Cellular and genetic control of antibody responses in vitro. III. Immune response gene regulation of accessory cell function

The possibility was investigated that Ir genes regulate the function of cells other than T or B cells in the primary IgM responses to the synthetic antigens trinitrophenylated poly-L-(Tyr,Glu)-poly-D,L-Ala--poly-L-Lys [TNP-(T,G)-A--L]and trinitrophenylated poly-,-(His,Glu)-poly-D, L-Ala--poly-L-Lys [TNP-(H,G)-A--L]. The primary responses of (B10 × B10.A)F(1) spleen cells to both antigens were abrogated by Sephadex G-10 passage, and restored by the addition of spleen adherent cells. The cell type in the spleen adherent cell population active in reconstituting the responses to TNP-(T,G)-A--L and TNP-(H,G)-A--L was a non-T, non-B, radiation-resistant, glass-adherent spleen cell. The responses of Sephadex G-10-passed (responder x nonresponder)F(1) spleen cells to TNP-(T,G)-A--L or TNP-(H,G)-A--L were reconstituted by spleen adherent cells from only responder strains. Spleen adherent cells from F(1) mice reconstituted the responses to both antigens. Spleen adherent cells from each of the strains tested reconstituted the non- Ir gene-controlled response to a third antigen, TNP-keyhole limpet hemocyanin. The inability of spleen adherent cells from nonresponder strains to reconstitute the responses to either TNP-(T,G)-A--L or TNP-(H,G)-A--L was not a result of active suppression induced by the presence of nonresponder adherent cells, since a mixture of responder and nonresponder spleen adherent cells reconstituted the responses to both antigens. The use of spleen adherent cells from recombinant strains demonstrated that the autosomal dominant genes controlling the ability of spleen adherent cells to function as accessory cells in the responses to TNP-(T,G)-A--L and TNP-(H,G)-A--L are located in the K or I-A regions of the responder H-2 complex, the same region(s) of H-2 as the Ir genes controlling overall in vitro and in vivo responsiveness to these antigens

Incidence of fatal food anaphylaxis in people with food allergy: a systematic review and meta-analysis

BACKGROUND: Food allergy is a common cause of anaphylaxis, but the incidence of fatal food anaphylaxis is not known. The aim of this study was to estimate the incidence of fatal food anaphylaxis for people with food allergy and relate this to other mortality risks in the general population. METHODS: We undertook a systematic review and meta-analysis, using the generic inverse variance method. Two authors selected studies by consensus, independently extracted data and assessed the quality of included studies using the Newcastle-Ottawa assessment scale. We searched Medline, Embase, PsychInfo, CINAHL, Web of Science, LILACS or AMED, between January 1946 and September 2012, and recent conference abstracts. We included registries, databases or cohort studies which described the number of fatal food anaphylaxis cases in a defined population and time period and applied an assumed population prevalence rate of food allergy. RESULTS: We included data from 13 studies describing 240 fatal food anaphylaxis episodes over an estimated 165 million food-allergic person-years. Study quality was mixed, and there was high heterogeneity between study results, possibly due to variation in food allergy prevalence and data collection methods. In food-allergic people, fatal food anaphylaxis has an incidence rate of 1.81 per million person-years (95%CI 0.94, 3.45; range 0.63, 6.68). In sensitivity analysis with different estimated food allergy prevalence, the incidence varied from 1.35 to 2.71 per million person-years. At age 0–19, the incidence rate is 3.25 (1.73, 6.10; range 0.94, 15.75; sensitivity analysis 1.18–6.13). The incidence of fatal food anaphylaxis in food-allergic people is lower than accidental death in the general European population. CONCLUSION: Fatal food anaphylaxis for a food-allergic person is rarer than accidental death in the general population

Development of a web-based insulin decision aid for the elderly: usability barriers and guidelines

In recent years, researchers have attempted to shift patient decision aids (PDAs) from paper-based to web-based to increase its accessibility. Insulin decision aids help diabetes patients, most of whom are elderly to make an informed decision to start insulin. However, the lack of usability guidelines applicable for such target group causes developers to struggle to answer the challenging question ‘How can such web service be made usable, and, ultimately, acceptable and accessible for elderly patients?’. Hence, the purpose of this study is to identify the common usability requirements that may facilitate good practices to empower elderly diabetes patients in utilizing a web-based insulin decision aid for their benefit. We set out an approach to use prototyping and retrospective think-aloud techniques to explore web usability barriers that elderly patients may encounter when using an insulin decision aid web site and use the feedback for improving the prototype. Usability requirements were captured iteratively through scoping, brainstorming, prototype, testing and evaluating. The study suggests that the insights from experts and users are equally important to assure the validity of the identified usability guidelines; they reflect the accessibility needs of the aging community while complementing the key requirements of an insulin decision aid. The study contributes to recommend web usability guidelines backed by a series of expert and user evaluations which could be a proactive resource to improve usability, acceptability and accessibility of online insulin decision aids for elderly with diabetes

