Meningitis due to Fusobacterium necrophorum in an adult

BACKGROUND: Fusobacterium necrophorum may cause a number of clinical syndromes, collectively known as necrobacillosis. Meningitis is a significant cause of mortality, rarely reported in the adult population. CASE PRESENTATION: We report a fatal case of meningitis, caused by Fusobacterium necrophorum, secondary to otitis media in an alcoholic male. Diagnosis was delayed due to the typical slow growth of the organism. The clinical course was complicated by encephalitis and by hydrocephalus. The patient failed to respond to metronidazole and penicillin. The patient died on day 12 from increased intracranial pressure and brain stem infarction. CONCLUSIONS: This case emphasizes the need for a high index of clinical suspicion to make the diagnosis of Fusobacterium necrophorum meningitis. We recommend the use of appropriate anaerobic culture techniques and antimicrobial coverage for anaerobic organisms when the gram stain shows gram negative bacilli

The influence of semantic and phonological factors on syntactic decisions: An event-related brain potential study

During language production and comprehension, information about a word's syntactic properties is sometimes needed. While the decision about the grammatical gender of a word requires access to syntactic knowledge, it has also been hypothesized that semantic (i.e., biological gender) or phonological information (i.e., sound regularities) may influence this decision. Event-related potentials (ERPs) were measured while native speakers of German processed written words that were or were not semantically and/or phonologically marked for gender. Behavioral and ERP results showed that participants were faster in making a gender decision when words were semantically and/or phonologically gender marked than when this was not the case, although the phonological effects were less clear. In conclusion, our data provide evidence that even though participants performed a grammatical gender decision, this task can be influenced by semantic and phonological factors

A Common Complement C3 Variant Is Associated with Protection against Wet Age-Related Macular Degeneration in a Japanese Population

博士（医学）神戸大

Using genetic variation and environmental risk factor data to identify individuals at high risk for age-related macular degeneration

A major goal of personalized medicine is to pre-symptomatically identify individuals at high risk for disease using knowledge of each individual's particular genetic profile and constellation of environmental risk factors. With the identification of several well-replicated risk factors for age-related macular degeneration (AMD), the leading cause of legal blindness in older adults, this previously unreachable goal is beginning to seem less elusive. However, recently developed algorithms have either been much less accurate than expected, given the strong effects of the identified risk factors, or have not been applied to independent datasets, leaving unknown how well they would perform in the population at large. We sought to increase accuracy by using novel modeling strategies, including multifactor dimensionality reduction (MDR) and grammatical evolution of neural networks (GENN), in addition to the traditional logistic regression approach. Furthermore, we rigorously designed and tested our models in three distinct datasets: a Vanderbilt-Miami (VM) clinic-based case-control dataset, a VM family dataset, and the population-based Age-related Maculopathy Ancillary (ARMA) Study cohort. Using a consensus approach to combine the results from logistic regression and GENN models, our algorithm was successful in differentiating between high- and low-risk groups (sensitivity 77.0%, specificity 74.1%). In the ARMA cohort, the positive and negative predictive values were 63.3% and 70.7%, respectively. We expect that future efforts to refine this algorithm by increasing the sample size available for model building, including novel susceptibility factors as they are discovered, and by calibrating the model for diverse populations will improve accuracy

Genetic and Functional Dissection of HTRA1 and LOC387715 in Age-Related Macular Degeneration

A common haplotype on 10q26 influences the risk of age-related macular degeneration (AMD) and encompasses two genes, LOC387715 and HTRA1. Recent data have suggested that loss of LOC387715, mediated by an insertion/deletion (in/del) that destabilizes its message, is causally related with the disorder. Here we show that loss of LOC387715 is insufficient to explain AMD susceptibility, since a nonsense mutation (R38X) in this gene that leads to loss of its message resides in a protective haplotype. At the same time, the common disease haplotype tagged by the in/del and rs11200638 has an effect on the transcriptional upregulation of the adjacent gene, HTRA1. These data implicate increased HTRA1 expression in the pathogenesis of AMD and highlight the importance of exploring multiple functional consequences of alleles in haplotypes that confer susceptibility to complex traits

Evaluation of Clustering and Genotype Distribution for Replication in Genome Wide Association Studies: The Age-Related Eye Disease Study

