fluorophores that were covalently linked to a photochromic molecule, for optical gating. Therefore we monitored the fluorescence intensity of the fluorophores as a function of the isomeric state of the photoswitch. From the analysis of our data we develop a kinetic model that allows us to predict quantitatively the degree of the fluorescence modulation as a function of the mutual intensities of the lasers that are used to induce the fluorescence and the switching of the photochromic unit. We find that the achievable contrast for the modulation of the fluorescence depends mainly on the intensity ratio of the two light beams and appears to be very robust against absolute changes of these intensities. The latter result provides valuable information for the development of all-optical circuits which would require to handle different signal strengths for the input and output levels.
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Phenotype and frequency of STUB1 mutations: next-generation screenings in Caucasian ataxia and spastic paraplegia cohorts.
Orphanet J Rare Dis
PUBLISHED: 02-18-2014
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Mutations in the gene STUB1, encoding the protein CHIP (C-terminus of HSC70-interacting protein), have recently been suggested as a cause of recessive ataxia based on the findings in few Chinese families. Here we aimed to investigate the phenotypic and genotypic spectrum of STUB1 mutations, and to assess their frequency in different Caucasian disease cohorts.
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[Epigenetic heredity (deoxyribonucleic acid methylation): Clinical context in neurodegenerative disorders and ATXN2 gene].
Med Clin (Barc)
PUBLISHED: 01-28-2014
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Epigenetics is the group of changes in the phenotype which are related with the process independently of the primary DNA sequence. These changes are intimately related with changes in the gene expression level and its profile across the body. These are mediated by histone tail modifications, DNA methylation, micro-RNAs, with chromatin remodeling remaining as the foundation of epigenetic changes. DNA methylation involves the covalent addition of methyl group to cytosine of the DNA, which is mediated by methyltransferases enzymes. DNA methylation regulates gene expression by repressing transcription, while de-methylation activates gene transcription. Several human diseases are related with the epigenetic process: cancer, Alzheimer disease, stroke, Parkinson disease, and diabetes. We present here the basis of epigenetic inheritance and show the pathogenic mechanisms relating epigenetics in human diseases, specifically with regard to neurodegeneration. We discuss current concepts aimed at understanding the contribution of epigenetics to human neurodegenerative diseases. We also discuss recent findings obtained in our and other centers regarding the ATXN2 gene that causes spinocerebellar ataxia 2 and amyotrophic lateral sclerosis. Epigenetics play a pivotal role in the pathogenesis of human diseases and in several neurodegenerative disorders, and this knowledge will illuminate the pathways in the diagnostic and therapeutic field, which ultimately will be translated into the clinic context of neurodegenerative diseases.
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Improvement of cardiac function with device-based diaphragmatic stimulation in chronic heart failure patients: the randomized, open-label, crossover Epiphrenic II Pilot Trial.
Eur. J. Heart Fail.
PUBLISHED: 01-28-2014
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Device-based pacing-induced diaphragmatic stimulation (PIDS) may have therapeutic potential for chronic heart failure (HF) patients. We studied the effects of PIDS on cardiac function and functional outcomes.
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AP5Z1/SPG48 frequency in autosomal recessive and sporadic spastic paraplegia.
Mol Genet Genomic Med
PUBLISHED: 01-22-2014
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Hereditary spastic paraplegias (HSP) constitute a rare and highly heterogeneous group of neurodegenerative disorders, defined clinically by progressive lower limb spasticity and pyramidal weakness. Autosomal recessive HSP as well as sporadic cases present a significant diagnostic challenge. Mutations in AP5Z1, a gene playing a role in intracellular membrane trafficking, have been recently reported to be associated with spastic paraplegia type 48 (SPG48). Our objective was to determine the relative frequency and clinical relevance of AP5Z1 mutations in a large cohort of 127 HSP patients. We applied a targeted next-generation sequencing approach to analyze all coding exons of the AP5Z1 gene. With the output of high-quality reads and a mean coverage of 51-fold, we demonstrated a robust detection of variants. One 43-year-old female with sporadic complicated paraplegia showed two heterozygous nonsynonymous variants of unknown significance (VUS3; p.[R292W];[(T756I)]). Thus, AP5Z1 gene mutations are rare, at least in Europeans. Due to its low frequency, systematic genetic testing for AP5Z1 mutations is not recommended until larger studies are performed to add further evidence. Our findings demonstrate that amplicon-based deep sequencing is technically feasible and allows a compact molecular characterization of multiple HSP patients with high accuracy.
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Maximum type 1 error rate inflation in multiarmed clinical trials with adaptive interim sample size modifications.
Biom J
PUBLISHED: 01-20-2014
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Sample size modifications in the interim analyses of an adaptive design can inflate the type 1 error rate, if test statistics and critical boundaries are used in the final analysis as if no modification had been made. While this is already true for designs with an overall change of the sample size in a balanced treatment-control comparison, the inflation can be much larger if in addition a modification of allocation ratios is allowed as well. In this paper, we investigate adaptive designs with several treatment arms compared to a single common control group. Regarding modifications, we consider treatment arm selection as well as modifications of overall sample size and allocation ratios. The inflation is quantified for two approaches: a naive procedure that ignores not only all modifications, but also the multiplicity issue arising from the many-to-one comparison, and a Dunnett procedure that ignores modifications, but adjusts for the initially started multiple treatments. The maximum inflation of the type 1 error rate for such types of design can be calculated by searching for the "worst case" scenarios, that are sample size adaptation rules in the interim analysis that lead to the largest conditional type 1 error rate in any point of the sample space. To show the most extreme inflation, we initially assume unconstrained second stage sample size modifications leading to a large inflation of the type 1 error rate. Furthermore, we investigate the inflation when putting constraints on the second stage sample sizes. It turns out that, for example fixing the sample size of the control group, leads to designs controlling the type 1 error rate.
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Autosomal dominant cerebellar ataxia with slow ocular saccades, neuropathy and orthostatism: a novel entity?
Parkinsonism Relat. Disord.
PUBLISHED: 01-16-2014
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We describe the clinical characteristics of a Swedish family with autosomal dominant cerebellar ataxia, sensory and autonomic neuropathy, additional neurological features and unknown genetic cause.
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Characterization of DNA hypermethylation in the cerebellum of c9FTD/ALS patients.
Brain Res.
PUBLISHED: 01-16-2014
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A significant number of patients suffering from amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two diseases commonly seen in comorbidity, carry an expanded noncoding hexanucleotide repeat in the C9orf72 gene, a condition collectively referred to as c9FTD/ALS. Repeat expansions, also present in other neurodegenerative diseases, have been shown to alter epigenetic mechanisms and consequently lead to decreased gene expression, while also leading to toxic RNA gain-of-function. As expression of multiple C9orf72 transcript variants is known to be reduced in c9FTD/ALS cases, our group and others have sought to uncover the mechanisms causing this reduction. We recently demonstrated that histones H3 and H4 undergo trimethylation at lysines 9 (H3K9), 27 (H3K27), 79 (H3K79), and 20 (H4K20) in all pathogenic repeat carrier brain samples, confirming the role of altered histone methylation in disease. It was also reported that about 40% of c9ALS cases show hypermethylation of the CpG island located at the 5' end of the repeat expansion in blood, frontal cortex, and spinal cord. To determine whether the same CpG island is hypermethylated in the cerebella of cases in whom aberrant histone methylation has been identified, we bisulfite-modified the extracted DNA and PCR-amplified 26 CpG sites within the C9orf72 promoter region. Among the ten c9FTD/ALS (4 c9ALS, 6 c9FTD), nine FTD/ALS, and eight disease control samples evaluated, only one c9FTD sample was found to be hypermethylated within the C9orf72 promoter region. This study is the first to report cerebellar hypermethylation in c9FTD/ALS, and the first to identify a c9FTD patient with aberrant DNA methylation. Future studies will need to evaluate hypermethylation of the C9orf72 promoter in a larger cohort of c9FTD patients, and to assess whether DNA methylation variation across brain regions reflects disease phenotype.
