Dissemination of Strongyloides stercoralis in a patient with systemic lupus erythematosus after initiation of albendazole: a case report

<p>Abstract</p> <p>Introduction</p> <p><it>Strongyloides stercoralis </it>infection affects hundreds of millions of people worldwide. As immigration rates and international travel increase, so does the number of cases of strongyloidiasis in the United States. Although described both in immigrant and in immunosuppressed populations, hyperinfection and dissemination of <it>S. stercoralis </it>following the initiation of antiparasitic medication is a previously unreported phenomenon.</p> <p>Case presentation</p> <p>Here we describe the case of a 38-year-old immunocompromised woman with systemic lupus erythematosus, who developed disseminated disease following treatment with albendazole (400 mg every 12 hours). Notably the patient was receiving oral prednisone (10 mg once daily), azathioprine (50 mg twice daily), and hydroxychloroquine (400 mg daily) at the time of hospitalization. The patient was subsequently treated successfully with ivermectin (200 mcg/kg daily).</p> <p>Conclusion</p> <p>The reader should be aware that dissemination of <it>S. stercoralis </it>can occur even after the initiation of antiparasitic medication.</p

Rpgrip1 is required for rod outer segment development and ciliary protein trafficking in zebrafish

The authors would like to thank the Royal Society of London, the National Eye Research Centre, the Visual Research Trust, Fight for Sight, the W.H. Ross Foundation, the Rosetrees Trust, and the Glasgow Children’s Hospital Charity for supporting this work. This work was also supported by the Deanship of Scientific Research at King Saud University for funding this research (Research Project) grant number ‘RGP – VPP – 219’.Mutations in the RPGR-interacting protein 1 (RPGRIP1) gene cause recessive Leber congenital amaurosis (LCA), juvenile retinitis pigmentosa (RP) and cone-rod dystrophy. RPGRIP1 interacts with other retinal disease-causing proteins and has been proposed to have a role in ciliary protein transport; however, its function remains elusive. Here, we describe a new zebrafish model carrying a nonsense mutation in the rpgrip1 gene. Rpgrip1homozygous mutants do not form rod outer segments and display mislocalization of rhodopsin, suggesting a role for RPGRIP1 in rhodopsin-bearing vesicle trafficking. Furthermore, Rab8, the key regulator of rhodopsin ciliary trafficking, was mislocalized in photoreceptor cells of rpgrip1 mutants. The degeneration of rod cells is early onset, followed by the death of cone cells. These phenotypes are similar to that observed in LCA and juvenile RP patients. Our data indicate RPGRIP1 is necessary for rod outer segment development through regulating ciliary protein trafficking. The rpgrip1 mutant zebrafish may provide a platform for developing therapeutic treatments for RP patients.Publisher PDFPeer reviewe

Reconstruction and analysis of genome-scale metabolic model of a photosynthetic bacterium

<p>Abstract</p> <p>Background</p> <p><it>Synechocystis </it>sp. PCC6803 is a cyanobacterium considered as a candidate photo-biological production platform - an attractive cell factory capable of using CO₂and light as carbon and energy source, respectively. In order to enable efficient use of metabolic potential of <it>Synechocystis </it>sp. PCC6803, it is of importance to develop tools for uncovering stoichiometric and regulatory principles in the <it>Synechocystis </it>metabolic network.</p> <p>Results</p> <p>We report the most comprehensive metabolic model of <it>Synechocystis </it>sp. PCC6803 available, <it>i</it>Syn669, which includes 882 reactions, associated with 669 genes, and 790 metabolites. The model includes a detailed biomass equation which encompasses elementary building blocks that are needed for cell growth, as well as a detailed stoichiometric representation of photosynthesis. We demonstrate applicability of <it>i</it>Syn669 for stoichiometric analysis by simulating three physiologically relevant growth conditions of <it>Synechocystis </it>sp. PCC6803, and through <it>in silico </it>metabolic engineering simulations that allowed identification of a set of gene knock-out candidates towards enhanced succinate production. Gene essentiality and hydrogen production potential have also been assessed. Furthermore, <it>i</it>Syn669 was used as a transcriptomic data integration scaffold and thereby we found metabolic hot-spots around which gene regulation is dominant during light-shifting growth regimes.</p> <p>Conclusions</p> <p><it>i</it>Syn669 provides a platform for facilitating the development of cyanobacteria as microbial cell factories.</p

