•DPE is a known genotoxic carcingogen.•No increases in DNA migration observed in liver in the rat comet assay.•Dose-dependent decrease in DNA migration observed in stomach tissue in the rat comet ...assay.•Further mechanistic understanding required to explain decrease in DNA migration in stomach tissue.
As a part of the Japanese Center for the Validation of Alternative Methods (JaCVAM)-initiative international validation study of the in vivo rat alkaline comet assay, 4,4′-diaminodiphenyl ether (DPE), a known rodent genotoxic carcinogen, was tested in this laboratory. Sprague Dawley rats (7–9 weeks of age) were given three oral doses of DPE, 24 and 21h apart and liver or stomach sampled 3h after the final dose. Under the conditions of the test, no increases in DNA damage in liver and stomach were observed with DPE (up to 200mg/kg/day). A dose-dependent decrease in DNA migration, compared to vehicle controls, was noted for DPE in rat stomach. Further analysis is required to elucidate fully whether this decrease is a consequence of the mode of action or due to the toxicity of DPE. What is perhaps surprising is the inability of the comet assay to detect a known rat genotoxic carcinogen in liver. Further investigation is needed to clarify whether this apparent lack of response results from limited tissue exposure or metabolic differences between species. This finding highlights a need for careful consideration of study design when evaluating assay performance as a measure of in vivo genotoxicity.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
About 35% of patients with 22q11 deletion syndrome (22q11DS), which includes DiGeorge and velocardiofacial syndromes, develops psychiatric disorders, mainly schizophrenia and bipolar disorder. We ...previously reported that mice carrying a multigene deletion (Dfl) that models 22q11DS have reduced prepulse inhibition (PPI), a behavioral abnormality and schizophrenia endophenotype. Impaired PPI is associated with several psychiatric disorders, including those that occur in 22q11DS, and recently, reduced PPI was reported in children with 22q11DS. Here, we have mapped PPI deficits in a panel of mouse mutants that carry deletions that partially overlap with Dfl and have defined a PPI critical region encompassing four genes. We then used single-gene mutants to identify the causative genes. We show that PPI deficits in Dfl/+ mice are caused by haploinsufficiency of two genes, Tbxl and Gnbll. Mutation of either gene is sufficient to cause reduced PPI. Tbxl is a transcription factor, the mutation of which is sufficient to cause most of the physical features of 22q11DS, but the gene had not been previously associated with the behavioral/psychiatric phenotype. A likely role for Tbxl haploinsufficiency in psychiatric disease is further suggested by the identification of a family in which the phenotypic features of 22q11DS, including psychiatric disorders, segregate with an inactivating mutation of TBX1. One family member has Asperger syndrome, an autistic spectrum disorder that is associated with reduced PPI. Thus, Tbxl and Gnbll are strong candidates for psychiatric disease in 22q11DS patients and candidate susceptibility genes for psychiatric disease in the wider population.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Despite numerous healthy eating campaigns, the prevalence of diets high in saturated fatty acids, sugar, and salt and low in fiber, fruit, and vegetables remains high. With more people than ever ...accessing the Internet, Web-based dietary assessment instruments have the potential to promote healthier dietary behaviors via personalized dietary advice.
The objectives of this study were to develop a dietary feedback system for the delivery of consistent personalized dietary advice in a multicenter study and to examine the impact of automating the advice system.
The development of the dietary feedback system included 4 components: (1) designing a system for categorizing nutritional intakes; (2) creating a method for prioritizing 3 nutrient-related goals for subsequent targeted dietary advice; (3) constructing decision tree algorithms linking data on nutritional intake to feedback messages; and (4) developing personal feedback reports. The system was used manually by researchers to provide personalized nutrition advice based on dietary assessment to 369 participants during the Food4Me randomized controlled trial, with an automated version developed on completion of the study.
Saturated fatty acid, salt, and dietary fiber were most frequently selected as nutrient-related goals across the 7 centers. Average agreement between the manual and automated systems, in selecting 3 nutrient-related goals for personalized dietary advice across the centers, was highest for nutrient-related goals 1 and 2 and lower for goal 3, averaging at 92%, 87%, and 63%, respectively. Complete agreement between the 2 systems for feedback advice message selection averaged at 87% across the centers.
The dietary feedback system was used to deliver personalized dietary advice within a multi-country study. Overall, there was good agreement between the manual and automated feedback systems, giving promise to the use of automated systems for personalizing dietary advice.
Clinicaltrials.gov NCT01530139; https://clinicaltrials.gov/ct2/show/NCT01530139 (Archived by WebCite at http://www.webcitation.org/6ht5Dgj8I).
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Management of eosinophilic esophagitis (EoE) requires repeated endoscopic collection of mucosal samples to assess disease activity and response to therapy. An easier and less expensive means of ...monitoring of EoE is required. We compared the accuracy, safety, and tolerability of sample collection via Cytosponge (an ingestible gelatin capsule comprising compressed mesh attached to a string) with those of endoscopy for assessment of EoE.
