MetaboNetworks, an interactive Matlab-based toolbox for creating, customizing and exploring sub-networks from KEGG.

Summary: MetaboNetworks is a tool to create custom sub-networks in Matlab using main reaction pairs as defined by the Kyoto Encyclopaedia of Genes and Genomes and can be used to explore transgenomic interactions, for example mammalian and bacterial associations. It calculates the shortest path between a set of metabolites (e.g. biomarkers from a metabonomic study) and plots the connectivity between metabolites as links in a network graph. The resulting graph can be edited and explored interactively. Furthermore, nodes and edges in the graph are linked to the Kyoto Encyclopaedia of Genes and Genomes compound and reaction pair web pages. Availability and implementation: MetaboNetworks is available from http://www.mathworks.com/matlabcentral/fileexchange/42684. Contact: [email protected] or [email protected] Supplementary information: Supplementary data are available at Bioinformatics online

Genetic determinants of metabolism in health and disease: from biochemical genetics to genome-wide associations

Increasingly sophisticated measurement technologies have allowed the fields of metabolomics and genomics to identify, in parallel, risk factors of disease; predict drug metabolism; and study metabolic and genetic diversity in large human populations. Yet the complementarity of these fields and the utility of studying genes and metabolites together is belied by the frequent separate, parallel applications of genomic and metabolomic analysis. Early attempts at identifying co-variation and interaction between genetic variants and downstream metabolic changes, including metabolic profiling of human Mendelian diseases and quantitative trait locus mapping of individual metabolite concentrations, have recently been extended by new experimental designs that search for a large number of gene-metabolite associations. These approaches, including metabolomic quantitiative trait locus mapping and metabolomic genome-wide association studies, involve the concurrent collection of both genomic and metabolomic data and a subsequent search for statistical associations between genetic polymorphisms and metabolite concentrations across a broad range of genes and metabolites. These new data-fusion techniques will have important consequences in functional genomics, microbial metagenomics and disease modeling, the early results and implications of which are reviewed

Characterization of a population of neural progenitor cells in the infant hippocampus.

Abnormalities of the hippocampus are associated with a range of diseases in children, including epilepsy and sudden death. A population of rod cells in part of the hippocampus, the polymorphic layer of the dentate gyrus, has long been recognized in infants. Previous work suggested that these cells were microglia and that their presence was associated with chronic illness and sudden infant death syndrome. Prompted by the observations that a sensitive immunohistochemical marker of microglia used in diagnostic practice does not typically stain these cells and that the hippocampus is a site of postnatal neurogenesis, we hypothesized that this transient population of cells were not microglia but neural progenitors

Use of Proteins Identified through a Functional Genomic Screen To Develop a Protein Subunit Vaccine That Provides Significant Protection against Virulent Streptococcus suis in Pigs.

Streptococcus suis is a bacterium that is commonly carried in the respiratory tract and that is also one of the most important invasive pathogens of swine, commonly causing meningitis, arthritis, and septicemia. Due to the existence of many serotypes and a wide range of immune evasion capabilities, efficacious vaccines are not readily available. The selection of S. suis protein candidates for inclusion in a vaccine was accomplished by identifying fitness genes through a functional genomics screen and selecting conserved predicted surface-associated proteins. Five candidate proteins were selected for evaluation in a vaccine trial and administered both intranasally and intramuscularly with one of two different adjuvant formulations. Clinical protection was evaluated by subsequent intranasal challenge with virulent S. suis While subunit vaccination with the S. suis proteins induced IgG antibodies to each individual protein and a cellular immune response to the pool of proteins and provided substantial protection from challenge with virulent S. suis, the immune response elicited and the degree of protection were dependent on the parenteral adjuvant given. Subunit vaccination induced IgG reactive against different S. suis serotypes, indicating a potential for cross protection

Advancing clinical and translational research in germ cell tumours (GCT): recommendations from the Malignant Germ Cell International Consortium