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Screening of mutations in GNAL in sporadic dystonia patients.
Mov. Disord.
PUBLISHED: 01-09-2014
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GNAL mutations have been shown to cause adult-onset isolated dystonia, a disabling movement disorder characterized by involuntary muscle contractions causing twisting and repetitive movements or abnormal postures.
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A novel form of ciliopathy underlies hyperphagia and obesity in Ankrd26 knockout mice.
Brain Struct Funct
PUBLISHED: 01-02-2014
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Human ciliopathies are genetic disorders caused by mutations in genes responsible for the formation and function of primary cilia. Some are associated with hyperphagia and obesity (e.g., Bardet-Biedl Syndrome, Alström Syndrome), but the mechanisms underlying these problems are not fully understood. The human gene ANKRD26 is located on 10p12, a locus that is associated with some forms of hereditary obesity. Previously, we reported that disruption of this gene causes hyperphagia, obesity and gigantism in mice. In the present study, we looked for the mechanisms that induce hyperphagia in the Ankrd26-/- mice and found defects in primary cilia in regions of the central nervous system that control appetite and energy homeostasis.
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Large-scale RNA interference screening in mammalian cells identifies novel regulators of mutant huntingtin aggregation.
PLoS ONE
PUBLISHED: 01-01-2014
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In polyglutamine (polyQ) diseases including Huntington's disease (HD), mutant proteins containing expanded polyQ stretch form aggregates in neurons. Genetic or RNAi screenings in yeast, C. elegans or Drosophila have identified multiple genes modifying polyQ aggregation, a few of which are confirmed effective in mammals. However, the overall molecular mechanism underlying polyQ protein aggregation in mammalian cells still remains obscure. We here perform RNAi screening in mouse neuro2a cells to identify mammalian modifiers for aggregation of mutant huntingtin, a causative protein of HD. By systematic cell transfection and automated cell image analysis, we screen ? 12000 shRNA clones and identify 111 shRNAs that either suppress or enhance mutant huntingtin aggregation, without altering its gene expression. Classification of the shRNA-targets suggests that genes with various cellular functions such as gene transcription and protein phosphorylation are involved in modifying the aggregation. Subsequent analysis suggests that, in addition to the aggregation-modifiers sensitive to proteasome inhibition, some of them, such as a transcription factor Tcf20, and kinases Csnk1d and Pik3c2a, are insensitive to it. As for Tcf20, which contains polyQ stretches at N-terminus, its binding to mutant huntingtin aggregates is observed in neuro2a cells and in HD model mouse neurons. Notably, except Pik3c2a, the rest of the modifiers identified here are novel. Thus, our first large-scale RNAi screening in mammalian system identifies previously undescribed genetic players that regulate mutant huntingtin aggregation by several, possibly mammalian-specific mechanisms.
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The tumour suppressor gene WWOX is mutated in autosomal recessive cerebellar ataxia with epilepsy and mental retardation.
Brain
PUBLISHED: 12-24-2013
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We previously localized a new form of recessive ataxia with generalized tonic-clonic epilepsy and mental retardation to a 19 Mb interval in 16q21-q23 by homozygosity mapping of a large consanguineous Saudi Arabian family. We now report the identification by whole exome sequencing of the missense mutation changing proline 47 into threonine in the first WW domain of the WW domain containing oxidoreductase gene, WWOX, located in the linkage interval. Proline 47 is a highly conserved residue that is part of the WW motif consensus sequence and is part of the hydrophobic core that stabilizes the WW fold. We demonstrate that proline 47 is a key amino acid essential for maintaining the WWOX protein fully functional, with its mutation into a threonine resulting in a loss of peptide interaction for the first WW domain. We also identified another highly conserved homozygous WWOX mutation changing glycine 372 to arginine in a second consanguineous family. The phenotype closely resembled the index family, presenting with generalized tonic-clonic epilepsy, mental retardation and ataxia, but also included prominent upper motor neuron disease. Moreover, we observed that the short-lived Wwox knock-out mouse display spontaneous and audiogenic seizures, a phenotype previously observed in the spontaneous Wwox mutant rat presenting with ataxia and epilepsy, indicating that homozygous WWOX mutations in different species causes cerebellar ataxia associated with epilepsy.
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Truncation of N-terminal regions of Digitalis lanata progesterone 5?-reductase alters catalytic efficiency and substrate preference.
Biochimie
PUBLISHED: 12-12-2013
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N-Terminal truncated forms of progesterone 5?-reductase (P5?R) were synthesized taking a full-length cDNA encoding for Digitalis lanata P5?R with a hexa-histidine tag attached at the C-terminus (rDlP5?Rc) as the starting point. Four pETite-c-His/DlP5?R constructs coding for P5?R derivatives truncated in the N-terminal region, termed rDlP5?Rcn-10, rDlP5?Rcn-20, rDlP5?Rcn-30, and rDlP5?Rcn-40 were obtained by site-directed mutagenesis. The cDNAs coding for full-length rDlP5?Rc, rDlP5?Rcn-10 and rDlP5?Rcn-20 were over-expressed in Escherichia coli and the respective enzymes were soluble and catalytically active (progesterone and 2-cyclohexen-1-one as substrates). GST-tagged recombinant DlP5?R (rDlP5?R-GST) and rDlP5?R-GSTr, with the GST-tag removed by protease treatment were produced as well and served as controls. The Km values and substrate preferences considerably differed between the various DlP5?R derivatives. As for the C-terminal His-tagged rDlP5?R the catalytic efficiency for progesterone was highest for the full-length rDlP5?Rc whereas the N-terminal truncated forms preferred 2-cyclohexen-1-one as the substrate. Affinity tags and artifacts resulting from the cloning strategy used may alter substrate specificity. Therefore enzyme properties determined with recombinant proteins should not be used to infer in vivo scenarios and should be considered for each particular case.
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De novo mutations in hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS).
Neurology
PUBLISHED: 11-06-2013
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Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) is caused by autosomal-dominantly inherited mutations in the colony stimulating factor 1 receptor (CSF1R) gene, and is clinically characterized by a progressive cognitive and motor decline leading to death within several years.
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SIL1 mutations and clinical spectrum in patients with Marinesco-Sjogren syndrome.
