Remission induction therapy for acute lymphoblastic leukemia (ALL) includes medications that may cause hepatotoxicity, including asparaginase. We used a genome‐wide association study to identify loci ...associated with elevated alanine transaminase (ALT) levels after induction therapy in children with ALL enrolled on St. Jude Children's Research Hospital (SJCRH) protocols. Germline DNA was genotyped using arrays and exome sequencing. Adjusting for age, body mass index, ancestry, asparaginase preparation, and dosage, the PNPLA3 rs738409 (C>G) I148M variant, previously associated with fatty liver disease risk, had the strongest genetic association with ALT (P = 2.5 × 10‐8). The PNPLA3 rs738409 variant explained 3.8% of the variability in ALT, and partly explained race‐related differences in ALT. The PNPLA3 rs738409 association was replicated in an independent cohort of 2,285 patients treated on Children's Oncology Group protocol AALL0232 (P = 0.024). This is an example of a pharmacogenetic variant overlapping with a disease risk variant.
Progress in the management of patients with myelodysplastic syndromes (MDS) has been hampered by the inability to detect cytogenetic abnormalities in 40-60% of cases. We prospectively analyzed ...matched pairs of bone marrow and buccal cell (normal) DNA samples from 51 MDS patients by single nucleotide polymorphism (SNP) arrays, and identified somatically acquired clonal genomic abnormalities in 21 patients (41%). Among the 33 patients with normal bone marrow cell karyotypes, 5 (15%) had clonal, somatically acquired aberrations by SNP array analysis, including 4 with segmental uniparental disomies (UPD) and 1 with three separate microdeletions. Each abnormality was detected more readily in CD34+ cells than in unselected bone marrow cells. Paired analysis of bone marrow and buccal cell DNA from each patient was necessary to distinguish true clonal genomic abnormalities from inherited copy number variations and regions with apparent loss of heterozygosity. UPDs affecting chromosome 7q were identified in two patients who had a rapidly deteriorating clinical course despite a low-risk International Prognostic Scoring System score. Further studies of larger numbers of patients will be needed to determine whether 7q UPD detected by SNP array analysis will identify higher risk MDS patients at diagnosis, analogous to those with 7q cytogenetic abnormalities.
Volatile organic compounds (VOCs) in honey are obtained from diverse biosynthetic pathways and extracted by using various methods associated with varying degrees of selectivity and effectiveness. ...These compounds are grouped into chemical categories such as aldehyde, ketone, acid, alcohol, hydrocarbon, norisoprenoids, terpenes and benzene compounds and their derivatives, furan and pyran derivatives. They represent a fingerprint of a specific honey and therefore could be used to differentiate between monofloral honeys from different floral sources, thus providing valuable information concerning the honey's botanical and geographical origin. However, only plant derived compounds and their metabolites (terpenes, norisoprenoids and benzene compounds and their derivatives) must be employed to discriminate among floral origins of honey. Notwithstanding, many authors have reported different floral markers for honey of the same floral origin, consequently sensory analysis, in conjunction with analysis of VOCs could help to clear this ambiguity. Furthermore, VOCs influence honey's aroma described as sweet, citrus, floral, almond, rancid, etc. Clearly, the contribution of a volatile compound to honey aroma is determined by its odor activity value. Elucidation of the aroma compounds along with floral origins of a particular honey can help to standardize its quality and avoid fraudulent labeling of the product. Although only present in low concentrations, VOCS could contribute to biomedical activities of honey, especially the antioxidant effect due to their natural radical scavenging potential.
Human blood is a self-regenerating lipid-rich biological fluid that is routinely collected in hospital settings. The inventory of lipid molecules found in blood plasma (plasma lipidome) offers ...insights into individual metabolism and physiology in health and disease. Disturbances in the plasma lipidome also occur in conditions that are not directly linked to lipid metabolism; therefore, plasma lipidomics based on MS is an emerging tool in an array of clinical diagnostics and disease management. However, challenges exist in the translation of such lipidomic data to clinical applications. These relate to the reproducibility, accuracy, and precision of lipid quantitation, study design, sample handling, and data sharing. This position paper emerged from a workshop that initiated a community-led process to elaborate and define a set of generally accepted guidelines for quantitative MS-based lipidomics of blood plasma or serum, with harmonization of data acquired on different instrumentation platforms across independent laboratories as an ultimate goal. We hope that other fields may benefit from and follow such a precedent.