Age-dependent changes in intervertebral disc cell mitochondria and bioenergetics

Robust cellular bioenergetics is vital in the energy-demanding process of maintaining matrix homeostasis in the intervertebral disc. Age-related decline in disc cellular bioenergetics is hypothesised to contribute to the matrix homeostatic perturbation observed in intervertebral disc degeneration. The present study aimed to measure how ageing impacted disc cell mitochondria and bioenergetics. Age-related changes measured included matrix content and cellularity in disc tissue, as well as matrix synthesis, cell proliferation and senescence markers in cell cultures derived from annulus fibrosus (AF) and nucleus pulposus (NP) isolated from the discs of young (6-9 months) and older (36-50 months) New Zealand White rabbits. Cellular bioenergetic parameters were measured using a Seahorse XFe96 Analyzer, in addition to quantitating mitochondrial morphological changes and membrane potential. Ageing reduced mitochondrial number and membrane potential in both cell types. Also, it significantly reduced glycolytic capacity, mitochondrial reserve capacity, maximum aerobic capacity and non-glucose-dependent respiration in NP. Moreover, NP cells exhibited age-related decline in matrix synthesis and reduced cellularity in older tissues. Despite a lack of changes in mitochondrial respiration with age, AF cells showed an increase in glycolysis and altered matrix production. While previous studies report age-related matrix degenerative changes in disc cells, the present study revealed, for the first time, that ageing affected mitochondrial number and function, particularly in NP cells. Consequently, age-related bioenergetic changes may contribute to the functional alterations in aged NP cells that underlie disc degeneration

FastTagger: an efficient algorithm for genome-wide tag SNP selection using multi-marker linkage disequilibrium

<p>Abstract</p> <p>Background</p> <p>Human genome contains millions of common single nucleotide polymorphisms (SNPs) and these SNPs play an important role in understanding the association between genetic variations and human diseases. Many SNPs show correlated genotypes, or linkage disequilibrium (LD), thus it is not necessary to genotype all SNPs for association study. Many algorithms have been developed to find a small subset of SNPs called tag SNPs that are sufficient to infer all the other SNPs. Algorithms based on the <it>r</it>²LD statistic have gained popularity because <it>r</it>²is directly related to statistical power to detect disease associations. Most of existing <it>r</it>²based algorithms use pairwise LD. Recent studies show that multi-marker LD can help further reduce the number of tag SNPs. However, existing tag SNP selection algorithms based on multi-marker LD are both time-consuming and memory-consuming. They cannot work on chromosomes containing more than 100 k SNPs using length-3 tagging rules.</p> <p>Results</p> <p>We propose an efficient algorithm called FastTagger to calculate multi-marker tagging rules and select tag SNPs based on multi-marker LD. FastTagger uses several techniques to reduce running time and memory consumption. Our experiment results show that FastTagger is several times faster than existing multi-marker based tag SNP selection algorithms, and it consumes much less memory at the same time. As a result, FastTagger can work on chromosomes containing more than 100 k SNPs using length-3 tagging rules.</p> <p>FastTagger also produces smaller sets of tag SNPs than existing multi-marker based algorithms, and the reduction ratio ranges from 3%-9% when length-3 tagging rules are used. The generated tagging rules can also be used for genotype imputation. We studied the prediction accuracy of individual rules, and the average accuracy is above 96% when <it>r</it>²≥ 0.9.</p> <p>Conclusions</p> <p>Generating multi-marker tagging rules is a computation intensive task, and it is the bottleneck of existing multi-marker based tag SNP selection methods. FastTagger is a practical and scalable algorithm to solve this problem.</p

