Natural killer cells become tolerogenic after interaction with apoptotic cells

NK cells are effectors in innate immunity and also participate in immunoregulation through the release of TGF-β1 and lysis of activated/autoreactive T cells. Apoptotic cells (AC) have been shown to induce tolerogenic properties in innate immune cells, including macrophages and dendritic cells, but not NK cells. In this study, we demonstrated that after interaction with AC, NK cells released TGF-β1, which in turn suppressed the production of IFN-γ by NK cells upon IL-12 and IgG activation.We further identified phosphatidylserine as a potential target on AC for the NK cells, as phosphatidylserine could stimulate NK cells to release TGF-β1, which in turn suppressed CD4+ T-cell proliferation and activation. Moreover, AC-treated NK cells displayed cytotoxicity against autologous-activated CD4 + T cells by upregulating NKp46. This lysis occurred in part through the NKp46-vimentin pathway, as activated CD4+ T cells expressed vimentin on the cell surface and blocking of vimentin or NKp46, but not other NK-cell receptors, significantly suppressed the NK-cell cytotoxicity.We report here a novel interaction between NK cells and AC, resulting in the tolerogenic properties of NK cells required for immune contraction. © 2010 Wiley-VCH Verlag GmbH & Co. KGaA.postprin

Reproducibility of adenosine stress cardiovascular magnetic resonance in multi-vessel symptomatic coronary artery disease

<p>Abstract</p> <p>Purpose</p> <p>First-pass perfusion cardiovascular magnetic resonance (CMR) is increasingly being utilized in both clinical practice and research. However, the reproducibility of this technique remains incompletely evaluated, particularly in patients with severe coronary artery disease (CAD). The purpose of this study was to determine the inter-study reproducibility of adenosine stress CMR in patients with symptomatic multi-vessel CAD and those at low risk for CAD.</p> <p>Methods</p> <p>Twenty patients (10 with CAD, 10 low risk CAD) underwent two CMR scans 8 ± 2 days apart. Basal, mid and apical left ventricular short axis slices were acquired using gadolinium 0.05 mmol/kg at peak stress (adenosine, 140 μ/kg/min, 4 min) and rest. Myocardial perfusion was evaluated qualitatively by assessing the number of ischemic segments, and semi-quantitatively by determining the myocardial perfusion reserve index (MPRi) using a normalized upslope method. Inter-study and observer reproducibility were assessed--the latter being defined by the coefficient of variation (CoV), which was calculated from the standard deviation of the differences of the measurements, divided by the mean. Additionally, the percentage of myocardial segments with perfect agreement and inter- and intra-observer MPRi correlation between studies, were also determined.</p> <p>Results</p> <p>The CoV for the number of ischemic segments was 31% with a mean difference of -0.15 ± 0.88 segments and 91% perfect agreement between studies. MPRi was lower in patients with CAD (1.13 ± 0.21) compared to those with low risk CAD (1.59 ± 0.58), p = 0.02. The reproducibility of MPRi was 19% with no significant difference between patients with CAD and those with low risk CAD (p = 0.850). Observer reproducibility for MPRi was high: inter-observer CoV 9%, r = 0.93 and intra-observer CoV 5%, r = 0.94. For trials using perfusion CMR as an endpoint, an estimated sample size of 12 subjects would be required to detect a two-segment change in the number of ischemic segments (power 0.9, α 0.05).</p> <p>Conclusions</p> <p>Adenosine stress CMR, by qualitative and semi-quantitative normalized upslope analyses are reproducible techniques in both patients with multi-vessel CAD and those without known CAD. The robust inter-study reproducibility of perfusion CMR supports its clinical and research application.</p

The association of RANTES polymorphism with severe acute respiratory syndrome in Hong Kong and Beijing Chinese