An Analysis of Factors Contributing to the Development of Total Parenteral Nutrition‐Induced Cholestasis

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141659/1/jpen0586.pd

ADEPT - Abnormal Doppler Enteral Prescription Trial

<p>Abstract</p> <p>Background</p> <p>Pregnancies complicated by abnormal umbilical artery Doppler blood flow patterns often result in the baby being born both preterm and growth-restricted. These babies are at high risk of milk intolerance and necrotising enterocolitis, as well as post-natal growth failure, and there is no clinical consensus about how best to feed them. Policies of both early milk feeding and late milk feeding are widely used. This randomised controlled trial aims to determine whether a policy of early initiation of milk feeds is beneficial compared with late initiation. Optimising neonatal feeding for this group of babies may have long-term health implications and if either of these policies is shown to be beneficial it can be immediately adopted into clinical practice.</p> <p>Methods and Design</p> <p>Babies with gestational age below 35 weeks, and with birth weight below 10th centile for gestational age, will be randomly allocated to an "early" or "late" enteral feeding regimen, commencing milk feeds on day 2 and day 6 after birth, respectively. Feeds will be gradually increased over 9-13 days (depending on gestational age) using a schedule derived from those used in hospitals in the Eastern and South Western Regions of England, based on surveys of feeding practice. Primary outcome measures are time to establish full enteral feeding and necrotising enterocolitis; secondary outcomes include sepsis and growth. The target sample size is 400 babies. This sample size is large enough to detect a clinically meaningful difference of 3 days in time to establish full enteral feeds between the two feeding policies, with 90% power and a 5% 2-sided significance level. Initial recruitment period was 24 months, subsequently extended to 38 months.</p> <p>Discussion</p> <p>There is limited evidence from randomised controlled trials on which to base decisions regarding feeding policy in high risk preterm infants. This multicentre trial will help to guide clinical practice and may also provide pointers for future research.</p> <p>Trial registration</p> <p>Current Controlled Trials ISRCTN: 87351483</p

Extended Interferon-Alpha Therapy Accelerates Telomere Length Loss in Human Peripheral Blood T Lymphocytes

BACKGROUND: Type I interferons have pleiotropic effects on host cells, including inhibiting telomerase in lymphocytes and antiviral activity. We tested the hypothesis that long-term interferon treatment would result in significant reduction in average telomere length in peripheral blood T lymphocytes. METHODS/PRINCIPAL FINDINGS: Using a flow cytometry-based telomere length assay on peripheral blood mononuclear cell samples from the Hepatitis-C Antiviral Long-term Treatment against Cirrhosis (HALT-C) study, we measured T cell telomere lengths at screening and at months 21 and 45 in 29 Hepatitis-C virus infected subjects. These subjects had failed to achieve a sustained virologic response following 24 weeks of pegylated-interferon-alpha plus ribavirin treatment and were subsequently randomized to either a no additional therapy group or a maintenance dose pegylated-IFNalpha group for an additional 3.5 years. Significant telomere loss in naive T cells occurred in the first 21 months in the interferon-alpha group. Telomere losses were similar in both groups during the final two years. Expansion of CD8(+)CD45RA(+)CD57(+) memory T cells and an inverse correlation of alanine aminotransferase levels with naive CD8(+) T cell telomere loss were observed in the control group but not in the interferon-alpha group. Telomere length at screening inversely correlated with Hepatitis-C viral load and body mass index. CONCLUSIONS/SIGNIFICANCE: Sustained interferon-alpha treatment increased telomere loss in naive T cells, and inhibited the accumulation of T cell memory expansions. The durability of this effect and consequences for immune senescence need to be defined

The kinase p38 activated by the metabolic regulator AMPK and scaffold TAB1 drives the senescence of human T cells

We thank S.S. Marelli for discussions. Supported by the Medical Research Council (A.L.), the Biotechnology and Biological Science Research Council (BB/J006750/1 to A.N.A. and S.M.H.) and the Instituto de Salud Carlos III, Spain (D.E.)