Case Report: Insulin hypersensitivity in youth with type 1 diabetes

OBJECTIVE: Immediate type I, type III, and delayed type IV hypersensitivity reactions to insulin are rare, but potentially serious complications of exogenous insulin administration required for the treatment of type 1 diabetes (T1D). METHODS: We present four cases of insulin hypersensitivity reactions occurring in youth with T1D and a literature review of this topic. RESULTS: Insulin hypersensitivity reactions included types I, III, and IV with presentations ranging from localized urticaria, erythematous nodules, and eczematous plaques to anaphylaxis with respiratory distress. Reactions occurred in youth with newly diagnosed T1D and in those with long-standing T1D who were using both injection and insulin pump therapy. Multidisciplinary care involving pediatric endocrinology and allergy/immunology utilizing trials of many adjunct therapies yielded minimal improvement. Despite the use of various treatments, including antihistamines, topical therapies, immunosuppressant medications, desensitization trials, and intravenous immune globulin, cutaneous reactions, elevated hemoglobin A1c levels, and negative effects on quality of life remain persistent challenges. One patient became one of the youngest pancreas transplant recipients in the world at age 12 years due to uncontrollable symptoms and intolerable adverse effects of attempted therapies. CONCLUSION: Although rare, insulin hypersensitivity reactions negatively affect glycemic control and quality of life. These cases demonstrate the varying severity and presentation of insulin hypersensitivity reactions along with the limited success of various treatment approaches. Given the life-sustaining nature of insulin therapy, further studies are needed to better understand the underlying pathophysiology of insulin hypersensitivity and to develop targeted treatment approaches

Infection of mouse macrophages by seasonal influenza viruses can be restricted at the level of virus entry and at a late stage in the virus life cycle

Airway epithelial cells are susceptible to infection with seasonal influenza A viruses (IAV), resulting in productive virus replication and release. Macrophages (MΦ) are also permissive to IAV infection; however, virus replication is abortive. Currently, it is unclear how productive infection of MΦ is impaired or the extent to which seasonal IAV replicate in MΦ. Herein, we compared mouse MΦ and epithelial cells for their ability to support genomic replication and transcription, synthesis of viral proteins, assembly of virions, and release of infectious progeny following exposure to genetically defined IAV. We confirm that seasonal IAV differ in their ability to utilize cell surface receptors for infectious entry and that this represents one level of virus restriction. Following virus entry, we demonstrate synthesis of all eight segments of genomic viral RNA (vRNA) and mRNA, as well as seven distinct IAV proteins, in IAV-infected mouse MΦ. Although newly synthesized hemagglutinin (HA) and neuraminidase (NA) glycoproteins are incorporated into the plasma membrane and expressed at the cell surface, electron microscopy confirmed that virus assembly was defective in IAV-infected MΦ, defining a second level of restriction late in the virus life cycle

Investigation of the deposition and emission of mercury in arctic snow during an atmospheric mercury depletion event

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/94701/1/jgrd14741.pd

The effect of beta-alanine supplementation on neuromuscular fatigue in elderly (55–92 Years): a double-blind randomized study

<p>Abstract</p> <p>Background</p> <p>Ageing is associated with a significant reduction in skeletal muscle carnosine which has been linked with a reduction in the buffering capacity of muscle and in theory, may increase the rate of fatigue during exercise. Supplementing beta-alanine has been shown to significantly increase skeletal muscle carnosine. The purpose of this study, therefore, was to examine the effects of ninety days of beta-alanine supplementation on the physical working capacity at the fatigue threshold (PWC_FT) in elderly men and women.</p> <p>Methods</p> <p>Using a double-blind placebo controlled design, twenty-six men (n = 9) and women (n = 17) (age ± SD = 72.8 ± 11.1 yrs) were randomly assigned to either beta-alanine (BA: 800 mg × 3 per day; n = 12; CarnoSyn™) or Placebo (PL; n = 14) group. Before (pre) and after (post) the supplementation period, participants performed a discontinuous cycle ergometry test to determine the PWC_FT.</p> <p>Results</p> <p>Significant increases in PWC_FT(28.6%) from pre- to post-supplementation were found for the BA treatment group (p < 0.05), but no change was observed with PL treatment. These findings suggest that ninety days of BA supplementation may increase physical working capacity by delaying the onset of neuromuscular fatigue in elderly men and women.</p> <p>Conclusion</p> <p>We suggest that BA supplementation, by improving intracellular pH control, improves muscle endurance in the elderly. This, we believe, could have importance in the prevention of falls, and the maintenance of health and independent living in elderly men and women.</p