Despite substantial investments by government, philanthropic, and commercial sources over the past several decades, traumatic brain injury (TBI) remains an unmet medical need and a major source of ...disability and mortality in both developed and developing societies. The U.S. Department of Defense neurotrauma research portfolio contains more than 500 research projects funded at more than $700 million and is aimed at developing interventions that mitigate the effects of trauma to the nervous system and lead to improved quality of life outcomes. A key area of this portfolio focuses on the need for effective pharmacological approaches for treating patients with TBI and its associated symptoms. The Neurotrauma Pharmacology Workgroup was established by the U.S. Army Medical Research and Materiel Command (USAMRMC) with the overarching goal of providing a strategic research plan for developing pharmacological treatments that improve clinical outcomes after TBI. To inform this plan, the Workgroup (a) assessed the current state of the science and ongoing research and (b) identified research gaps to inform future development of research priorities for the neurotrauma research portfolio. The Workgroup identified the six most critical research priority areas in the field of pharmacological treatment for persons with TBI. The priority areas represent parallel efforts needed to advance clinical care; each requires independent effort and sufficient investment. These priority areas will help the USAMRMC and other funding agencies strategically guide their research portfolios to ensure the development of effective pharmacological approaches for treating patients with TBI.
The composition of ultra-high-energy cosmic rays is measured with the High Resolution Fly's Eye cosmic-ray observatory data using the X sub(max) technique. Data were collected in stereo between 1999 ...November and 2001 September. The data are reconstructed with well-determined geometry. Measurements of the atmospheric transmission are incorporated in the reconstruction. The detector resolution is found to be 30 g cm super(-2) in X sub(max) and 13% in energy. The X sub(max) elongation rate between 10 super(18.0) and 10 super(19.4) eV is measured to be 54.5 c 6.5 (stat) c 4.5 (sys) g cm super(-2) per decade. This is compared with predictions using the QGSJet01 and SIBYLL 2.1 hadronic interaction models for both protons and iron nuclei. CORSIKA-generated extensive air showers are incorporated directly into a detailed detector Monte Carlo program. The elongation rate and the X sub(max) distribution widths are consistent with a constant or slowly changing and predominantly light composition. A simple model containing only protons and iron nuclei is compared with QGSJet and SIBYLL. The best agreement between the model and the data is for 80% protons for QGSJet and 60% protons for SIBYLL.
Summary
Background
Egg allergy is a leading cause of food allergy in young infants; however, little is known about early allergen‐specific T‐cell responses which predate the presentation of egg ...allergy, and if these are altered by early egg exposure.
Objective
To investigate the early T‐cell responses to multiple egg proteins in relation to patterns of egg exposure and subsequent IgE‐mediated egg allergy.
Methods
Egg‐specific T‐cell cytokine responses (IL‐5, IL‐13, IL‐10, IFNγ and TNFα) to ovomucoid (OM), ovalbumin (OVA), conalbumin (CON) and lysozyme (LYS) were measured in infants with eczema at 4 months of age (n = 40), before randomization to receive ‘early egg’ or a placebo as part of a randomized controlled trial (Australian New Zealand Clinical Trials Registry number 12609000415202) and at 12 months of age (n = 58), when IgE‐mediated egg allergy was assessed by skin prick test and food challenge.
Results
In 4–month‐old infants, who had not directly ingested egg, those who subsequently developed egg allergy already had significantly higher Th2 cytokine responses to multiple egg allergens, particularly elevated IL‐13 responses to OVA (P = 0.004), OM (P = 0.012) and LYS (P = 0.003) and elevated IL‐5 to the same antigens (P = 0.031, 0.04 and 0.003, respectively). IL‐13 responses (to OVA and LYS) and IL‐5 responses (to LYS) at 4 months significantly predicted egg allergy at 12 months. All responses significantly declined with age in the egg‐allergic infants, and this did not appear to be modified by ‘early’ introduction of egg.
Conclusions & Clinical Relevance
Elevated egg‐specific Th2 cytokine responses were established prior to egg ingestion at 4 months and were not significantly altered by introduction of egg. Th2 responses at 4 months of age predicted egg allergy at 12 months, suggesting that this could be used as a biomarker to select infants for early prevention and management strategies.
A 79-year-old woman presented with a large fresh rectal bleed. Computed tomography revealed that she had a large type IV hiatus hernia, which contained the stomach and pancreas. Compression of the ...inferior mesenteric vein and splenic vein had led to thrombosis within these vessels and retrograde flow within the inferior mesenteric vein. This had led to the formation of portosystemic rectal varices. Ectopic varices occasionally form in the rectum, often in the context of liver cirrhosis. At the time of writing, ours is the first reported case of portosystemic rectal varices formulated in response to obstruction of vessels within a hiatus hernia.
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