Synthesis, structural and magnetic characterization of lead-metaniobate/cobalt-ferrite nanocomposite films deposited by pulsed laser ablation

Detailed structural, microstructural and magnetic measurements were performed on (PbNb2O6)(1-x) -(CoFe2O4) (x) nanocomposite thin films deposited by laser ablation on Si(001)\Pt substrates, with different cobalt ferrite concentrations. The tuning of the lead concentration, due to the lead volatility, was found to be particularly important in order to obtain the orthorhombic (ferroelectric) lead niobate phase. The lattice parameter of CoFe2O4 was below the bulk value, indicating the presence of compressive strains on this phase. A magnetic anisotropy was observed, which favored the orientation of the magnetization in the direction perpendicular to the plane of the films, for cobalt ferrite concentrations 40-50 %. The shape, stress and magnetocrystalline anisotropy fields on the composites were calculated and compared. It was found that the perpendicular magnetic anisotropy was induced by the presence of strain on the ferrite phase in the films.- This work has been supported by Fundacao para a Ciencia e Tecnologia (FCT) and FEDER, through the projects POCI/CTM/60181/2004 and PTDC/CTM/099415/2008. J. Barbosa and I. T. Gomes gratefully acknowledge Ph.D. grants from Fundacao para a Ciencia e Tecnologia (SFRH/BD/41913/2007 and SFRH/BD/36348/2007, respectively).info:eu-repo/semantics/publishedVersio

A network perspective on the topological importance of enzymes and their phylogenetic conservation

<p>Abstract</p> <p>Background</p> <p>A metabolic network is the sum of all chemical transformations or reactions in the cell, with the metabolites being interconnected by enzyme-catalyzed reactions. Many enzymes exist in numerous species while others occur only in a few. We ask if there are relationships between the phylogenetic profile of an enzyme, or the number of different bacterial species that contain it, and its topological importance in the metabolic network. Our null hypothesis is that phylogenetic profile is independent of topological importance. To test our null hypothesis we constructed an enzyme network from the KEGG (Kyoto Encyclopedia of Genes and Genomes) database. We calculated three network indices of topological importance: the degree or the number of connections of a network node; closeness centrality, which measures how close a node is to others; and betweenness centrality measuring how frequently a node appears on all shortest paths between two other nodes.</p> <p>Results</p> <p>Enzyme phylogenetic profile correlates best with betweenness centrality and also quite closely with degree, but poorly with closeness centrality. Both betweenness and closeness centralities are non-local measures of topological importance and it is intriguing that they have contrasting power of predicting phylogenetic profile in bacterial species. We speculate that redundancy in an enzyme network may be reflected by betweenness centrality but not by closeness centrality. We also discuss factors influencing the correlation between phylogenetic profile and topological importance.</p> <p>Conclusion</p> <p>Our analysis falsifies the hypothesis that phylogenetic profile of enzymes is independent of enzyme network importance. Our results show that phylogenetic profile correlates better with degree and betweenness centrality, but less so with closeness centrality. Enzymes that occur in many bacterial species tend to be those that have high network importance. We speculate that this phenomenon originates in mechanisms driving network evolution. Closeness centrality reflects phylogenetic profile poorly. This is because metabolic networks often consist of distinct functional modules and some are not in the centre of the network. Enzymes in these peripheral parts of a network might be important for cell survival and should therefore occur in many bacterial species. They are, however, distant from other enzymes in the same network.</p

Diagnostic delay for giant cell arteritis – a systematic review and meta-analysis