Brain
PUBLISHED: 10-30-2013
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Marinesco-Sjögren syndrome is a rare autosomal recessive multisystem disorder featuring cerebellar ataxia, early-onset cataracts, chronic myopathy, variable intellectual disability and delayed motor development. More recently, mutations in the SIL1 gene, which encodes an endoplasmic reticulum resident co-chaperone, were identified as the main cause of Marinesco-Sjögren syndrome. Here we describe the results of SIL1 mutation analysis in 62 patients presenting with early-onset ataxia, cataracts and myopathy or combinations of at least two of these. We obtained a mutation detection rate of 60% (15/25) among patients with the characteristic Marinesco-Sjögren syndrome triad (ataxia, cataracts, myopathy) whereas the detection rate in the group of patients with more variable phenotypic presentation was below 3% (1/37). We report 16 unrelated families with a total of 19 different SIL1 mutations. Among these mutations are 15 previously unreported changes, including single- and multi-exon deletions. Based on data from our screening cohort and data compiled from the literature we found that SIL1 mutations are invariably associated with the combination of a cerebellar syndrome and chronic myopathy. Cataracts were observed in all patients beyond the age of 7 years, but might be missing in infants. Six patients with SIL1 mutations had no intellectual disability, extending the known wide range of cognitive capabilities in Marinesco-Sjögren syndrome to include normal intelligence. Modestly constant features were somatic growth retardation, skeletal abnormalities and pyramidal tract signs. Examination of mutant SIL1 expression in cultured patient lymphoblasts suggested that SIL1 mutations result in severely reduced SIL1 protein levels irrespective of the type and position of mutations. Our data broaden the SIL1 mutation spectrum and confirm that SIL1 is the major Marinesco-Sjögren syndrome gene. SIL1 patients usually present with the characteristic triad but cataracts might be missing in young children. As cognitive impairment is not obligatory, patients without intellectual disability but a Marinesco-Sjögren syndrome-compatible phenotype should receive SIL1 mutation analysis. Despite allelic heterogeneity and many families with private mutations, the phenotype related to SIL1 mutations is relatively homogenous. Based on SIL1 expression studies we speculate that this may arise from a uniform effect of different mutations on protein expression.
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Targeted manipulation of the sortilin-progranulin axis rescues progranulin haploinsufficiency.
Hum. Mol. Genet.
PUBLISHED: 10-26-2013
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Progranulin (GRN) mutations causing haploinsufficiency are a major cause of frontotemporal lobar degeneration (FTLD-TDP). Recent discoveries demonstrating sortilin (SORT1) is a neuronal receptor for PGRN endocytosis and a determinant of plasma PGRN levels portend the development of enhancers targeting the SORT1-PGRN axis. We demonstrate the preclinical efficacy of several approaches through which impairing PGRNs interaction with SORT1 restores extracellular PGRN levels. Our report is the first to demonstrate the efficacy of enhancing PGRN levels in iPSC neurons derived from frontotemporal dementia (FTD) patients with PGRN deficiency. We validate a small molecule preferentially increases extracellular PGRN by reducing SORT1 levels in various mammalian cell lines and patient-derived iPSC neurons and lymphocytes. We further demonstrate that SORT1 antagonists and a small-molecule binder of PGRN588-593, residues critical for PGRN-SORT1 binding, inhibit SORT1-mediated PGRN endocytosis. Collectively, our data demonstrate that the SORT1-PGRN axis is a viable target for PGRN-based therapy, particularly in FTD-GRN patients.
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Association between repeat sizes and clinical and pathological characteristics in carriers of C9ORF72 repeat expansions (Xpansize-72): a cross-sectional cohort study.
Lancet Neurol
PUBLISHED: 09-05-2013
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Hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9ORF72) are the most common known genetic cause of frontotemporal dementia (FTD) and motor neuron disease (MND). We assessed whether expansion size is associated with disease severity or phenotype.
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2-Aminoethyl diphenylborinate (2-APB) analogues: regulation of Ca2+ signaling.
Biochem. Biophys. Res. Commun.
PUBLISHED: 08-29-2013
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In order to obtain compounds with modified 2-APB activities, we synthesized number of 2-APB analogues and analyzed their inhibitory activities for SOCE. The IC50 of 2-APB for SOCE inhibition is 3 ?M while IC50 of some of our 2-APB analogues range 0.1-10 ?M. The adducts of amino acids with diphenyl borinic acid have strong inhibitory activities. By using these compounds, we will be able to regulate intracellular Ca(2+) concentration and consequent cellular processes more efficiently than with 2-APB.
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Surrounding greenness and birth weight: Results from the GINIplus and LISAplus birth cohorts in Munich.
Health Place
PUBLISHED: 07-31-2013
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We investigated the association between surrounding greenness at the mothers residential address at the time of delivery and birth weight in two German birth cohorts and explored potential underlying hypotheses.
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Traffic, asthma and genetics: combining international birth cohort data to examine genetics as a mediator of traffic-related air pollutions impact on childhood asthma.
Eur. J. Epidemiol.
PUBLISHED: 07-10-2013
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Associations between traffic-related air pollution and incident childhood asthma can be strengthened by analysis of gene-environment interactions, but studies have typically been limited by lack of study power. We combined data from six birth cohorts on: asthma, eczema and allergic rhinitis to 7/8 years, and candidate genes. Individual-level assessment of traffic-related air pollution exposure was estimated using land use regression or dispersion modeling. A total of 11,760 children were included in the Traffic, Asthma and Genetics (TAG) Study; 6.3 % reported physician-diagnosed asthma at school-age, 16.0 % had asthma at anytime during childhood, 14.1 % had allergic rhinitis at school-age, 10.0 % had eczema at school-age and 33.1 % were sensitized to any allergen. For GSTP1 rs1138272, the prevalence of heterozygosity was 16 % (range amongst individual cohorts, 11-17 %) and homozygosity for the minor allele was 1 % (0-2 %). For GSTP1 rs1695, the prevalence of heterozygosity was 45 % (40-48 %) and homozygosity for the minor allele, 12 % (10-12 %). For TNF rs1800629, the prevalence of heterozygosity was 29 % (25-32 %) and homozygosity for the minor allele, 3 % (1-3 %). TAG comprises a rich database, the largest of its kind, for investigating the effect of genotype on the association between air pollution and childhood allergic disease.
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X-linked intellectual disability type Nascimento is a clinically distinct, probably underdiagnosed entity.
Orphanet J Rare Dis
PUBLISHED: 07-09-2013
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X-linked intellectual disability type Nascimento (MIM #300860), caused by mutations in UBE2A (MIM *312180), is characterized by craniofacial dysmorphism (synophrys, prominent supraorbital ridges, deep-set, almond-shaped eyes, depressed nasal bridge, prominent columella, hypoplastic alae nasi, and macrostomia), skin anomalies (hirsutism, myxedematous appearance, onychodystrophy), micropenis, moderate to severe intellectual disability (ID), motor delay, impaired/absent speech, and seizures. Hitherto only five familial point mutations and four different deletions including UBE2A have been reported in the literature.We present eight additional individuals from five families with UBE2A associated ID - three males from a consanguineous family, in whom we identified a small deletion of only 7.1 kb encompassing the first three exons of UBE2A, two related males with a UBE2A missense mutation in exon 4, a patient with a de novo nonsense mutation in exon 6, and two sporadic males with larger deletions including UBE2A. All affected male individuals share the typical clinical phenotype, all carrier females are unaffected and presented with a completely skewed X inactivation in blood. We conclude that 1.) X-linked intellectual disability type Nascimento is a clinically very distinct entity that might be underdiagnosed to date. 2.) So far, all females carrying a familial UBE2A aberration have a completely skewed X inactivation and are clinically unaffected. This should be taken in to account when counselling those families. 3.) The coverage of an array should be checked carefully prior to analysis since not all arrays have a sufficient resolution at specific loci, or alternative quantitative methods should be applied not to miss small deletions.
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Reduced C9orf72 gene expression in c9FTD/ALS is caused by histone trimethylation, an epigenetic event detectable in blood.
Acta Neuropathol.
