The purpose of this study was to investigate the relationship between donor-recipient height, gender and predicted estimates of total lung capacity (pTLC) mismatches and post-transplant survival.
The ...lung transplant databases at three programs were reviewed. The pTLC ratios (donor pTLC/recipient pTLC) and height ratios (donor height/recipient height) were calculated retrospectively. Patients were grouped according to pTLC ratio ≤1.0 or >1.0 and height ratio ≤1.0 or >1.0, and according to gender (mis-)matching. A time-to-event analysis was performed for risk of death after transplantation conditional on 30-day survival using Kaplan-Meier survival and Cox proportional hazard models.
There were 211 adult bilateral lung transplant recipients who qualified for the analysis. Mean follow-up was comparable for all cohorts (range 2.21 to 3.85 years). In the univariate Cox proportional hazard models, a pTLC ratio >1.0 (HR 0.43, p = 0.002) and a height ratio >1.0 (HR 0.61, p = 0.03) were associated with better survival, and a female-donor-to-male-recipient gender mismatch (F-to-M) was associated with worse survival (HR 2.35, p = 0.01). In the multivariate Cox proportional hazard model accounting for F-to-M gender mismatch and height ratio >1.0, a pTLC ratio >1.0 remained associated with survival (HR 0.38, p = 0.015). However, accounting for a pTLC ratio >1.0, a height ratio of >1.0 and F-to-M mismatch were not associated with survival.
A pTLC ratio >1.0 is associated with improved survival after bilateral lung transplantation. The pTLC ratio might better reflect allograft-thorax mismatch than the height ratio, as it also accounts for effects of gender on lung and thoracic volumes.
Background The genetic determinants of the human innate immune response are poorly understood. Apolipoprotein (Apo) E, a lipid-trafficking protein that affects inflammation, has well-described ...wild-type (ε3) and disease-associated (ε2 and ε4) alleles, but its connection to human innate immunity is undefined. Objective We sought to define the relationship of APOε4 to the human innate immune response. Methods We evaluated APOε4 in several functional models of the human innate immune response, including intravenous LPS challenge in human subjects, and assessed APOε4 association to organ injury in patients with severe sepsis, a disease driven by dysregulated innate immunity. Results Whole blood from healthy APOε3 / APOε4 volunteers induced higher cytokine levels on ex vivo stimulation with Toll-like receptor (TLR) 2, TLR4, or TLR5 ligands than blood from APOε3 / APOε3 patients, whereas TLR7/8 responses were similar. This was associated with increased lipid rafts in APOε3/APOε4 monocytes. By contrast, APOε3 / APOε3 and APOε3 / APOε4 serum neutralized LPS equivalently and supported similar LPS responses in Apoe -deficient macrophages, arguing against a differential role for secretory APOE4 protein. After intravenous LPS, APOε3/APOε4 patients had higher hyperthermia and plasma TNF-α levels and earlier plasma IL-6 than APOε3/APOε3 patients. APOE4-targeted replacement mice displayed enhanced hypothermia, plasma cytokines, and hepatic injury and altered splenic lymphocyte apoptosis after systemic LPS compared with APOE3 counterparts. In a cohort of 828 patients with severe sepsis, APOε4 was associated with increased coagulation system failure among European American patients. Conclusions APOε4 is a determinant of the human innate immune response to multiple TLR ligands and associates with altered patterns of organ injury in human sepsis.
Background Sensitization to house dust mite allergens is strongly correlated with asthma. Der p 7 elicits strong IgE antibody and T-cell responses in patients with mite allergy. However, the ...structure and biological function of this important allergen are unknown. Allergen function might contribute to allergenicity, as shown for the protease activity of group 1 mite allergens and the interaction with the innate immune system by group 2 mite allergens. Objective We sought to determine the crystal structure of Der p 7 and to investigate its biological function. Methods X-ray crystallography was used to determine the Der p 7 structure. Nuclear magnetic resonance analysis and biochemical assays were used to examine the binding of Der p 7 to predicted ligands. Results Der p 7 has an elongated structure, with two 4-stranded antiparallel β-sheets that wrap around a long C-terminal helix. The fold of Der p 7 is similar to that of LPS-binding protein (LBP), which interacts with Toll-like receptors after binding LPS and other bacterially derived lipid ligands. Nuclear magnetic resonance and biochemical assays indicate that Der p 7 does not bind LPS but binds with weak affinity to the bacterial lipopeptide polymyxin B in the predicted binding site of Der p 7. Conclusions Der p 7 binds a bacterially derived lipid product, a common feature of some allergens. The finding that the group 7, as well as the group 2, mite allergens are structurally similar to different proteins in the Toll-like receptor pathway further strengthens the connections between dust mites, innate immunity, and allergy.