YesGerm cell tumours (GCTs) are a heterogeneous group of rare neoplasms that present in different anatomical sites and across a wide spectrum of patient ages from birth through to adulthood. Once these strata are applied, cohort numbers become modest, hindering inferences regarding management and therapeutic advances. Moreover, patients with GCTs are treated by different medical professionals including paediatric oncologists, neuro-oncologists, medical oncologists, neurosurgeons, gynaecological oncologists, surgeons, and urologists. Silos of care have thus formed, further hampering knowledge dissemination between specialists. Dedicated biobank specimen collection is therefore critical to foster continuous growth in our understanding of similarities and differences by age, gender, and site, particularly for rare cancers such as GCTs. Here, the Malignant Germ Cell International Consortium provides a framework to create a sustainable, global research infrastructure that facilitates acquisition of tissue and liquid biopsies together with matched clinical data sets that reflect the diversity of GCTs. Such an effort would create an invaluable repository of clinical and biological data which can underpin international collaborations that span professional boundaries, translate into clinical practice, and ultimately impact patient outcomes.ALF, JFA, and MJM declare funding from St Baldrick’s Foundation; grant reference number 358099

Development of an invasively monitored porcine model of acetaminophen-induced acute liver failure

Background: The development of effective therapies for acute liver failure (ALF) is limited by our knowledge of the pathophysiology of this condition, and the lack of suitable large animal models of acetaminophen toxicity. Our aim was to develop a reproducible invasively-monitored porcine model of acetaminophen-induced ALF. Method: 35kg pigs were maintained under general anaesthesia and invasively monitored. Control pigs received a saline infusion, whereas ALF pigs received acetaminophen intravenously for 12 hours to maintain blood concentrations between 200-300 mg/l. Animals surviving 28 hours were euthanased. Results: Cytochrome p450 levels in phenobarbital pre-treated animals were significantly higher than non pre-treated animals (300 vs 100 pmol/mg protein). Control pigs (n=4) survived 28-hour anaesthesia without incident. Of nine pigs that received acetaminophen, four survived 20 hours and two survived 28 hours. Injured animals developed hypotension (mean arterial pressure; 40.8+/-5.9 vs 59+/-2.0 mmHg), increased cardiac output (7.26+/-1.86 vs 3.30+/-0.40 l/min) and decreased systemic vascular resistance (8.48+/-2.75 vs 16.2+/-1.76 mPa/s/m3). Dyspnoea developed as liver injury progressed and the increased pulmonary vascular resistance (636+/-95 vs 301+/-26.9 mPa/s/m3) observed may reflect the development of respiratory distress syndrome. Liver damage was confirmed by deterioration in pH (7.23+/-0.05 vs 7.45+/-0.02) and prothrombin time (36+/-2 vs 8.9+/-0.3 seconds) compared with controls. Factor V and VII levels were reduced to 9.3 and 15.5% of starting values in injured animals. A marked increase in serum AST (471.5+/-210 vs 42+/-8.14) coincided with a marked reduction in serum albumin (11.5+/-1.71 vs 25+/-1 g/dL) in injured animals. Animals displayed evidence of renal impairment; mean creatinine levels 280.2+/-36.5 vs 131.6+/-9.33 mumol/l. Liver histology revealed evidence of severe centrilobular necrosis with coagulative necrosis. Marked renal tubular necrosis was also seen. Methaemoglobin levels did not rise >5%. Intracranial hypertension was not seen (ICP monitoring), but there was biochemical evidence of encephalopathy by the reduction of Fischer's ratio from 5.6 +/- 1.1 to 0.45 +/- 0.06. Conclusion: We have developed a reproducible large animal model of acetaminophen-induced liver failure, which allows in-depth investigation of the pathophysiological basis of this condition. Furthermore, this represents an important large animal model for testing artificial liver support systems

Optimising use of electronic health records to describe the presentation of rheumatoid arthritis in primary care: a strategy for developing code lists