PUBLISHED: 07-01-2013
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Individuals carrying (GGGGCC) expanded repeats in the C9orf72 gene represent a significant portion of patients suffering from amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Elucidating how these expanded repeats cause "c9FTD/ALS" has since become an important goal of the field. Toward this end, we sought to investigate whether epigenetic changes are responsible for the decrease in C9orf72 expression levels observed in c9FTD/ALS patients. We obtained brain tissue from ten c9FTD/ALS individuals, nine FTD/ALS cases without a C9orf72 repeat expansion, and nine disease control participants, and generated fibroblastoid cell lines from seven C9orf72 expanded repeat carriers and seven participants carrying normal alleles. Chromatin immunoprecipitation using antibodies for histone H3 and H4 trimethylated at lysines 9 (H3K9), 27 (H3K27), 79 (H3K79), and 20 (H4K20) revealed that these trimethylated residues bind strongly to C9orf72 expanded repeats in brain tissue, but not to non-pathogenic repeats. Our finding that C9orf72 mRNA levels are reduced in the frontal cortices and cerebella of c9FTD/ALS patients is consistent with trimethylation of these histone residues, an event known to repress gene expression. Moreover, treating repeat carrier-derived fibroblasts with 5-aza-2-deoxycytidine, a DNA and histone demethylating agent, not only decreased C9orf72 binding to trimethylated histone residues, but also increased C9orf72 mRNA expression. Our results provide compelling evidence that trimethylation of lysine residues within histones H3 and H4 is a novel mechanism involved in reducing C9orf72 mRNA expression in expanded repeat carriers. Of importance, we show that mutant C9orf72 binding to trimethylated H3K9 and H3K27 is detectable in blood of c9FTD/ALS patients. Confirming these exciting results using blood from a larger cohort of patients may establish this novel epigenetic event as a biomarker for c9FTD/ALS.
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Genetic screening for Niemann-Pick disease type C in adults with neurological and psychiatric symptoms: findings from the ZOOM study.
Hum. Mol. Genet.
PUBLISHED: 06-16-2013
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Niemann-Pick disease type C (NP-C) is a rare, autosomal-recessive, progressive neurological disease caused by mutations in either the NPC1 gene (in 95% of cases) or the NPC2 gene. This observational, multicentre genetic screening study evaluated the frequency and phenotypes of NP-C in consecutive adult patients with neurological and psychiatric symptoms. Diagnostic testing for NP-C involved NPC1 and NPC2 exonic gene sequencing and gene dosage analysis. When available, results of filipin staining, plasma cholestane-3?,5?,6?-triol assays and measurements of relevant sphingolipids were also collected. NPC1 and NPC2 gene sequencing was completed in 250/256 patients from 30 psychiatric and neurological reference centres across the EU and USA [median (range) age 38 (18-90) years]. Three patients had a confirmed diagnosis of NP-C; two based on gene sequencing alone (two known causal disease alleles) and one based on gene sequencing and positive filipin staining. A further 12 patients displayed either single mutant NP-C alleles (8 with NPC1 mutations and 3 with NPC2 mutations) or a known causal disease mutation and an unclassified NPC1 allele variant (1 patient). Notably, high plasma cholestane-3?,5?,6?-triol levels were observed for all NP-C cases (n = 3). Overall, the frequency of NP-C patients in this study [1.2% (95% CI; 0.3%, 3.5%)] suggests that there may be an underdiagnosed pool of NP-C patients among adults who share common neurological and psychiatric symptoms.
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Genome-wide comparison of medieval and modern Mycobacterium leprae.
Science
PUBLISHED: 06-13-2013
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Leprosy was endemic in Europe until the Middle Ages. Using DNA array capture, we have obtained genome sequences of Mycobacterium leprae from skeletons of five medieval leprosy cases from the United Kingdom, Sweden, and Denmark. In one case, the DNA was so well preserved that full de novo assembly of the ancient bacterial genome could be achieved through shotgun sequencing alone. The ancient M. leprae sequences were compared with those of 11 modern strains, representing diverse genotypes and geographic origins. The comparisons revealed remarkable genomic conservation during the past 1000 years, a European origin for leprosy in the Americas, and the presence of an M. leprae genotype in medieval Europe now commonly associated with the Middle East. The exceptional preservation of M. leprae biomarkers, both DNA and mycolic acids, in ancient skeletons has major implications for palaeomicrobiology and human pathogen evolution.
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A novel transgenic rat model for spinocerebellar ataxia type 17 recapitulates neuropathological changes and supplies in vivo imaging biomarkers.
J. Neurosci.
PUBLISHED: 05-24-2013
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Spinocerebellar ataxia 17 (SCA17) is an autosomal-dominant, late-onset neurodegenerative disorder caused by an expanded polyglutamine (polyQ) repeat in the TATA-box-binding protein (TBP). To further investigate this devastating disease, we sought to create a first transgenic rat model for SCA17 that carries a full human cDNA fragment of the TBP gene with 64 CAA/CAG repeats (TBPQ64). In line with previous observations in mouse models for SCA17, TBPQ64 rats show a severe neurological phenotype including ataxia, impairment of postural reflexes, and hyperactivity in early stages followed by reduced activity, loss of body weight, and early death. Neuropathologically, the severe phenotype of SCA17 rats was associated with neuronal loss, particularly in the cerebellum. Degeneration of Purkinje, basket, and stellate cells, changes in the morphology of the dendrites, nuclear TBP-positive immunoreactivity, and axonal torpedos were readily found by light and electron microscopy. While some of these changes are well recapitulated in existing mouse models for SCA17, we provide evidence that some crucial characteristics of SCA17 are better mirrored in TBPQ64 rats. Thus, this SCA17 model represents a valuable tool to pursue experimentation and therapeutic approaches that may be difficult or impossible to perform with SCA17 transgenic mice. We show for the first time positron emission tomography (PET) and diffusion tensor imaging (DTI) data of a SCA animal model that replicate recent PET studies in human SCA17 patients. Our results also confirm that DTI are potentially useful correlates of neuropathological changes in TBPQ64 rats and raise hope that DTI imaging could provide a biomarker for SCA17 patients.
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The association between road traffic noise exposure and blood pressure among children in Germany: the GINIplus and LISAplus studies.
Noise Health
PUBLISHED: 05-22-2013
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Studies examining the association between road traffic noise and blood pressure in children are scarce. Nighttime noise levels and window orientations have not been considered in most previous studies. Investigate the association between road traffic noise exposure and blood pressure among children, and investigate the impact of bedroom window direction on this association. We measured blood pressure in 605 children aged 10 years from two Munich cohorts. Demographic and health information was collected by parent completed questionnaires. Road traffic noise levels were assessed by day-evening-night noise indicator "Lden" and night noise indicator "Lnight". Minimum and maximum levels within a 50 m buffer around childs home address were derived. Generalized additive models were applied to explore effect of noise levels on systolic and diastolic blood pressure (SBP and DBP). The orientation of childs bedroom window was considered in sensitivity analyses. DBP was significantly associated with the minimum level of noise during 24 h (Lden_min) and nightime (Lnight_min). Specifically, DBP increased by 0.67 and 0.89 mmHg for every 5 A-weighted decibels increase in Lden_min and Lnight_min. After adjusting for Lden_min (Lnight_min), DBP of children whose bedroom window faced the street was 1.37 (1.28) mmHg higher than those whose bedroom window did not, these children showed statistically significant increased SBP for Lden_min (3.05 mmHg) and Lnight_min (3.27 mmHg) compared to children whose bedroom window did not face the street. Higher minimum levels of weighted day-evening-night noise and nighttime noise around the home residence may increase a childs blood pressure.