<p>Abstract</p> <p>Background</p> <p>Chemokines play important roles in inflammation and antiviral action. We examined whether polymorphisms of <it>RANTES, IP-10 </it>and <it>Mig </it>affect the susceptibility to and outcome of severe acute respiratory syndrome (SARS).</p> <p>Methods</p> <p>We tested the polymorphisms of <it>RANTES, IP-10 </it>and <it>Mig </it>for their associations with SARS in 495 Hong Kong Chinese SARS patients and 578 controls. Then we tried to confirm the results in 356 Beijing Chinese SARS patients and 367 controls.</p> <p>Results</p> <p><it>RANTES </it>-28 G allele was associated with SARS susceptibility in Hong Kong Chinese (<it>P </it>< 0.0001, OR = 2.80, 95%CI:2.11–3.71). Individuals with <it>RANTES </it>-28 CG and GG genotypes had a 3.28-fold (95%CI:2.32–4.64) and 3.06-fold (95%CI:1.47–6.39) increased risk of developing SARS respectively (<it>P </it>< 0.0001). This -28 G allele conferred risk of death in a gene-dosage dependent manner (<it>P </it>= 0.014) with CG and GG individuals having a 2.12-fold (95% CI: 1.11–4.06) and 4.01-fold (95% CI: 1.30–12.4) increased risk. For the replication of <it>RANTES </it>data in Beijing Chinese, the -28 G allele was not associated with susceptibility to SARS. However, -28 CG (OR = 4.27, 95%CI:1.64–11.1) and GG (OR = 3.34, 95%CI:0.37–30.7) were associated with admission to intensive care units or death due to SARS (<it>P </it>= 0.011).</p> <p>Conclusion</p> <p><it>RANTES </it>-28 G allele plays a role in the pathogenesis of SARS.</p

Trends in CD4 counts in HIV-infected patients with HIV viral load monitoring while on combination antiretroviral treatment: results from The TREAT Asia HIV Observational Database

<p>Abstract</p> <p>Background</p> <p>The aim of this study was to examine the relationship between trends in CD4 counts (slope) and HIV viral load (VL) after initiation of combination antiretroviral treatment (cART) in Asian patients in The TREAT Asia HIV Observational Database (TAHOD).</p> <p>Methods</p> <p>Treatment-naive HIV-infected patients who started cART with three or more and had three or more CD4 count and HIV VL tests were included. CD4 count slopes were expressed as changes of cells per microliter per year. Predictors of CD4 count slopes from 6 months after initiation were assessed by random-effects linear regression models.</p> <p>Results</p> <p>A total of 1676 patients (74% male) were included. The median time on cART was 4.2 years (IQR 2.5-5.8 years). In the final model, CD4 count slope was associated with age, concurrent HIV VL and CD4 count, disease stage, hepatitis B or C co-infection, and time since cART initiation. CD4 count continues to increase with HIV VL up to 20 000 copies/mL during 6-12 months after cART initiation. However, the HIV VL has to be controlled below 5 000, 4 000 and 500 copies/mL for the CD4 count slope to remain above 20 cells/microliter per year during 12-18, 18-24, and beyond 24 months after cART initiation.</p> <p>Conclusions</p> <p>After cART initiation, CD4 counts continued to increase even when the concurrent HIV VL was detectable. However, HIV VL needed to be controlled at a lower level to maintain a positive CD4 count slope when cART continues. The effect on long-term outcomes through the possible development of HIV drug resistance remains uncertain.</p

Predictors of mortality in HIV-associated hospitalizations in Portugal: a hierarchical survival model

<p>Abstract</p> <p>Background</p> <p>The beneficial effects of highly active antiretroviral therapy, increasing survival and the prevention of AIDS defining illness development are well established. However, the annual Portuguese hospital mortality is still higher than expected. It is crucial to understand the hospitalization behaviour to better allocate resources. This study investigates the predictors of mortality in HIV associated hospitalizations in Portugal through a hierarchical survival model.</p> <p>Methods</p> <p>The study population consists of 12,078 adult discharges from patients with HIV infection diagnosis attended at Portuguese hospitals from 2005–2007 that were registered on the diagnosis-related groups' database.</p> <p>We used discharge and hospital level variables to develop a hierarchical model. The discharge level variables were: age, gender, type of admission, type of diagnoses-related group, related HIV complication, the region of the patient's residence, the number of diagnoses and procedures, the Euclidean distance from hospital to the centroid of the patient's ward, and if patient lived in the hospital's catchment area. The hospital characteristics include size and hospital classification according to the National Health System. Kaplan-Meier plots were used to examine differences in survival curves. Cox proportional hazard models with frailty were applied to identify independent predictors of hospital mortality and to calculate hazard ratios (HR).</p> <p>Results</p> <p>The Cox proportional model with frailty showed that male gender, older patient, great number of diagnoses and pneumonia increased the hazard of HIV related hospital mortality. On the other hand tuberculosis was associated with a reduced risk of death. Central hospital discharge also presents less risk of mortality.</p> <p>The frailty variance was small but statistically significant, indicating hazard ratio heterogeneity among hospitals that varied between 0.67 and 1.34, and resulted in two hospitals with HR different from the average risk.</p> <p>Conclusion</p> <p>The frailty model suggests that there are unmeasured factors affecting mortality in HIV associated hospitalizations. Consequently, for healthcare policy purposes, hospitals should not all be treated in an equal manner.</p