Genome-wide association studies (GWASs) assess correlation between traits and DNA sequence variation using large numbers of genetic variants such as single nucleotide polymorphisms (SNPs) distributed across the genome. A GWAS produces many trait-SNP associations with low p-values, but few are replicated in subsequent studies. We sought to determine if characteristics of the genomic loci associated with a trait could be used to identify initial associations with a higher chance of replication in a second cohort. Data from the age-related eye disease study (AREDS) of 100,000 SNPs on 395 subjects with and 198 without age-related macular degeneration (AMD) were employed. Loci highly associated with AMD were characterized based on the distribution of genotypes, level of significance, and clustering of adjacent SNPs also associated with AMD suggesting linkage disequilibrium or multiple effects. Forty nine loci were highly associated with AMD, including 3 loci (CFH, C2/BF, LOC387715/HTRA1) already known to contain important genetic risks for AMD. One additional locus (C3) reported during the course of this study was identified and replicated in an additional study group. Tag-SNPs and haplotypes for each locus were evaluated for association with AMD in additional cohorts to account for population differences between discovery and replication subjects, but no additional clearly significant associations were identified. Relying on a significant genotype tests using a log-additive model would have excluded 57% of the non-replicated and none of the replicated loci, while use of other SNP features and clustering might have missed true associations

A review of elliptical and disc galaxy structure, and modern scaling laws

A century ago, in 1911 and 1913, Plummer and then Reynolds introduced their models to describe the radial distribution of stars in `nebulae'. This article reviews the progress since then, providing both an historical perspective and a contemporary review of the stellar structure of bulges, discs and elliptical galaxies. The quantification of galaxy nuclei, such as central mass deficits and excess nuclear light, plus the structure of dark matter halos and cD galaxy envelopes, are discussed. Issues pertaining to spiral galaxies including dust, bulge-to-disc ratios, bulgeless galaxies, bars and the identification of pseudobulges are also reviewed. An array of modern scaling relations involving sizes, luminosities, surface brightnesses and stellar concentrations are presented, many of which are shown to be curved. These 'redshift zero' relations not only quantify the behavior and nature of galaxies in the Universe today, but are the modern benchmark for evolutionary studies of galaxies, whether based on observations, N-body-simulations or semi-analytical modelling. For example, it is shown that some of the recently discovered compact elliptical galaxies at 1.5 < z < 2.5 may be the bulges of modern disc galaxies.Comment: Condensed version (due to Contract) of an invited review article to appear in "Planets, Stars and Stellar Systems"(www.springer.com/astronomy/book/978-90-481-8818-5). 500+ references incl. many somewhat forgotten, pioneer papers. Original submission to Springer: 07-June-201

The NEI/NCBI dbGAP database: Genotypes and haplotypes that may specifically predispose to risk of neovascular age-related macular degeneration

<p>Abstract</p> <p>Background</p> <p>To examine if the significantly associated SNPs derived from the genome wide allelic association study on the AREDS cohort at the NEI (dbGAP) specifically confer risk for neovascular age-related macular degeneration (AMD). We ascertained 134 unrelated patients with AMD who had one sibling with an AREDS classification 1 or less and was past the age at which the affected sibling was diagnosed (268 subjects). Genotyping was performed by both direct sequencing and Sequenom iPLEX system technology. Single SNP analyses were conducted with McNemar's Test (both 2 × 2 and 3 × 3 tests) and likelihood ratio tests (LRT). Conditional logistic regression was used to determine significant gene-gene interactions. LRT was used to determine the best fit for each genotypic model tested (additive, dominant or recessive).</p> <p>Results</p> <p>Before release of individual data, <it>p</it>-value information was obtained directly from the AREDS dbGAP website. Of the 35 variants with <it>P </it>< 10^-6examined, 23 significantly modified risk of neovascular AMD. Many variants located in tandem on 1q32-q22 including those in <it>CFH</it>, <it>CFHR4</it>, <it>CFHR2</it>, <it>CFHR5</it>, <it>F13B</it>, <it>ASPM </it>and <it>ZBTB </it>were significantly associated with AMD risk. Of these variants, single SNP analysis revealed that <it>CFH </it>rs572515 was the most significantly associated with AMD risk (P < 10^-6). Haplotype analysis supported our findings of single SNP association, demonstrating that the most significant haplotype, GATAGTTCTC, spanning <it>CFH</it>, <it>CFHR4</it>, and <it>CFHR2 </it>was associated with the greatest risk of developing neovascular AMD (<it>P </it>< 10^-6). Other than variants on 1q32-q22, only two SNPs, rs9288410 (<it>MAP2</it>) on 2q34-q35 and rs2014307 (<it>PLEKHA1</it>/<it>HTRA1</it>) on 10q26 were significantly associated with AMD status (<it>P </it>= .03 and <it>P </it>< 10^-6respectively). After controlling for smoking history, gender and age, the most significant gene-gene interaction appears to be between rs10801575 (<it>CFH</it>) and rs2014307 (<it>PLEKHA1</it>/<it>HTRA1</it>) (<it>P </it>< 10^-11). The best genotypic fit for rs10801575 and rs2014307 was an additive model based on LRT. After applying a Bonferonni correction, no other significant interactions were identified between any other SNPs.</p> <p>Conclusion</p> <p>This is the first replication study on the NEI dbGAP SNPs, demonstrating that alleles on 1q, 2q and 10q may predispose an individual to AMD.</p