Background Cholesterol exerts complex effects on inflammation. There has been little investigation of whether serum cholesterol is associated with asthma, an inflammatory airways disease with great ...public health impact. Objective To determine relationships between levels of 3 serum cholesterol measures (total cholesterol TC, high-density lipoprotein cholesterol HDL-C, and non–HDL-C) and asthma/wheeze in a sample representative of the US population. Methods Cross-sectional study of 7005 participants age ≥6 years from the 2005 to 2006 National Health and Nutrition Examination Survey. Results Serum TC and non–HDL-C were lower in patients with current asthma than in subjects without current asthma in the overall population (TC, 188.5 vs 192.2 mg/dL; non–HDL-C, 133.9 vs 137.7 mg/dL; P < .05 for both), whereas HDL-C was not different. Adjusted odds ratios (ORs) from multivariate logistic regression per 1-SD increase of TC and non–HDL-C for current asthma were 0.92 (95% CI, 0.86-0.98) and 0.91 (95% CI, 0.85-0.98), respectively. On racial/ethnic stratification, these relationships reflect marked reductions unique to Mexican Americans (MAs; TC, 171.4 vs 189.3 mg/dL; P < .001; OR, 0.62; 95% CI, 0.48-0.80; non–HDL-C, 119.8 vs 137.9 mg/dL; P < .001; OR, 0.62; 95% CI, 0.48-0.79). Among MAs, the adjusted OR for wheeze requiring medical attention was 0.57 (95% CI, 0.43-0.75) for TC and 0.53 (95% CI, 0.33-0.85) for non–HDL-C. Relationships between cholesterol and asthma/wheeze were independent of body mass index and serum C-reactive protein, and similar between atopic and nonatopic participants. Conclusion Serum TC and non–HDL-C are inversely related to asthma in the US population, chiefly reflecting a relationship among MAs.
Background Although rodent studies indicate that atherosclerosis is a TH 1-mediated disease and that atopic TH 2 immunity is atheroprotective, findings in humans are conflicting. Total IgE (tIgE) is ...associated with atherosclerotic disease but has limited specificity for atopy. Objective Our aim was to determine the relation between atopy, as indicated by a broad panel of serum allergen-specific IgE (sIgE), and past myocardial infarction (MI) in a sample representative of the US population. Methods Data were analyzed from 4002 participants aged ≥20 years from the 2005-2006 National Health and Nutrition Examination Survey. Results Subjects reporting a history of MI had lower summed sIgE (5.51 vs 7.71 kU/L; P < .001) and were less likely to have ≥1 positive sIgE test (29.9% vs 44.6%; P = .02) or current hay fever (3.3% vs 7.6%; P = .002). After adjustment for age, sex, race/ethnicity, diabetes mellitus, hypertension, family history of MI, smoking, total/high-density lipoprotein cholesterol, body mass index, and C-reactive protein, the odds ratio (OR) for MI was 0.91 (95% CI, 0.85-0.97) per positive sIgE; 0.70 (95% CI, 0.57-0.85) per 2-fold increase in sumsIgE; and 0.82 (95% CI, 0.69-0.98) per 10% increase in the ratio of sumsIgE to tIgE. Analysis with 7 data-driven, prespecified allergen clusters found that house dust mite is the only allergen cluster for which sIgE is associated with reduced odds for MI (fully adjusted OR, 0.36; 95% CI, 0.20-0.64). Conclusion Serum sIgE is inversely related to MI in the US population in a manner independent of multiple coronary risk factors.
Reply Jaramillo, Renee, MStat; Cohn, Richard D., PhD; Crockett, Patrick W., PhD ...
Journal of allergy and clinical immunology,
2013, Letnik:
131, Številka:
6
Journal Article
Background The contribution of IL-1β signaling through the IL-1 type 1 receptor (IL-1R1) to the development of persistent LPS-induced airway disease has not been investigated. Objective To determine ...the importance of signaling through the IL-1 type 1 receptor in the development of LPS-induced airway disease. Methods We exposed IL-1R1–deficient (C57BL/6IL-1RI–/– ) mice to an aerosol of LPS or filtered air for 1 day, 1 week, or 4 weeks. Results After 4 weeks of LPS inhalation, C57BL/6IL-1RI–/– mice failed to develop significant submucosal thickening, whereas C57BL/6 mice had significantly thickened submucosa in small, medium, and large airways compared with those of unexposed control mice. Cell proliferation in the airways of both the 1-week and 4-week LPS-exposed C57BL/6IL-1RI–/– mice was significantly reduced compared with LPS-exposed C57BL/6 mice. mRNA for type III α-3 procollagen was significantly elevated over baseline in C57BL/6 yet remained unchanged compared with baseline in C57BL/6IL-1RI–/– mice after 1 week or 4 weeks of LPS inhalation. mRNA for tissue inhibitor of metalloprotease 1 in C57BL/6 mice in the 1-week and 4-week groups was significantly elevated over both control mice and C57BL/6IL-1RI–/– mice. Conclusion These data support the hypothesis that signaling through the IL-1 receptor modulates extracellular matrix homeostasis in response to inhaled LPS. Clinical implications Attenuating IL-1R1–mediated signaling might be an effective therapy against the development of airway remodeling in chronic inflammatory diseases.