Acute bronchiolitis in infancy as risk factor for wheezing and reduced pulmonary function by seven years in Akershus County, Norway

BACKGROUND: Acute viral bronchiolitis is one of the most common causes of hospitalisation during infancy in our region with respiratory syncytial virus (RSV) historically being the major causative agent. Many infants with early-life RSV bronchiolitis have sustained bronchial hyperreactivity for many years after hospitalisation and the reasons for this are probably multifactorial. The principal aim of the present study was to investigate if children hospitalised for any acute viral bronchiolitis during infancy in our region, and not only those due to RSV, had more episodes of subsequent wheezing up to age seven years and reduced lung function at that age compared to children not hospitalised for acute bronchiolitis during infancy. A secondary aim was to compare the hospitalised infants with proven RSV bronchiolitis (RS+) to the hospitalised infants with non-RSV bronchiolitis (RS-) according to the same endpoints. METHODS: 57 infants hospitalised at least once with acute viral bronchiolitis during two consecutive winter seasons in 1993–1994 were examined at age seven years. An age-matched control group of 64 children, who had not been hospitalised for acute viral bronchiolitis during infancy, were recruited from a local primary school. Epidemiological and clinical data were collected retrospectively from hospital discharge records and through structured clinical interviews and physical examinations at the follow-up visit. RESULTS: The children hospitalised for bronchiolitis during infancy had decreased lung function, more often wheezing episodes, current medication and follow-up for asthma at age seven years than did the age matched controls. They also had lower average birth weight and more often first order family members with asthma. We did not find significant differences between the RSV+ and RSV- groups. CONCLUSION: Children hospitalised for early-life bronchiolitis are susceptible to recurrent wheezing and reduced pulmonary function by seven years compared to age-matched children not hospitalised for early-life bronchiolitis. We propose that prolonged bronchial hyperreactivity could follow early-life RSV negative as well as RSV positive bronchiolitis

Enabling New ALMA Science with Improved Support for Time-Domain Observations

While the Atacama Large Millimeter/submillimeter Array (ALMA) is a uniquely powerful telescope, its impact in certain fields of astrophysics has been limited by observatory policies rather than the telescope's innate technical capabilities. In particular, several observatory policies present challenges for observations of variable, mobile, and/or transient sources --- collectively referred to here as "time-domain" observations. In this whitepaper we identify some of these policies, describe the scientific applications they impair, and suggest changes that would increase ALMA's science impact in Cycle 6 and beyond. Parties interested in time-domain science with ALMA are encouraged to join the ALMA Time-domain Special Interest Group (ATSIG) by signing up for the ATSIG mailing list at https://groups.google.com/group/alma-td-sig

Enabling New ALMA Science with Improved Support for Time-Domain Observations

While the Atacama Large Millimeter/submillimeter Array (ALMA) is a uniquely powerful telescope, its impact in certain fields of astrophysics has been limited by observatory policies rather than the telescope's innate technical capabilities. In particular, several observatory policies present challenges for observations of variable, mobile, and/or transient sources --- collectively referred to here as "time-domain" observations. In this whitepaper we identify some of these policies, describe the scientific applications they impair, and suggest changes that would increase ALMA's science impact in Cycle 6 and beyond. Parties interested in time-domain science with ALMA are encouraged to join the ALMA Time-domain Special Interest Group (ATSIG) by signing up for the ATSIG mailing list at https://groups.google.com/group/alma-td-sig