The Epoch of Disk Settling: z~1 to Now

We present evidence from a sample of 544 galaxies from the DEEP2 Survey for evolution of the internal kinematics of blue galaxies with stellar masses ranging 8.0 < log M* (M_Sun) < 10.7 over 0.2<z<1.2. DEEP2 provides galaxy spectra and Hubble imaging from which we measure emission-line kinematics and galaxy inclinations, respectively. Our large sample allows us to overcome scatter intrinsic to galaxy properties in order to examine trends in kinematics. We find that at a fixed stellar mass galaxies systematically decrease in disordered motions and increase in rotation velocity and potential well depth with time. Massive galaxies are the most well-ordered at all times examined, with higher rotation velocities and less disordered motions than less massive galaxies. We quantify disordered motions with an integrated gas velocity dispersion corrected for beam smearing (sigma_g). It is unlike the typical pressure-supported velocity dispersion measured for early type galaxies and galaxy bulges. Because both seeing and the width of our spectral slits comprise a significant fraction of the galaxy sizes, sigma_g integrates over velocity gradients on large scales which can correspond to non-ordered gas kinematics. We compile measurements of galaxy kinematics from the literature over 1.2<z<3.8 and do not find any trends with redshift, likely for the most part because these datasets are biased toward the most highly star-forming systems. In summary, over the last ~8 billion years since z=1.2, blue galaxies evolve from disordered to ordered systems as they settle to become the rotation-dominated disk galaxies observed in the Universe today, with the most massive galaxies being the most evolved at any time.Comment: submitted to ApJ and responded to referee repor

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Ecological Determinants of Highly Pathogenic Avian Influenza (H5N1) Outbreaks in Bangladesh

BACKGROUND: The agro-ecology and poultry husbandry of the south Asian and south-east Asian countries share common features, however, with noticeable differences. Hence, the ecological determinants associated with risk of highly pathogenic avian influenza (HPAI-H5N1) outbreaks are expected to differ between Bangladesh and e.g., Thailand and Vietnam. The primary aim of the current study was to establish ecological determinants associated with the risk of HPAI-H5N1 outbreaks at subdistrict level in Bangladesh. The secondary aim was to explore the performance of two different statistical modeling approaches for unmeasured spatially correlated variation. METHODOLOGY/PRINCIPAL FINDINGS: An ecological study at subdistrict level in Bangladesh was performed with 138 subdistricts with HPAI-H5N1 outbreaks during 2007-2008, and 326 subdistricts with no outbreaks. The association between ecological determinants and HPAI-H5N1 outbreaks was examined using a generalized linear mixed model. Spatial clustering of the ecological data was modeled using 1) an intrinsic conditional autoregressive (ICAR) model at subdistrict level considering their first order neighbors, and 2) a multilevel (ML) model with subdistricts nested within districts. Ecological determinants significantly associated with risk of HPAI-H5N1 outbreaks at subdistrict level were migratory birds' staging areas, river network, household density, literacy rate, poultry density, live bird markets, and highway network. Predictive risk maps were derived based on the resulting models. The resulting models indicate that the ML model absorbed some of the covariate effect of the ICAR model because of the neighbor structure implied in the two different models. CONCLUSIONS/SIGNIFICANCE: The study identified a new set of ecological determinants related to river networks, migratory birds' staging areas and literacy rate in addition to already known risk factors, and clarified that the generalized concept of free grazing duck and duck-rice cultivation interacted ecology are not significant determinants for Bangladesh. These findings will refine current understanding of the HPAI-H5N1 epidemiology in Bangladesh

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN