Research in network data management and resource sharing : experimental system progress report

Includes bibliographic references (p. 18, 56).This report covers three topics: the implementation of an experimental distributed data management system, the design of a network virtual file system, and recent research in query strategies for distributed data management systems

Identification of distinct human invariant natural killer T-cell response phenotypes to alpha-galactosylceramide.

Background Human CD1d-restricted, invariant natural killer T cells (iNKT) are a unique class of T lymphocytes that recognise glycolipid antigens such as α-galactosylceramide (αGalCer) and upon T cell receptor (TCR) activation produce both Th1 and Th2 cytokines. iNKT cells expand when cultured in-vitro with αGalCer and interleukin 2 (IL-2) in a CD1d-restricted manner. However, the expansion ratio of human iNKT cells varies between individuals and this has implications for attempts to manipulate this pathway therapeutically. We have studied a panel of twenty five healthy human donors to assess the variability in their in-vitro iNKT cell expansion responses to stimulation with CD1d ligands and investigated some of the factors that may influence this phenomenon. Results Although all donors had comparable numbers of circulating iNKT cells their growth rates in-vitro over 14 days in response to a range of CD1d ligands and IL-2 were highly donor-dependent. Two reproducible donor response patterns of iNKT expansion were seen which we have called 'strong' or 'poor' iNKT responders. Donor response phenotype did not correlate with age, gender, frequency of circulating iNKT, or with the CD1d ligand utilised. Addition of exogenous recombinant human interleukin 4 (IL-4) to 'poor' responder donor cultures significantly increased their iNKT proliferative capacity, but not to levels equivalent to that of 'strong' responder donors. However in 'strong' responder donors, addition of IL-4 to their cultures did not significantly alter the frequency of iNKT cells in the expanded CD3+ population. Conclusion (i) in-vitro expansion of human iNKT cells in response to CD1d ligand activation is highly donor variable, (ii) two reproducible patterns of donor iNKT expansion were observed, which could be classified into 'strong' and 'poor' responder phenotypes, (iii) donor iNKT response phenotypes did not correlate with age, gender, frequency of circulating iNKT cells, or with the CD1d ligand utilised, (iv) addition of IL-4 to 'poor' but not 'strong' responder donor cultures significantly increased their in-vitro iNKT cell expansion to αGalCer

Gestational weight gain information: seeking and sources among pregnant women

BACKGROUND: Promoting healthy gestational weight gain (GWG) is important for preventing obstetric and perinatal morbidity, along with obesity in both mother and child. Provision of GWG guidelines by health professionals predicts women meeting GWG guidelines. Research concerning women\u27s GWG information sources is limited. This study assessed pregnant women\u27s sources of GWG information and how, where and which women seek GWG information. METHODS: Consecutive women (n = 1032) received a mailed questionnaire after their first antenatal visit to a public maternity hospital in Melbourne, Australia. Recalled provision of GWG guidelines by doctors and midwives, recalled provided GWG goals, and the obtaining of GWG information and information sources were assessed. RESULTS: Participants (n = 368; 35.7 % response) averaged 32.5 years of age and 20.8 weeks gestation, with 33.7 % speaking a language other than English. One in ten women recalled receiving GWG guidelines from doctors or midwives, of which half were consistent with Institute of Medicine guidelines. More than half the women (55.4 %) had actively sought GWG information. Nulliparous (OR 7.07, 95 % CI = 3.91-12.81) and obese (OR 1.96, 95 % CI = 1.05-3.65) women were more likely to seek information. Underweight (OR 0.29, 95 % CI = 0.09-0.97) women and those working part time (OR 0.52, 95 % CI = 0.28-0.97) were less likely to seek information. Most frequently reported GWG sources included the internet (82.7 %), books (55.4 %) and friends (51.5 %). The single most important sources were identified as the internet (32.8 %), general practitioners (16.9 %) and books (14.9 %). CONCLUSION: More than half of women were seeking GWG guidance and were more likely to consult non-clinician sources. The small numbers given GWG targets, and the dominance of non-clinical information sources, reinforces that an important opportunity to provide evidence based advice and guidance in the antenatal care setting is currently being missed

The TFOS International Workshop on Contact Lens Discomfort: Introduction

Nichols, J. J., Jones, L., Nelson, J. D., Stapleton, F., Sullivan, D. A., & Willcox, M. D. P. (2013). The TFOS International Workshop on Contact Lens Discomfort: Introduction. Investigative Opthalmology & Visual Science, 54(11), TFOS1. https://doi.org/10.1167/iovs.13-13195For many years, the contact lens field had focused on safety associated with contact lens wear—and for good reason, given the lack of understanding of the risk factors and etiology of serious complications such as microbial keratitis. However, as knowledge came to light on these complications through the 1980s and 1990s, it allowed for practitioners to become more comfortable managing these complications, along with the introduction of products that helped reduce or prevent some of these problems. It was during this time, beginning in the mid-1980s, that the field itself became cognizant of the issues associated with comfort, or discomfort, during contact lens wear. Since that time, we have witnessed the field (and industry) shift its attention toward understanding the issue of contact lens discomfort (CLD). Contact lens discomfort is a substantial and burdensome problem experienced frequently by contact lens wearers. It is well established that most contact lens wearers experience CLD, at least occasionally, although many experience CLD to such a severity that they feel compelled to alter their wearing habits. Common, although palliative at best, treatments include the periodic use of rewetting drops, contact lens removal, contact lens refitting (using different lens designs or materials or replacement schedules), and changes in the contact lens care solutions or regimens, in addition to other less commonly used approaches including topical or systemic medications, alterations in diet, and punctal plugs. Ultimately, CLD is the primary factor associated with permanent discontinuation from contact lens wear. Given the importance of the issue of CLD to both patients and practitioners alike, the time was right to move the field forward by taking steps to bring global consensus to our current understanding of this condition.Supported by unrestricted financial support from Alcon (title sponsor), Allergan, Bausch & Lomb, Santen, Menicon, Vistakon, Laboratoires Théa, Optima, Oculus, CooperVision, and Contact Lens Spectrum

Physical Aspects of Healthy Aging: Assessments of Three Measures of Balance for Studies in Middle-Aged and Older Adults

Objectives. To investigate the reliability and correlations with age of the balance components of the EPESE, NHANES, and the Good Balance Platform System (GBPS) in a normal population of adults. Design. Cross-sectional. Setting. Urban Medical Center in the Pacific. Participants. A random sample of 203 healthy offspring of Honolulu Heart Program participants, ages 38–71. Measurements. Subjects were examined twice at visits one week apart using the balance components of the EPESE, NHANES, and the good balance system tests. Results. The EPESE and NHANES batteries of tests were not sufficiently challenging to allow successful discrimination among subjects in good health, even older subjects. The GBPS allowed objective quantitative measurements, but the test-retest correlations generally were not high. The GBPS variables correlated with age only when subjects stood on a foam pad; they also were correlated with anthropometric variables. Conclusion. Both EPESE and NHANES balance tests were too easy for healthy subjects. The GBPS had generally low reliability coefficients except for the most difficult testing condition (foam pad, eyes closed). Both height and body fat were associated with GBPS scores, necessitating adjusting for these variables if using balance as a predictor of future health

Framework engineering to produce dominant T cell receptors with enhanced antigen-specific function

Immunobiology of allogeneic stem cell transplantation and immunotherapy of hematological disease

EM-mosaic detects mosaic point mutations that contribute to congenital heart disease.

BackgroundThe contribution of somatic mosaicism, or genetic mutations arising after oocyte fertilization, to congenital heart disease (CHD) is not well understood. Further, the relationship between mosaicism in blood and cardiovascular tissue has not been determined.MethodsWe developed a new computational method, EM-mosaic (Expectation-Maximization-based detection of mosaicism), to analyze mosaicism in exome sequences derived primarily from blood DNA of 2530 CHD proband-parent trios. To optimize this method, we measured mosaic detection power as a function of sequencing depth. In parallel, we analyzed our cohort using MosaicHunter, a Bayesian genotyping algorithm-based mosaic detection tool, and compared the two methods. The accuracy of these mosaic variant detection algorithms was assessed using an independent resequencing method. We then applied both methods to detect mosaicism in cardiac tissue-derived exome sequences of 66 participants for which matched blood and heart tissue was available.ResultsEM-mosaic detected 326 mosaic mutations in blood and/or cardiac tissue DNA. Of the 309 detected in blood DNA, 85/97 (88%) tested were independently confirmed, while 7/17 (41%) candidates of 17 detected in cardiac tissue were confirmed. MosaicHunter detected an additional 64 mosaics, of which 23/46 (50%) among 58 candidates from blood and 4/6 (67%) of 6 candidates from cardiac tissue confirmed. Twenty-five mosaic variants altered CHD-risk genes, affecting 1% of our cohort. Of these 25, 22/22 candidates tested were confirmed. Variants predicted as damaging had higher variant allele fraction than benign variants, suggesting a role in CHD. The estimated true frequency of mosaic variants above 10% mosaicism was 0.14/person in blood and 0.21/person in cardiac tissue. Analysis of 66 individuals with matched cardiac tissue available revealed both tissue-specific and shared mosaicism, with shared mosaics generally having higher allele fraction.ConclusionsWe estimate that ~ 1% of CHD probands have a mosaic variant detectable in blood that could contribute to cardiac malformations, particularly those damaging variants with relatively higher allele fraction. Although blood is a readily available DNA source, cardiac tissues analyzed contributed ~ 5% of somatic mosaic variants identified, indicating the value of tissue mosaicism analyses