Interventional pulmonology (IP) is a rapidly evolving subspecialty of pulmonary medicine. In the last 10 years, formal IP fellowships have increased substantially in number from five to now > 30. The ...vast majority of IP fellowship trainees are selected through the National Resident Matching Program, and validated in-service and certification examinations for IP exist. Practice standards and training guidelines for IP fellowship programs have been published; however, considerable variability in the environment, curriculum, and experience offered by the various fellowship programs remains, and there is currently no formal accreditation process in place to standardize IP fellowship training. Recognizing the need for more uniform training across the various fellowship programs, a multisociety accreditation committee was formed with the intent to establish common accreditation standards for all IP fellowship programs in the United States. This article provides a summary of those standards and can serve as an accreditation template for training programs and their offices of graduate medical education as they move through the accreditation process.
The Scleroderma Lung Study enrolled 158 patients with scleroderma-related interstitial lung disease in a placebo-controlled trial of oral cyclophosphamide (CYC). Although treatment-related benefits ...in pulmonary function, skin scores, and patient-centered outcomes were demonstrated after 1 year of therapy, the duration of benefit beyond 1 year was unclear.
A second year of follow-up was performed to determine if these effects persisted after stopping treatment.
A detailed analysis of data obtained over the two years of the study was performed.
Using a longitudinal joint model, we analyzed FVC, total lung capacity, transitional dyspnea index, Rodnan skin scores, and the Health Assessment Questionnaire-Disability Index during the second year, after adjusting for baseline values, baseline fibrosis score, and nonignorable missing data. Evaluable subjects (72 CYC; 73 placebo) included 93 who completed all visits plus 52 who completed at least 6 months of therapy and returned at 24 month or had their 24-month data imputed. The beneficial effects of CYC on pulmonary function and health status continued to increase through 18 months, after which they dissipated, whereas skin improvements dissipated after 12 months. In contrast, the positive effect on dyspnea persisted through 24 months. Adverse events were uncommon.
One year of CYC improved lung function, skin scores, dyspnea, and health status/disability, effects which either persisted or increased further for several months after stopping therapy. However, except for a sustained impact on dyspnea, all of these effects waned and were no longer apparent at 24 months. Treatment strategies aimed at extending the positive therapeutic effects observed with CYC should be considered. Clinical trial registered with www.clinicaltrials.gov (NCT 000004563).
Cyclophosphamide versus Placebo in Scleroderma Lung Disease Tashkin, Donald P; Elashoff, Robert; Clements, Philip J ...
New England journal of medicine/The New England journal of medicine,
06/2006, Letnik:
354, Številka:
25
Journal Article
Recenzirano
Odprti dostop
Interstitial lung disease is a common complication of systemic sclerosis, but there is no widely accepted treatment. In this randomized, placebo-controlled trial, treatment with cyclophosphamide for ...one year was associated with a small but significant improvement in lung function and symptom outcomes. The long-term adverse effects of this treatment are unknown.
Interstitial lung disease is a common complication of systemic sclerosis, but there is no widely accepted treatment. In this trial, treatment with cyclophosphamide for one year was associated with a small but significant improvement in lung function and symptom outcomes.
Scleroderma (also called systemic sclerosis) is an autoimmune connective-tissue disorder that is characterized by microvascular injury, excessive fibrosis of the skin, and distinctive visceral changes that can involve the lungs, heart, kidneys, and gastrointestinal tract. Forty percent of patients with scleroderma have ventilatory restriction, mainly as a result of interstitial lung disease. Together with pulmonary hypertension, ventilatory restriction has emerged as the leading cause of death related to scleroderma.
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The mortality rate among patients with severe ventilatory restriction (as reflected by a forced vital capacity FVC that is less than 50 percent of the predicted value) from scleroderma-related interstitial . . .
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