C2 and CFB Genes in Age-Related Maculopathy and Joint Action with CFH and LOC387715 Genes

Background: Age-related maculopathy (ARM) is a common cause of visual impairment in the elderly populations of industrialized countries and significantly affects the quality of life of those suffering from the disease. Variants within two genes, the complement factor H (CFH) and the poorly characterized LOC387715 (ARMS2), are widely recognized as ARM risk factors. CFH is important in regulation of the alternative complement pathway suggesting this pathway is involved in ARM pathogenesis. Two other complement pathway genes, the closely linked complement component receptor (C2) and complement factor B (CFB), were recently shown to harbor variants associated with ARM. Methods/Principal Findings: We investigated two SNPs in C2 and two in CFB in independent case-control and family cohorts of white subjects and found rs547154, an intronic SNP in C2, to be significantly associated with ARM in both our case-control (P-value 0.00007) and family data (P-value 0.00001). Logistic regression analysis suggested that accounting for the effect at this locus significantly (P-value 0.002) improves the fit of a genetic risk model of CFH and LOC387715 effects only. Modeling with the generalized multifactor dimensionality reduction method showed that adding C2 to the two-factor model of CFH and LOC387715 increases the sensitivity (from 63% to 73%). However, the balanced accuracy increases only from 71% to 72%, and the specificity decreases from 80% to 72%. Conclusions/Significance: C2/CFB significantly influences AMD susceptibility and although accounting for effects at this locus does not dramatically increase the overall accuracy of the genetic risk model, the improvement over the CFH-LOC387715 model is statistically significant. © 2008 Jakobsdottir et al

Density of Common Complex Ocular Traits in the Aging Eye: Analysis of Secondary Traits in Genome-Wide Association Studies

Genetic association studies are identifying genetic risks for common complex ocular traits such as age-related macular degeneration (AMD). The subjects used for discovery of these loci have been largely from clinic-based, case-control studies. Typically, only the primary phenotype (e.g., AMD) being studied is systematically documented and other complex traits (e.g., affecting the eye) are largely ignored. The purpose of this study was to characterize these other or secondary complex ocular traits present in the cases and controls of clinic-based studies being used for genetic study of AMD. The records of 100 consecutive new patients (of any diagnosis) age 60 or older for which all traits affecting the eye had been recorded systematically were reviewed. The average patient had 3.5 distinct diagnoses. A subset of 10 complex traits was selected for further study because they were common and could be reliably diagnosed. The density of these 10 complex ocular traits increased by 0.017 log-traits/year (P = 0.03), ranging from a predicted 2.74 at age 60 to 4.45 at age 90. Trait-trait association was observed only between AMD and primary vitreomacular traction (P = 0.0009). Only 1% of subjects age 60 or older had no common complex traits affecting the eye. Extrapolations suggested that a study of 2000 similar subjects would have sufficient power to detect genetic association with an odds ratio of 2.0 or less for 4 of these 10 traits. In conclusion, the high prevalence of complex traits affecting the aging eye and the inherent biases in referral patterns leads to the potential for confounding by undocumented secondary traits within case-control studies. In addition to the primary trait, other common ocular phenotypes should be systematically documented in genetic association studies so that adjustments for potential trait-trait associations and other bias can be made and genetic risk variants identified in secondary analyses