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Effects of air pollution on exhaled nitric oxide in children: Results from the GINIplus and LISAplus studies.
Int J Hyg Environ Health
PUBLISHED: 04-25-2013
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Most previous studies which have investigated the short-term effects of air pollution on airway inflammation, assessed by an increase of exhaled nitric oxide (eNO), have been conducted among asthmatic children. Few studies have considered this potential association among non-asthmatics. Furthermore, although both short- and long-term effects of air pollution on eNO had been reported separately, studies which include both are scarce. We explored associations between 24h NO2 and PM10 (particles with aerodynamic diameters below 10?m) mass with eNO in 1985 children (192 asthmatics and 1793 non-asthmatics) aged 10 years and accounted for the long-term effects of air pollution by adjusting for annual averages of NO2, PM10 mass, PM2.5 mass (particles with aerodynamic diameters below 2.5?m) and PM2.5 absorbance, using data from two German birth cohorts in Munich and Wesel. In total, robust associations between 24h NO2 and eNO were observed in both single-pollutant (percentage change: 18.30%, 95% confidence interval: 11.63-25.37) and two-pollutant models (14.62%, 6.71-23.11). The association between 24h PM10 mass and eNO was only significant in the single-pollutant model (9.59%, 4.80-14.61). The same significant associations were also observed in non-asthmatic children, while they did not reach significant levels in asthmatic children. Associations between annual averages of ambient air pollution (NO2, PM10 mass, PM2.5 mass and PM2.5 absorbance) and eNO were consistently null. In conclusion, significantly positive associations were observed between short-term ambient air pollution and eNO. No long-term effects of air pollution on eNO were found in this study.
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The associations between traffic-related air pollution and noise with blood pressure in children: Results from the GINIplus and LISAplus studies.
Int J Hyg Environ Health
PUBLISHED: 04-15-2013
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Although traffic emits both air pollution and noise, studies jointly examining the effects of both of these exposures on blood pressure (BP) in children are scarce. We investigated associations between land-use regression modeled long-term traffic-related air pollution and BP in 2368 children aged 10 years from Germany (1454 from Munich and 914 from Wesel). We also studied this association with adjustment of long-term noise exposure (defined as day-evening-night noise indicator "Lden" and night noise indicator "Lnight") in a subgroup of 605 children from Munich inner city. In the overall analysis including 2368 children, NO2, PM2.5 mass (particles with aerodynamic diameters below 2.5?m), PM10 mass (particles with aerodynamic diameters below 10?m) and PM2.5 absorbance were not associated with BP. When restricting the analysis to the subgroup of children with noise information (N=605), a significant association between NO2 and diastolic BP was observed (-0.88 (95% confidence interval: -1.67, -0.08)). However, upon adjusting the models for noise exposure, only noise remained independently and significantly positively associated with diastolic BP. Diastolic BP increased by 0.50 (-0.03, 1.02), 0.59 (0.05, 1.13), 0.55 (0.03, 1.07), and 0.58 (0.05, 1.11)mmHg for every five decibel increase in Lden and by 0.59 (-0.05, 1.22), 0.69 (0.04, 1.33), 0.64 (0.02, 1.27), and 0.68 (0.05, 1.32)mmHg for every five decibel increase in Lnight, in different models of NO2, PM2.5 mass, PM10 mass and PM2.5 absorbance as the main exposure, respectively. In conclusion, air pollution was not consistently associated with BP with adjustment for noise, noise was independently and positively associated with BP in children.
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A photoswitchable poly(3-hexylthiophene).
Chem. Commun. (Camb.)
PUBLISHED: 04-11-2013
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A well-defined main-chain conjugated photoswitchable poly(3-hexylthiophene) with homogeneous hydrogen end groups was synthesized. Opening and closing the photoswitch enables reversible modulation of P3HT emission, which is quenched by 70% when the switch is closed. The optical properties during switching cycles were quantified by irradiation/spectroscopy sequences.
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Niemann-Pick Disease Type C: New Aspects in a Long Published Family - Partial Manifestations in Heterozygotes.
JIMD Rep
PUBLISHED: 03-27-2013
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Decades ago, a family with three children with a neurovisceral lysosomal storage disease was described. The patient siblings died at ages 7, 9, and 11 years, respectively, and according to the current concept had the late-infantile neurologic form of Niemann-Pick type C1 (NPC) disease, given by the present molecular study that there were severe NPC1 gene variants: Blood samples preserved since that time from one patient sibling and his presently 55-year-old essentially healthy sister have now been studied, revealing the variants p.I1061T and p.G1162V in the NPC1 gene, the first long known, the second newly found but predicted to be pathogenic and similar to the known G1162A. Now, with the molecular diagnosis, that initial description warrants new interest for the following reasons. The mentioned sister carries only the I1061T variant. She had storage macrophages ("Niemann-Pick cells") in her bone marrow, but also displayed distinct splenomegaly with indurated consistency of the organ, proven in childhood and confirmed several times up to age 13, but disappeared at age 55 years. She shares the I1061T variant with her still healthy mother, and the bone marrow finding with both parents, her father having died at 66 years from a carcinoma. The present study is one of the first describing hematological and relevant clinical symptomatology, even in heterozygotes, of molecularly diagnosed human NPC. Feline NPC is known to model such a situation. For human diagnostic and clinical NPC management, the possibility of "heterozygous disease" should be kept in mind.
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No cross-sectional and longitudinal association of ferritin and symptoms of attention-deficit-/hyperactivity disorder in a large population-based sample of children: results from the GINIplus and LISAplus studies.
Atten Defic Hyperact Disord
PUBLISHED: 03-22-2013
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Attention-deficit/hyperactivity disorder (ADHD) has been associated with alterations in iron metabolism, and low ferritin concentrations in peripheral blood have inconsistently been reported in clinically referred samples of children with ADHD. This study examined whether higher peripheral concentrations of ferritin, the major iron storage protein, are associated with decreased symptoms of ADHD in 2,805 children aged 10 years participating in two large population-based birth cohorts (GINIplus and LISAplus). Whether high ferritin concentrations at age 4 months predict lower ADHD symptoms at age 10 years was also investigated using a longitudinal approach in a subsample of 193 children. No indications for an association between peripheral ferritin concentrations and ADHD symptoms were found in this large population-based study. Re-evaluating iron substitution as a therapeutic measure for ADHD may be warranted.
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Genome-wide associations of signaling pathways in glioblastoma multiforme.
BMC Med Genomics
PUBLISHED: 03-12-2013
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eQTL analysis is a powerful method that allows the identification of causal genomic alterations, providing an explanation of expression changes of single genes. However, genes mediate their biological roles in groups rather than in isolation, prompting us to extend the concept of eQTLs to whole gene pathways.
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Genotype-specific patterns of atrophy progression are more sensitive than clinical decline in SCA1, SCA3 and SCA6.