Background Giant cell arteritis (GCA), if untreated, can lead to blindness and stroke. The study’s objectives were to (1) determine a new evidence-based benchmark of the extent of diagnostic delay for GCA and (2) examine the role of GCA-specific characteristics on diagnostic delay. Methods Medical literature databases were searched from inception to November 2015. Articles were included if reporting a time-period of diagnostic delay between onset of GCA symptoms and diagnosis. Two reviewers assessed the quality of the final articles and extracted data from these. Random-effects meta-analysis was used to pool the mean time-period (95% confidence interval (CI)) between GCA symptom onset and diagnosis, and the delay observed for GCA-specific characteristics. Heterogeneity was assessed by I 2 and by 95% prediction interval (PI). Results Of 4128 articles initially identified, 16 provided data for meta-analysis. Mean diagnostic delay was 9.0 weeks (95% CI, 6.5 to 11.4) between symptom onset and GCA diagnosis (I 2 = 96.0%; P < 0.001; 95% PI, 0 to 19.2 weeks). Patients with a cranial presentation of GCA received a diagnosis after 7.7 (95% CI, 2.7 to 12.8) weeks (I 2 = 98.4%; P < 0.001; 95% PI, 0 to 27.6 weeks) and those with non-cranial GCA after 17.6 (95% CI, 9.7 to 25.5) weeks (I 2 = 96.6%; P < 0.001; 95% PI, 0 to 46.1 weeks). Conclusions The mean delay from symptom onset to GCA diagnosis was 9 weeks, or longer when cranial symptoms were absent. Our research provides an evidence-based benchmark for diagnostic delay of GCA and supports the need for improved public awareness and fast-track diagnostic pathways

Extreme Evolutionary Disparities Seen in Positive Selection across Seven Complex Diseases

Positive selection is known to occur when the environment that an organism inhabits is suddenly altered, as is the case across recent human history. Genome-wide association studies (GWASs) have successfully illuminated disease-associated variation. However, whether human evolution is heading towards or away from disease susceptibility in general remains an open question. The genetic-basis of common complex disease may partially be caused by positive selection events, which simultaneously increased fitness and susceptibility to disease. We analyze seven diseases studied by the Wellcome Trust Case Control Consortium to compare evidence for selection at every locus associated with disease. We take a large set of the most strongly associated SNPs in each GWA study in order to capture more hidden associations at the cost of introducing false positives into our analysis. We then search for signs of positive selection in this inclusive set of SNPs. There are striking differences between the seven studied diseases. We find alleles increasing susceptibility to Type 1 Diabetes (T1D), Rheumatoid Arthritis (RA), and Crohn's Disease (CD) underwent recent positive selection. There is more selection in alleles increasing, rather than decreasing, susceptibility to T1D. In the 80 SNPs most associated with T1D (p-value <7.01×10−5) showing strong signs of positive selection, 58 alleles associated with disease susceptibility show signs of positive selection, while only 22 associated with disease protection show signs of positive selection. Alleles increasing susceptibility to RA are under selection as well. In contrast, selection in SNPs associated with CD favors protective alleles. These results inform the current understanding of disease etiology, shed light on potential benefits associated with the genetic-basis of disease, and aid in the efforts to identify causal genetic factors underlying complex disease

Functional Analysis of Retinitis Pigmentosa 2 (RP2) Protein Reveals Variable Pathogenic Potential of Disease-Associated Missense Variants

Genetic mutations are frequently associated with diverse phenotypic consequences, which limits the interpretation of the consequence of a variation in patients. Mutations in the retinitis pigmentosa 2 (RP2) gene are associated with X-linked RP, which is a phenotypically heterogenic form of retinal degeneration. The purpose of this study was to assess the functional consequence of disease-associated mutations in the RP2 gene using an in vivo assay. Morpholino-mediated depletion of rp2 in zebrafish resulted in perturbations in photoreceptor development and microphthalmia (small eye). Ultrastructural and immunofluorescence analyses revealed defective photoreceptor outer segment development and lack of expression of photoreceptor-specific proteins. The retinopathy phenotype could be rescued by expressing the wild-type human RP2 protein. Notably, the tested RP2 mutants exhibited variable degrees of rescue of rod versus cone photoreceptor development as well as microphthalmia. Our results suggest that RP2 plays a key role in photoreceptor development and maintenance in zebrafish and that the clinical heterogeneity associated with RP2 mutations may, in part, result from its potentially distinct functional relevance in rod versus cone photoreceptors