Report of the Inaugural Meeting of the TFOS i2 = initiating innovation Series: Targeting the Unmet Need for Dry Eye Treatment

In March 2015, a meeting was held in London, United Kingdom, to address the progress in targeting the unmet need for dry eye disease (DED) treatment. The meeting, which launched the i2 = initiating innovation series, was sponsored by the Tear Film & Ocular Surface Society (TFOS; www.TearFilm.org) and supported by Dompé. The TFOS i2 meeting was designed to review advances in the understanding of DED since publication of the 2007 TFOS International Dry Eye WorkShop (DEWS) report, and to help launch the highly anticipated sequel, DEWS II. The meeting was structured to discuss the scope of the DED problem, to review the clinical challenges of DED, and to consider the treatment challenges of DED. This article provides a synopsis of the presentations of this TFOS i2 meeting

Blood and islet phenotypes indicate immunological heterogeneity in type 1 diabetes

This is an author-created, uncopyedited electronic version of an article accepted for publication in Diabetes. The American Diabetes Association (ADA), publisher of Diabetes, is not responsible for any errors or omissions in this version of the manuscript or any version derived from it by third parties. The definitive publisher-authenticated version is available in Diabetes in print and online at http://diabetes.diabetesjournals.orgThe erratum to this article is available in ORE at http://hdl.handle.net/10871/40335Studies in type 1 diabetes indicate potential disease heterogeneity, notably in the rate of β-cell loss, responsiveness to immunotherapies, and, in limited studies, islet pathology. We sought evidence for different immunological phenotypes using two approaches. First, we defined blood autoimmune response phenotypes by combinatorial, multiparameter analysis of autoantibodies and autoreactive T-cell responses in 33 children/adolescents with newly diagnosed diabetes. Multidimensional cluster analysis showed two equal-sized patient agglomerations characterized by proinflammatory (interferon-γ-positive, multiautoantibody-positive) and partially regulated (interleukin-10-positive, pauci-autoantibody-positive) responses. Multiautoantibody-positive nondiabetic siblings at high risk of disease progression showed similar clustering. Additionally, pancreas samples obtained post mortem from a separate cohort of 21 children/adolescents with recently diagnosed type 1 diabetes were examined immunohistologically. This revealed two distinct types of insulitic lesions distinguishable by the degree of cellular infiltrate and presence of B cells that we termed "hyper-immune CD20Hi" and "pauci-immune CD20Lo." Of note, subjects had only one infiltration phenotype and were partitioned by this into two equal-sized groups that differed significantly by age at diagnosis, with hyper-immune CD20Hi subjects being 5 years younger. These data indicate potentially related islet and blood autoimmune response phenotypes that coincide with and precede disease. We conclude that different immunopathological processes (endotypes) may underlie type 1 diabetes, carrying important implications for treatment and prevention strategies.JDRFNational Institute for Health Research (NIHR) Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust and King’s College LondonEuropean Union (EU FP7) award - Persistent Virus Infection in Diabetes Network Study Group (PEVNET)EU FP7 Large-Scale Focused Collaborative Research Project on Natural Immunomodulators as Novel Immunotherapies for Type 1 Diabetes (NAIMIT)EU FP7 Large-Scale Focused Collaborative Research Project on β-cell preservation through antigen-specific immunotherapy in Type 1 Diabetes: Enhanced Epidermal Antigen Delivery Systems (EE-ASI)National Institutes of Health (NIH)National Institute of Diabetes and Digestive and Kidney DiseasesNational Institute of Allergy and Infectious DiseasesEunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNational Center for Research ResourcesGeneral Clinical Research CenterAmerican Diabetes Association (ADA