Brain
PUBLISHED: 02-18-2013
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Spinocerebellar ataxias are dominantly inherited disorders that are associated with progressive brain degeneration, mainly affecting the cerebellum and brainstem. As part of the multicentre European integrated project on spinocerebellar ataxias study, 37 patients with spinocerebellar ataxia-1, 19 with spinocerebellar ataxia-3 and seven with spinocerebellar ataxia-6 were clinically examined and underwent magnetic resonance imaging at baseline and after a 2-year follow-up. All patients were compared with age-matched and gender-matched healthy control subjects. Magnetic resonance imaging analysis included three-dimensional volumetry and observer-independent longitudinal voxel-based morphometry. Volumetry revealed loss of brainstem, cerebellar and basal ganglia volume in all genotypes. Most sensitive to change was the pontine volume in spinocerebellar ataxia-1, striatal volume in spinocerebellar ataxia-3 and caudate volume in spinocerebellar ataxia-6. Sensitivity to change, as measured by standard response mean, of the respective MRI measures was greater than that of the most sensitive clinical measure, the Scale for the Assessment and Rating of Ataxia. Longitudinal voxel-based morphometry revealed greatest grey matter loss in the cerebellum and brainstem in spinocerebellar ataxia-1, in the putamen and pallidum in spinocerebellar ataxia-3 and in the cerebellum, thalamus, putamen and pallidum in spinocerebellar ataxia-6. There was a mild correlation between CAG repeat length and volume loss of the bilateral cerebellum and the pons in spinocerebellar ataxia-1. Quantitative volumetry and voxel-based morphometry imaging demonstrated genotype-specific patterns of atrophy progression in spinocerebellar ataxias-1, 3 and 6, and they showed a high sensitivity to detect change that was superior to clinical scales. These structural magnetic resonance imaging findings have the potential to serve as surrogate markers, which might help to delineate quantifiable endpoints and non-invasive methods for rapid and reliable data acquisition, encouraging their use in clinical trials.
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Clinical and functional characterisation of the combined respiratory chain defect in two sisters due to autosomal recessive mutations in MTFMT.
Mitochondrion
PUBLISHED: 02-11-2013
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Exome sequencing identified compound heterozygous mutations in the recently discovered mitochondrial methionyl-tRNA formyltransferase (MTFMT) gene in two sisters with mild Leigh syndrome and combined respiratory chain deficiency. The mutations lead to undetectable levels of the MTFMT protein. Blue native polyacrylamide gel electrophoresis showed decreased complexes I and IV, and additional products stained with complex V antibodies, however the overall steady state level of mt-tRNA(Met) was normal. Our data illustrate that exome sequencing is an excellent diagnostic tool, and its value in clinical medicine is enormous, however it can only be optimally exploited if combined with detailed phenotyping and functional studies.
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The reciprocal cerebellar circuitry in human hereditary ataxia.
Cerebellum
PUBLISHED: 02-08-2013
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Clinicoanatomic correlation in the spinocerebellar ataxias (SCA) and Friedreichs ataxia (FRDA) is difficult as these diseases differentially affect multiple sites in the central and peripheral nervous systems. A new way to study cerebellar ataxia is the systematic analysis of the "reciprocal cerebellar circuitry" that consists of tightly organized reciprocal connections between Purkinje cells, dentate nuclei (DN), and inferior olivary nuclei (ION). This circuitry is similar to but not identical with the "cerebellar module" in experimental animals. Neurohumoral transmitters operating in the circuitry are both inhibitory (?-aminobutyric acid in corticonuclear and dentato-olivary fibers) and excitatory (glutamate in olivocerebellar or climbing fibers). Glutamatergic climbing fibers also issue collaterals to the DN. The present study applied five immunohistochemical markers in six types of SCA (1, 2, 3, 6, 7, 17), genetically undefined SCA, FRDA, and FRDA carriers to identify interruptions within the circuitry: calbindin-D28k, neuron-specific enolase, glutamic acid decarboxylase, and vesicular glutamate transporters 1 and 2. Lesions of the cerebellar cortex, DN, and ION were scored according to a guide as 0 (normal), 1 (mild), 2 (moderate), and 3 (severe). Results of each of the five immunohistochemical stains were examined separately for each of the three regions. Combining scores of each anatomical region and each stain yielded a total score as an indicator of pathological severity. Total scores ranged from 16 to 38 in SCA-1 (nine cases); 22 to 39 in SCA-2 (six cases); 9 to 15 in SCA-3 (four cases); and 13 and 25 in SCA-6 (two cases). In single cases of SCA-7 and SCA-17, scores were 16 and 31, respectively. In two genetically undefined SCA, scores were 36 and 37, respectively. In nine cases of FRDA, total scores ranged from 11 to 19. The low scores in SCA-3 and FRDA reflect selective atrophy of the DN. The FRDA carriers did not differ from normal controls. These observations offer a semiquantitative assessment of the critical role of the DN in the ataxic phenotype of SCA and FRDA while other parts of the circuitry appear less important.
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Healthcare use and costs associated with childrens behavior problems.
Eur Child Adolesc Psychiatry
PUBLISHED: 02-04-2013
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The objective of the study was to investigate associations between severity of behavior problems, specific symptom domains with healthcare use and costs in school-aged children. A cross-sectional study using data from the 10-year follow-up of two population-based birth cohorts was conducted on four rural and urban communities in Germany. There were 3,579 participants [1,834 boys (51%), 1,745 girls (49%)] on average aged 10.4 years. The severity levels (normal, at risk, abnormal) and symptom domains of behavioral problems were assessed by parent-reported strengths and difficulties questionnaire (SDQ).The outcomes were medical use categories (physicians, therapists, hospital, and rehabilitation), medical costs categories and total direct medical use and costs (calculated from parent-reported utilization of healthcare services during the last 12 months). Total direct medical costs showed a graded relationship with severity level (adjusted p < 0.0001). Average annual cost difference in total direct medical costs between at risk and normal total difficulties was Euro () 271 (SD 858), and 1,237 (SD 2,528) between abnormal and normal total difficulties. A significant increase in physician costs showed between children with normal and at risk total difficulties (1.30), and between normal and abnormal total difficulties (1.29; p < 0.0001). Between specific symptom domains, children with emotional symptoms showed highest costs for physicians, psychotherapist, and hospitalization as well as total direct medical costs. Children with hyperactivity/inattention showed highest costs for therapists and emergency room costs. Healthcare use and costs are related to the severity of child behavior problems. In general, childrens costs for psychotherapy treatments have been low relative to general medical treatments which may indicate that some children with behavioral problems did not get appropriate care. To some degree, medical conditions may be attributable to some of the high hospitalization costs found in children with emotional symptom.
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Tuning the magnetic properties of metal oxide nanocrystal heterostructures by cation exchange.
Nano Lett.
PUBLISHED: 02-04-2013
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For three types of colloidal magnetic nanocrystals, we demonstrate that postsynthetic cation exchange enables tuning of the nanocrystals magnetic properties and achieving characteristics not obtainable by conventional synthetic routes. While the cation exchange procedure, performed in solution phase approach, was restricted so far to chalcogenide based semiconductor nanocrystals, here ferrite-based nanocrystals were subjected to a Fe(2+) to Co(2+) cation exchange procedure. This allows tracing of the compositional modifications by systematic and detailed magnetic characterization. In homogeneous magnetite nanocrystals and in gold/magnetite core shell nanocrystals the cation exchange increases the coercivity field, the remanence magnetization, as well as the superparamagnetic blocking temperature. For core/shell nanoheterostructures a selective doping of either the shell or predominantly of the core with Co(2+) is demonstrated. By applying the cation exchange to FeO/CoFe(2)O(4) core/shell nanocrystals the Neél temperature of the core material is increased and exchange-bias effects are enhanced so that vertical shifts of the hysteresis loops are obtained which are superior to those in any other system.
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Association of atopic and non-atopic asthma with emotional symptoms in school children.
Pediatr Allergy Immunol
PUBLISHED: 01-29-2013
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To date, there is conflicting evidence whether the association between asthma and depression depends on the atopic or non-atopic asthma phenotype. This study investigates associations between emotional symptoms and atopic and non-atopic asthma in school-aged children.
