There are numerous reference equations available for the single-breath transfer factor of the lung for carbon monoxide (
); however, it is not always clear which reference set should be used in ...clinical practice. The aim of the study was to develop the Global Lung Function Initiative (GLI) all-age reference values for
Data from 19 centres in 14 countries were collected to define
reference values. Similar to the GLI spirometry project, reference values were derived using the LMS (lambda, mu, sigma) method and the GAMLSS (generalised additive models for location, scale and shape) programme in R.12 660
measurements from asymptomatic, lifetime nonsmokers were submitted; 85% of the submitted data were from Caucasians. All data were uncorrected for haemoglobin concentration. Following adjustments for elevation above sea level, gas concentration and assumptions used for calculating the anatomic dead space volume, there was a high degree of overlap between the datasets. Reference values for Caucasians aged 5-85 years were derived for
, transfer coefficient of the lung for carbon monoxide and alveolar volume.This is the largest collection of normative
data, and the first global reference values available for
.
Background Eosinophilic airway inflammation is heterogeneous in asthmatic patients. We recently described a distinct subtype of asthma defined by the expression of genes inducible by TH 2 cytokines ...in bronchial epithelium. This gene signature, which includes periostin, is present in approximately half of asthmatic patients and correlates with eosinophilic airway inflammation. However, identification of this subtype depends on invasive airway sampling, and hence noninvasive biomarkers of this phenotype are desirable. Objective We sought to identify systemic biomarkers of eosinophilic airway inflammation in asthmatic patients. Methods We measured fraction of exhaled nitric oxide (F eno ), peripheral blood eosinophil, periostin, YKL-40, and IgE levels and compared these biomarkers with airway eosinophilia in asthmatic patients. Results We collected sputum, performed bronchoscopy, and matched peripheral blood samples from 67 asthmatic patients who remained symptomatic despite maximal inhaled corticosteroid treatment (mean FEV1 , 60% of predicted value; mean Asthma Control Questionnaire ACQ score, 2.7). Serum periostin levels are significantly increased in asthmatic patients with evidence of eosinophilic airway inflammation relative to those with minimal eosinophilic airway inflammation. A logistic regression model, including sex, age, body mass index, IgE levels, blood eosinophil numbers, F eno levels, and serum periostin levels, in 59 patients with severe asthma showed that, of these indices, the serum periostin level was the single best predictor of airway eosinophilia ( P = .007). Conclusion Periostin is a systemic biomarker of airway eosinophilia in asthmatic patients and has potential utility in patient selection for emerging asthma therapeutics targeting TH 2 inflammation.
To determine the effect of baseline estimated glomerular filtration rate (eGFR) on the causal association between intravenous iodinated contrast material exposure and subsequent development of acute ...kidney injury (AKI) in propensity score-matched groups of patients who underwent contrast material-enhanced or unenhanced computed tomography (CT).
This retrospective study was HIPAA compliant and institutional review board approved. All patients who underwent contrast-enhanced (contrast material group) or unenhanced (non-contrast material group) CT between 2000 and 2010 were identified and stratified according to baseline eGFR by using Kidney Disease Outcomes Quality Initiative cutoffs for chronic kidney disease into subgroups with eGFR of 90 or greater, 60-89, 30-59, and less than 30 mL/min/1.73 m(2). Propensity score generation and 1:1 matching of patients were performed in each eGFR subgroup. Incidence of AKI (serum creatinine SCr increase of ≥0.5 mg/dL ≥44.2 μmol/L above baseline) was compared in the matched subgroups by using the Fisher exact test.
A total of 12 508 propensity score-matched patients with contrast-enhanced and unenhanced scans met all inclusion criteria. In this predominantly inpatient cohort, the incidence of AKI significantly increased with decreasing baseline eGFR (P < .0001). However, this incidence was not significantly different between contrast material and non-contrast material groups in any eGFR subgroup; for the subgroup with eGFR of 90 or greater (n = 1642), odds ratio (OR) was 0.91 (95% confidence interval CI: 0.38, 2.15), P = .82; for the subgroup with eGFR of 60-89 (n = 3870), OR was 1.03 (95% CI: 0.66, 1.60), P = .99; for the subgroup with eGFR of 30-59 (n = 5510), OR was 0.94 (95% CI: 0.76, 1.18), P = .65; and for the subgroup with eGFR of less than 30 mL/min/1.73 m(2) (n = 1486), OR was 0.97 (95% CI: 0.72, 1.30), P = .89.
Diminished eGFR is associated with an increased risk of SCr-defined AKI following CT examinations. However, the risk of AKI is independent of contrast material exposure, even in patients with eGFR of less than 30 mL/min/1.73 m(2).