Esophageal tissues were collected from 20 patients with EoE (all with dysphagia, 15 with stricture, 13 with active EoE) via Cytosponge and then by endoscopy. Number of eosinophils/high-power field and levels of eosinophil-derived neurotoxin were determined; hematoxylin-eosin staining was performed. We compared the adequacy, diagnostic accuracy, safety, and patient preference for sample collection via Cytosponge vs endoscopy procedures.
All 20 samples collected by Cytosponge were adequate for analysis. By using a cutoff value of 15 eosinophils/high power field, analysis of samples collected by Cytosponge identified 11 of the 13 individuals with active EoE (83%); additional features such as abscesses were also identified. Numbers of eosinophils in samples collected by Cytosponge correlated with those in samples collected by endoscopy (r = 0.50, P = .025). Analysis of tissues collected by Cytosponge identified 4 of the 7 patients without active EoE (57% specificity), as well as 3 cases of active EoE not identified by analysis of endoscopy samples. Including information on level of eosinophil-derived neurotoxin did not increase the accuracy of diagnosis. No complications occurred during the Cytosponge procedure, which was preferred by all patients, compared with endoscopy.
In a feasibility study, the Cytosponge is a safe and well-tolerated method for collecting near mucosal specimens. Analysis of numbers of eosinophils/high-power field identified patients with active EoE with 83% sensitivity. Larger studies are needed to establish the efficacy and safety of this method of esophageal tissue collection. ClinicalTrials.gov number: NCT01585103.
Since 2012, the United States of America has experienced a biennial spike in pediatric acute flaccid myelitis (AFM)
. Epidemiologic evidence suggests non-polio enteroviruses (EVs) are a potential ...etiology, yet EV RNA is rarely detected in cerebrospinal fluid (CSF)
. CSF from children with AFM (n = 42) and other pediatric neurologic disease controls (n = 58) were investigated for intrathecal antiviral antibodies, using a phage display library expressing 481,966 overlapping peptides derived from all known vertebrate and arboviruses (VirScan). Metagenomic next-generation sequencing (mNGS) of AFM CSF RNA (n = 20 cases) was also performed, both unbiased sequencing and with targeted enrichment for EVs. Using VirScan, the viral family significantly enriched by the CSF of AFM cases relative to controls was Picornaviridae, with the most enriched Picornaviridae peptides belonging to the genus Enterovirus (n = 29/42 cases versus 4/58 controls). EV VP1 ELISA confirmed this finding (n = 22/26 cases versus 7/50 controls). mNGS did not detect additional EV RNA. Despite rare detection of EV RNA, pan-viral serology frequently identified high levels of CSF EV-specific antibodies in AFM compared with controls, providing further evidence for a causal role of non-polio EVs in AFM.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
We have conducted a genotyping study using a custom Illumina Infinium HD genotyping array, the ImmunoChip, in a new UK sample of 1,218 bipolar disorder cases and 2,913 controls that have not been ...used in any studies previously reported independently or in meta-analyses. The ImmunoChip was designed prior to the publication of the Psychiatric GWAS Consortium Bipolar Disorder Working Group (PGC-BD) meta-analysis data. As such 3106 SNPs with a P value less than 1×10
−3
from the bipolar disorder meta-analysis by Ferreira
et al
., 2008 were genotyped. We report support for two of the three most strongly associated chromosomal regions in the Ferreira study,
CACNA1C
(rs1006737, p=4.09×10
−4
) and 15q14 (rs2172835, p=0.043) but not
ANK3
(rs10994336, p=0.912). We have combined our ImmunoChip data (569 quasi-independent SNPs from the 3016 SNPs genotyped) with the recently published PGC-BD meta-analysis data, using either the PGC-BD combined discovery and replication data where available or just the discovery data where the SNP was not typed in a replication sample in PGC-BD. Our data provide support for two regions, at
ODZ4
and
CACNA1C,
with prior evidence for genome-wide significant association in PGC-BD meta-analysis. In addition, the combined analysis shows two novel genome-wide significant associations. First, rs7296288 (P = 8.97 × 10
−9
, OR = 0.9), an intergenic polymorphism on chromosome 12 located between
RHEBL1
and
DHH
. Secondly, rs3818253 (P = 3.88 × 10
−8
, OR = 1.16), an intronic SNP on chromosome 20q11.2 in the gene
TRPC4AP
which lies in a high linkage disequilibrium region along with the genes
GSS
and
MYH7B
.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
We describe implementation of a set-based method to assess the significance of findings from genome-wide association study data. Our method, implemented in PLINK, is based on theoretical ...approximation of Fisher’s statistics such that the combination of p-vales at a gene or across a pathway are done in a manner that accounts for the correlation structure, or linkage disequilibrium, between SNPs. We compare our method to a permutation based product of p-values approach and show a typical correlation in excess of 0.98 for a number of comparisons. The method gives Type I error rates that are less than or equal to the corresponding nominal significance levels, making it robust to the effects of false positives. We show that in broadly similar populations, reference datasets of markers are an appropriate substrate for deriving marker-marker LD, negating the need to access individual level genotypes, greatly facilitating its generic applicability. We show that the method is thus robust to LD-associated bias and has equivalent performance to permutation-based methods, with a significantly shorter runtime. This is particularly relevant at a time of increasing public availability of significantly larger genetic datasets and should go a long way to assist in the rapid analysis of these datasets.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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