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A functional IL-6 receptor (IL6R) variant is a risk factor for persistent atopic dermatitis.
J. Allergy Clin. Immunol.
PUBLISHED: 01-24-2013
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Atopic dermatitis (AD) is a common inflammatory skin disease. Previous studies have revealed shared genetic determinants among different inflammatory disorders, suggesting that markers associated with immune-related traits might also play a role in AD.
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Important miRs of pathways in different tumor types.
PLoS Comput. Biol.
PUBLISHED: 01-24-2013
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We computationally determined miRs that are significantly connected to molecular pathways by utilizing gene expression profiles in different cancer types such as glioblastomas, ovarian and breast cancers. Specifically, we assumed that the knowledge of physical interactions between miRs and genes indicated subsets of important miRs (IM) that significantly contributed to the regression of pathway-specific enrichment scores. Despite the different nature of the considered cancer types, we found strongly overlapping sets of IMs. Furthermore, IMs that were important for many pathways were enriched with literature-curated cancer and differentially expressed miRs. Such sets of IMs also coincided well with clusters of miRs that were experimentally indicated in numerous other cancer types. In particular, we focused on an overlapping set of 99 overall important miRs (OIM) that were found in glioblastomas, ovarian and breast cancers simultaneously. Notably, we observed that interactions between OIMs and leading edge genes of differentially expressed pathways were characterized by considerable changes in their expression correlations. Such gains/losses of miR and gene expression correlation indicated miR/gene pairs that may play a causal role in the underlying cancers.
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Exposure to road traffic noise and childrens behavioural problems and sleep disturbance: results from the GINIplus and LISAplus studies.
Environ. Res.
PUBLISHED: 01-23-2013
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Exposure to transportation noise showed negative health effects in children and adults. Studies in children mainly focussed on aircraft noise at school.
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Physical activity and its correlates in children: a cross-sectional study (the GINIplus & LISAplus studies).
BMC Public Health
PUBLISHED: 01-14-2013
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Physical inactivity among children is an increasing problem that adversely affects childrens health. A better understanding of factors which affect physical activity (PA) will help create effective interventions aimed at raising the activity levels of children. This cross-sectional study examined the associations of PA with individual (biological, social, behavioral, psychological) and environmental (East vs. West Germany, rural vs. urban regions) characteristics in children.
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A revised timescale for human evolution based on ancient mitochondrial genomes.
Curr. Biol.
PUBLISHED: 01-07-2013
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Recent analyses of de novo DNA mutations in modern humans have suggested a nuclear substitution rate that is approximately half that of previous estimates based on fossil calibration. This result has led to suggestions that major events in human evolution occurred far earlier than previously thought.
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Autosomal recessive spastic ataxia of Charlevoix Saguenay (ARSACS): expanding the genetic, clinical and imaging spectrum.
Orphanet J Rare Dis
PUBLISHED: 01-04-2013
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Mutations in SACS, leading to autosomal-recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), have been identified as a frequent cause of recessive early-onset ataxia around the world. Here we aimed to enlarge the spectrum of SACS mutations outside Quebec, to establish the pathogenicity of novel variants, and to expand the clinical and imaging phenotype.
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Body mass index trajectory classes and incident asthma in childhood: results from 8 European Birth Cohorts--a Global Allergy and Asthma European Network initiative.
J. Allergy Clin. Immunol.
PUBLISHED: 01-03-2013
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The causal link between body mass index (BMI) or obesity and asthma in children is still being debated. Analyses of large longitudinal studies with a sufficient number of incident cases and in which the time-dependent processes of both excess weight and asthma development can be validly analyzed are lacking.
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A longitudinal analysis of associations between traffic-related air pollution with asthma, allergies and sensitization in the GINIplus and LISAplus birth cohorts.
PeerJ
PUBLISHED: 01-01-2013
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Background. There is a need to study whether the adverse effects of traffic-related air pollution (TRAP) on childhood asthma and allergic diseases documented during early-life persist into later childhood. This longitudinal study examined whether TRAP is associated with the prevalence of asthma, allergic rhinitis and aeroallergen sensitization in two German cohorts followed from birth to 10 years. Materials. Questionnaire-derived annual reports of doctor diagnosed asthma and allergic rhinitis, as well as eye and nose symptoms, were collected from 6,604 children. Aeroallergen sensitization was assessed for 3,655 children who provided blood samples. Associations between these health outcomes and nitrogen dioxide (NO2), particles with aerodynamic diameters less than 2.5 µg/m(3) (PM2.5) mass, PM2.5 absorbance and ozone, individually estimated for each child at the birth, six and 10 year home addresses, were assessed using generalized estimation equations including adjustments for relevant covariates. Odds ratios [95% confidence intervals] per increase in interquartile range of pollutant are presented for the total population and per geographical area (GINI/LISA South, GINI/LISA North and LISA East, Germany). Results. The risk estimates for the total population were generally null across outcomes and pollutants. The area-specific results were heterogeneous. In GINI/LISA North, all associations were null. In LISA East, associations with ozone were elevated for all outcomes, and those for allergic rhinitis and eyes and nose symptom prevalence reached statistical significance (1.30 [1.02, 1.64] and 1.35 [1.16, 1.59], respectively). For GINI/LISA South, two associations with aeroallergen sensitization were significant (0.84 [0.73, 0.97] for NO2 and 0.87 [0.78, 0.97] for PM2.5 absorbance), as well as the association between allergic rhinitis and PM2.5 absorbance (0.83 [0.72, 0.96]). Conclusions. This study did not find consistent evidence that TRAP increases the prevalence of childhood asthma, allergic rhinitis or aeroallergen sensitization in later childhood using data from birth cohort participants followed for 10 years in three locations in Germany. Results were heterogeneous across the three areas investigated.
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De novo mutations in ataxin-2 gene and ALS risk.
PLoS ONE
PUBLISHED: 01-01-2013
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Pathogenic CAG repeat expansion in the ataxin-2 gene (ATXN2) is the genetic cause of spinocerebellar ataxia type 2 (SCA2). Recently, it has been associated with Parkinsonism and increased genetic risk for amyotrophic lateral sclerosis (ALS). Here we report the association of de novo mutations in ATXN2 with autosomal dominant ALS. These findings support our previous conjectures based on population studies on the role of large normal ATXN2 alleles as the source for new mutations being involved in neurodegenerative pathologies associated with CAG expansions. The de novo mutations expanded from ALS/SCA2 non-risk alleles as proven by meta-analysis method. The ALS risk was associated with SCA2 alleles as well as with intermediate CAG lengths in the ATXN2. Higher risk for ALS was associated with pathogenic CAG repeat as revealed by meta-analysis.
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Children with ADHD symptoms have a higher risk for reading, spelling and math difficulties in the GINIplus and LISAplus cohort studies.
PLoS ONE
PUBLISHED: 01-01-2013
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Attention-deficit/hyperactivity disorder (ADHD) and dyslexia belong to the most common neuro-behavioral childhood disorders with prevalences of around 5% in school-aged children. It is estimated that 20-60% of individuals affected with ADHD also present with learning disorders. We investigated the comorbidity between ADHD symptoms and reading/spelling and math difficulties in two on-going population-based birth cohort studies. Children with ADHD symptoms were at significantly higher risk of also showing reading/spelling difficulties or disorder (Odds Ratio (OR)?=?2.80, p?=?6.59×10?¹³) as compared to children without ADHD symptoms. For math difficulties the association was similar (OR?=?2.55, p?=?3.63×10???). Our results strengthen the hypothesis that ADHD and learning disorders are comorbid and share, at least partially, the same underlying process. Up to date, it is not clear, on which exact functional processes this comorbidity is based.