The acute toxicities of 19 chemicals were assessed using G. mellonella larvae. The results obtained were compared against LD50 values derived from in vitro cytotoxicity tests and against in vivo ...acute oral LD50 values. In general, cell culture systems overestimated the toxicity of chemicals, especially low toxicity chemicals. In contrast, toxicity testing in G. mellonella larvae was found to be a reliable predictor for low toxicity chemicals. For the 9 chemicals tested which were assigned to Globally Harmonised System (GHS) category 5, the toxicity measured in G. mellonella larvae was consistent with their GHS categorisation but cytotoxicity measured in 3T3 or NHK cells predicted 4 out of 9 chemicals as having low toxicity. A more robust assessment of the likely toxicity of chemicals in mammals could be made by taking into account their toxicities in both cell cultures and in G. mellonella larvae.
•The acute toxicities of 19 chemicals were assessed using G. mellonella larvae.•Globally Harmonised System category 5 chemicals were better predicted using G. mellonella larvae than cell culture systems.•A more robust assessment chemical toxicity would take into account activity in cell cultures and in G. mellonella larvae.
Infrastructure public-private partnerships (PPPs) are dominantly seen as part of an increasingly fragmented and uncertain public management paradigm known as New Public Governance (NPG). However, the ...effects of institutional maturity on PPP utilization within this domain remain understudied. In order to (re)define PPPs within the NPG paradigm, we develop a PPP institutional maturity model based on three institutional capabilities-legitimacy, trust, and capacity. We then use the U.S. PPP market as a case example to explore how the maturity of PPPs in an institutional setting depends on legitimacy, trust, and capacity in the PPP model.
Reservoirs of infectious HIV-1 persist despite years of combination antiretroviral therapy and make curing HIV-1 infections a major challenge. Most of the proviral DNA resides in CD4⁺T cells. Some of ...these CD4⁺T cells are clonally expanded; most of the proviruses are defective. It is not known if any of the clonally expanded cells carry replication-competent proviruses. We report that a highly expanded CD4⁺ T-cell clone contains an intact provirus. The highly expanded clone produced infectious virus that was detected as persistent plasma viremia during cART in an HIV-1–infected patient who had squamous cell cancer. Cells containing the intact provirus were widely distributed and significantly enriched in cancer metastases. These results show that clonally expanded CD4⁺T cells can be a reservoir of infectious HIV-1.
Huntington's disease (HD) is a fatal, dominant neurodegenerative disease caused by a polyglutamine repeat expansion in exon 1 of the HD gene, which encodes the huntingtin protein. We and others have ...shown that RNAi is a candidate therapy for HD because expression of inhibitory RNAs targeting mutant human HD transgenes improved neuropathology and behavioral deficits in HD mouse models. Here, we developed shRNAs targeting conserved sequences in human HD and mouse HD homolog (HDh) mRNAs to initiate preclinical testing in a knockin mouse model of HD. We screened 35 shRNAs in vitro and subsequently narrowed our focus to three candidates for in vivo testing. Unexpectedly, two active shRNAs induced significant neurotoxicity in mouse striatum, although HDh mRNA expression was reduced to similar levels by all three. Additionally, a control shRNA containing mismatches also induced toxicity, although it did not reduce HDh mRNA expression. Interestingly, the toxic shRNAs generated higher antisense RNA levels, compared with the nontoxic shRNA. These results demonstrate that the robust levels of antisense RNAs emerging from shRNA expression systems can be problematic in the mouse brain. Importantly, when sequences that were toxic in the context of shRNAs were placed into artificial microRNA (miRNA) expression systems, molecular and neuropathological readouts of neurotoxicity were significantly attenuated without compromising mouse HDh silencing efficacy. Thus, miRNA-based approaches may provide more appropriate biological tools for expressing inhibitory RNAs in the brain, the implications of which are crucial to the development of RNAi for both basic biological and therapeutic applications.
To determine the risk of emergent dialysis and short-term mortality following intravenous iodinated contrast material exposure.
This single-center retrospective study was HIPAA compliant and ...institutional review board approved. All contrast material-enhanced (contrast group) and unenhanced (noncontrast group) abdominal, pelvic, and thoracic computed tomography scans from 2000-2010 were identified. Patients in the contrast and noncontrast groups were compared following propensity score-based 1:1 matching to reduce intergroup selection bias. Patients with preexisting diabetes mellitus, congestive heart failure, or chronic or acute renal failure were identified as high-risk patient subgroups for nephrotoxicity. The effects of contrast material exposure on the rate of acute kidney injury ( AKI acute kidney injury ) (serum creatinine level ≥ 0.5 mg/dL 44.2 μmol/L above baseline within 24-72 hours of exposure) and dialysis or death within 30 days of exposure were determined by using odds ratios ( OR odds ratio s) and covariate-adjusted Cox proportional hazards models. Results were validated with a bootstrapped sensitivity analysis.