Background Research using electronic health records (EHRs) relies heavily on coded clinical data. Due to variation in coding practices, it can be difficult to aggregate the codes for a condition in order to define cases. This paper describes a methodology to develop ‘indicator markers’ found in patients with early rheumatoid arthritis (RA); these are a broader range of codes which may allow a probabilistic case definition to use in cases where no diagnostic code is yet recorded. Methods We examined EHRs of 5,843 patients in the General Practice Research Database, aged ≥30y, with a first coded diagnosis of RA between 2005 and 2008. Lists of indicator markers for RA were developed initially by panels of clinicians drawing up code-lists and then modified based on scrutiny of available data. The prevalence of indicator markers, and their temporal relationship to RA codes, was examined in patients from 3y before to 14d after recorded RA diagnosis. Findings Indicator markers were common throughout EHRs of RA patients, with 83.5% having 2 or more markers. 34% of patients received a disease-specific prescription before RA was coded; 42% had a referral to rheumatology, and 63% had a test for rheumatoid factor. 65% had at least one joint symptom or sign recorded and in 44% this was at least 6-months before recorded RA diagnosis. Conclusion Indicator markers of RA may be valuable for case definition in cases which do not yet have a diagnostic code. The clinical diagnosis of RA is likely to occur some months before it is coded, shown by markers frequently occurring ≥6 months before recorded diagnosis. It is difficult to differentiate delay in diagnosis from delay in recording. Information concealed in free text may be required for the accurate identification of patients and to assess the quality of care in general practice

Quantitative lipoprotein subclass and low molecular weight metabolite analysis in human serum and plasma by 1H NMR spectroscopy in a multilaboratory trial

We report an extensive 600 MHz NMR trial of a quantitative lipoprotein and small molecule measurements in human blood serum and plasma. Five centers with eleven 600 MHz NMR spectrometers were used to analyze 98 samples including: 20 QCs, 37 commercially sourced, paired serum and plasma samples and 2 National Institute of Science and Technology, NIST, reference material 1951c replicates. Samples were analyzed using rigorous protocols for sample preparation and experimental acquisition. A commercial lipoprotein subclass analysis was used to quantify 105 lipoprotein subclasses and 24 low molecular weight metabolites from the nuclear magnetic resonance, NMR, spectra. For all spectrometers, the instrument specific variance in measuring internal quality controls, QCs, was lower than the percentage described by the National Cholesterol Education Program, NCEP, criteria for lipid testing (triglycerides<2.7%, cholesterol<2.8%; LDL-cholesterol<2.8%; HDL-cholesterol<2.3%), showing exceptional reproducibility for direct quantitation of lipoproteins in both matrices. The average RSD for the 105 lipoprotein parameters in the 11 instruments was 4.6% and 3.9% for the two NIST samples while it was 38% and 40% for the 37 commercially sourced plasmas and sera, respectively, showing negligible analytical compared to biological variation. The coefficient of variance, CV, obtained for the quantification of the small molecules across the 11 spectrometers was below 15% for 20 out of the 24 metabolites analyzed. This study provides further evidence of the suitability of NMR for high-throughput lipoprotein subcomponent analysis and small molecule quantitation with the exceptional reproducibility required for clinical and other regulatory settings

Diagnostic criteria for idiopathic pulmonary fibrosis: a Fleischner Society White Paper.

This Review provides an updated approach to the diagnosis of idiopathic pulmonary fibrosis (IPF), based on a systematic search of the medical literature and the expert opinion of members of the Fleischner Society. A checklist is provided for the clinical evaluation of patients with suspected usual interstitial pneumonia (UIP). The role of CT is expanded to permit diagnosis of IPF without surgical lung biopsy in select cases when CT shows a probable UIP pattern. Additional investigations, including surgical lung biopsy, should be considered in patients with either clinical or CT findings that are indeterminate for IPF. A multidisciplinary approach is particularly important when deciding to perform additional diagnostic assessments, integrating biopsy results with clinical and CT features, and establishing a working diagnosis of IPF if lung tissue is not available. A working diagnosis of IPF should be reviewed at regular intervals since the diagnosis might change. Criteria are presented to establish confident and working diagnoses of IPF

Drug resistance in cancer

Cancer Research UK has recently sponsored a meeting, organized by the UK Medical Research Council, on cancer drug resistance. Several of the molecular mechanisms responsible for this clinical outcome, such as DNA interstrand crosslink repair, apoptosis evasion, cytochrome P450 and P-glycoprotein, were discussed. There was a special focus on leukaemia, breast and ovarian cancer, and the potential use of positron-emission tomography to study anticancer-drug resistance. The progress made in translating these findings to the clinic, like Gefitinib, P-glycoprotein phenotyping, or genome-wide analysis technology, was also discussed