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Genetic ablation and chemical inhibition of IP3R1 reduce mutant huntingtin aggregation.
Biochem. Biophys. Res. Commun.
PUBLISHED: 10-19-2011
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Huntingtons disease (HD) is a dominantly inherited neurodegenerative disease caused by an expansion of the polyglutamine (polyQ) stretch in huntingtin (htt). Previously, it has been shown that inhibition of the inositol 1,4,5-trisphosphate receptor type 1 (IP3R1) activity reduced aggregation of pathogenic polyQ proteins. Experimentally, this effect was achieved by modification of the intracellular IP3 levels or by application of IP3R1 inhibitors, such as 2-aminoethyl diphenylborinate (2-APB). Unfortunately, there are certain concerns about the 2-APB specificity and cytotoxicity. Moreover, a direct link between IP3R1 and polyQ aggregation has not been shown yet. In this study we show, that down-regulation of the IP3R1 levels by shRNA reduced the aggregation of mutant htt. We tested 2-APB analogs in an attempt to identify less toxic and more IP3R1-specific compounds and found that the effect of these analogs on the reduction of the mutant htt aggregation did weakly correlate with their inhibitory action toward the IP3-induced Ca(2+) release (IICR). Their effect on aggregation was not correlated with the store-operated Ca(2+) entry (SOCE), which is another target of the 2-APB related compounds. Our findings suggest that besides functional contribution of the IP3R inhibition on the mutant htt aggregation there are additional mechanisms for the anti-aggregation effect of the 2-APB related compounds.
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Discrepancies in reporting the CAG repeat lengths for Huntingtons disease.
Eur. J. Hum. Genet.
PUBLISHED: 08-03-2011
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Huntingtons disease results from a CAG repeat expansion within the Huntingtin gene; this is measured routinely in diagnostic laboratories. The European Huntingtons Disease Network REGISTRY project centrally measures CAG repeat lengths on fresh samples; these were compared with the original results from 121 laboratories across 15 countries. We report on 1326 duplicate results; a discrepancy in reporting the upper allele occurred in 51% of cases, this reduced to 13.3% and 9.7% when we applied acceptable measurement errors proposed by the American College of Medical Genetics and the Draft European Best Practice Guidelines, respectively. Duplicate results were available for 1250 lower alleles; discrepancies occurred in 40% of cases. Clinically significant discrepancies occurred in 4.0% of cases with a potential unexplained misdiagnosis rate of 0.3%. There was considerable variation in the discrepancy rate among 10 of the countries participating in this study. Out of 1326 samples, 348 were re-analysed by an accredited diagnostic laboratory, based in Germany, with concordance rates of 93% and 94% for the upper and lower alleles, respectively. This became 100% if the acceptable measurement errors were applied. The central laboratory correctly reported allele sizes for six standard reference samples, blind to the known result. Our study differs from external quality assessment (EQA) schemes in that these are duplicate results obtained from a large sample of patients across the whole diagnostic range. We strongly recommend that laboratories state an error rate for their measurement on the report, participate in EQA schemes and use reference materials regularly to adjust their own internal standards.
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How many spots with missing values can be tolerated in quantitative two-dimensional gel electrophoresis when applying univariate statistics?
J Proteomics
PUBLISHED: 08-02-2011
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Quantitative proteomic comparisons require a sufficient number of samples to reach an acceptable level of significance. But 2D gel electrophoresis commonly results in incomplete data sets due to spots with missing values reducing thereby the number of parallel measurements for individual proteins. Here we investigated how many missing values per spot can be tolerated. The number of spots in common between all gels was found to decrease with the number of parallel gels in a non-linear fashion. Increasing numbers of missing values were associated with a moderate increase in the quantitative variation of spot volumes. Based on the missing value pattern in 20 gels we performed an analysis of the multiple testing power for the hypothetical scenario of a comparative 2DE study with six or twelve parallel gels. The calculation considered the statistical power of the individual spot as well as the number of spots included in the analysis. The power increased with inclusion of spots with higher number of missing values and showed an optimum at a specific minimum number of spot replicates. The results suggest that proteins with missing values can be included in a univariate analysis as long as a sufficient number of parallel gels are made.
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A draft genome of Yersinia pestis from victims of the Black Death.
Nature
PUBLISHED: 07-25-2011
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Technological advances in DNA recovery and sequencing have drastically expanded the scope of genetic analyses of ancient specimens to the extent that full genomic investigations are now feasible and are quickly becoming standard. This trend has important implications for infectious disease research because genomic data from ancient microbes may help to elucidate mechanisms of pathogen evolution and adaptation for emerging and re-emerging infections. Here we report a reconstructed ancient genome of Yersinia pestis at 30-fold average coverage from Black Death victims securely dated to episodes of pestilence-associated mortality in London, England, 1348-1350. Genetic architecture and phylogenetic analysis indicate that the ancient organism is ancestral to most extant strains and sits very close to the ancestral node of all Y. pestis commonly associated with human infection. Temporal estimates suggest that the Black Death of 1347-1351 was the main historical event responsible for the introduction and widespread dissemination of the ancestor to all currently circulating Y. pestis strains pathogenic to humans, and further indicates that contemporary Y. pestis epidemics have their origins in the medieval era. Comparisons against modern genomes reveal no unique derived positions in the medieval organism, indicating that the perceived increased virulence of the disease during the Black Death may not have been due to bacterial phenotype. These findings support the notion that factors other than microbial genetics, such as environment, vector dynamics and host susceptibility, should be at the forefront of epidemiological discussions regarding emerging Y. pestis infections.
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Epigenetics DNA methylation in the core ataxin-2 gene promoter: novel physiological and pathological implications.
Hum. Genet.
PUBLISHED: 07-15-2011
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Pathogenic CAG (cytosine-adenine-guanine) expansions beyond certain thresholds in the ataxin-2 (ATXN2) gene cause spinocerebellar ataxia type 2 (SCA2) and were shown to contribute to Parkinson disease, amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Regulation of ATXN2 gene expression and the function of the protein product are not known. SCA2 exhibits an inverse correlation between the size of the CAG repeat and the age at disease onset. However, a wide range of age at onset are typically observed, with CAG repeat number alone explaining only partly this variability. In this study, we explored the hypothesis that ATXN2 levels could be controlled by DNA methylation and that the derangement of this control may lead to escalation of disease severity and influencing the age at onset. We found that CpG methylation in human ATXN2 gene promoter is associated with pathogenic CAG expansions in SCA2 patients. Different levels of methylation in a SCA2 pedigree without an intergenerational CAG repeat instability caused the disease anticipation in a SCA2 family. DNA methylation also influenced the disease onset in SCA2 homozygotes and SCA3 patients. In conclusion, our study points to a novel regulatory mechanism of ATXN2 expression involving an epigenetic event resulting in differential disease course in SCA2 patients.
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Predictive value of food sensitization and filaggrin mutations in children with eczema.
J. Allergy Clin. Immunol.
PUBLISHED: 07-15-2011
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It was reported that in infants with eczema and food sensitization, the presence of a filaggrin (FLG) null mutation predicts future asthma with a specificity and positive predictive value of 100%.
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What is Visualize?

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

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In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.