The 1:1 matching on the basis of the propensity score yielded a cohort of 21 346 patients (10 673 in the contrast group, 10 673 in the noncontrast group). Within this cohort, the risks of AKI acute kidney injury ( OR odds ratio , 0.94; 95% confidence interval CI confidence interval : 0.83, 1.07; P = .38), emergent dialysis ( OR odds ratio , 0.96; 95% CI confidence interval : 0.54, 1.60; P = .89), and 30-day mortality (hazard ratio HR hazard ratio , 0.97; 95% CI confidence interval : 0.87, 1.06; P = .45) were not significantly different between the contrast group and the noncontrast group. Although patients who developed AKI acute kidney injury had higher rates of dialysis and mortality, contrast material exposure was not an independent risk factor for either outcome for dialysis ( OR odds ratio , 0.89; 95% CI confidence interval : 0.40, 2.01; P = .78) or for mortality ( HR hazard ratio , 1.03; 95% CI confidence interval : 0.82, 1.32; P = .63), even among patients with compromised renal function or predisposing comorbidities.
Intravenous contrast material administration was not associated with excess risk of AKI acute kidney injury , dialysis, or death, even among patients with comorbidities reported to predispose them to nephrotoxicity.
Inflammatory cells, most especially neutrophils, can be a necessary component of the antitumor activity occurring after administration of photodynamic therapy. Generation of neutrophil responses has ...been suggested to be particularly important in instances when the delivered photodynamic therapy (PDT) dose is insufficient. In these cases, the release of neutrophil granules and engagement of antitumor immunity may play an important role in eliminating residual disease. Herein, we utilize in vivo imaging of luminol chemiluminescence to noninvasively monitor neutrophil activation after PDT administration. Studies were performed in the AB12 murine model of mesothelioma, treated with Photofrin‐PDT. Luminol‐generated chemiluminescence increased transiently 1 h after PDT, followed by a subsequent decrease at 4 h after PDT. The production of luminol signal was not associated with the influx of Ly6G+ cells, but was related to oxidative burst, as an indicator of neutrophil function. Most importantly, greater levels of luminol chemiluminescence 1 h after PDT were prognostic of a complete response at 90 days after PDT. Taken together, this research supports an important role for early activity by Ly6G+ cells in the generation of long‐term PDT responses in mesothelioma, and it points to luminol chemiluminescence as a potentially useful approach for preclinical monitoring of neutrophil activation by PDT.
As neutrophils can be necessary for antitumor activity after photodynamic therapy, we utilized in vivo imaging of luminol chemiluminescence to noninvasively monitor neutrophil activation after its administration. In murine mesothelioma, chemiluminescence increased at 1 h after photodynamic therapy (PDT) and subsequently decreased at 4 h after PDT. Luminol signal was not representative of neutrophil influx, but instead with neutrophil function (oxidative burst). Importantly, greater luminol signal 1 h after PDT predicted tumors with no regrowth after 90 days. This supports an important role for early neutrophil activity in optimal PDT response and highlights luminol chemiluminescence as a useful approach for preclinical studies.
To examine the effect of intravenous iodinated contrast material administration on the subsequent development of acute kidney injury (AKI), emergent dialysis, and short-term mortality using a ...propensity score-adjusted analysis of computed tomographic scan recipients with chronic kidney disease (CKD).
In this institutional review board-approved retrospective study, all patients with CKD who received a contrast-enhanced (contrast group) or unenhanced (noncontrast group) computed tomographic scan from January 1, 2000, to August 1, 2013 were identified. Patients were subdivided into CKD stage III (baseline estimated glomerular filtration rate, 30-59 mL/min per 1.73 m(2)) and CKD stage IV-V (baseline estimated glomerular filtration rate, <30 mL/min per 1.73 m(2)) subgroups and separately underwent propensity score generation, stratification, and 1:1 matching. Rates of AKI, 30-day emergent dialysis, and mortality were compared between contrast and noncontrast groups. Sensitivity analyses examining only patients with stable prescan serum creatinine levels and incorporating intravenous fluid administration at the time of the CT scan into the model were also performed.
A total of 6902 patients (4496 CKD stage III, matched: 1220 contrast and 1220 noncontrast; 2086 CKD stage IV-V, matched: 491 contrast and 491 noncontrast) were included in the study. After propensity score adjustment, rates of AKI, emergent dialysis, and mortality were not significantly higher in the contrast group than in the noncontrast group in either CKD subgroup (CKD stage III: OR, 0.65-1.00; P<.001-.99 and CKD stage IV-V: OR, 0.93-2.33; P=.22-.99). Both sensitivity analyses revealed similar results.
Intravenous contrast material administration was not associated with an increased risk of AKI, emergent dialysis, and short-term mortality in a cohort of patients with diminished renal function.
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