Search

Rationale: The role of pulmonary function before stem cell transplant as a potential risk factor for the development of early post-transplant respiratory failure and mortality is controversial.Methods: We conducted a retrospective analysis of the pretransplant pulmonary function of 2,852 patients who received their transplant between 1990 and 2001.Measurements: Pretransplant FEV(1), FVC, total lung capacity (TLC), diffusing capacity of carbon monoxide (DL(CO)), and the alveolar-arterial oxygen tension difference P(A-a)O(2) were measured and assessed for association with development of early respiratory failure and mortality in Cox proportional hazard logistic models.Main Results: In multivariate analyses, progressive decrease of all lung function parameters was associated with a stepwise increase in risk of developing early respiratory failure and mortality when assessed in independent models. On the basis of a significant correlation between FEV(1) and FVC (r = 0.81), FEV(1) and TLC (r = 0.61), and FVC and TLC (r = 0.80), and a lack of correlation between FEV(1) and DL(CO), we developed a pretransplant lung function score based on pretransplant FEV(1) and DL(CO) to determine the extent of pulmonary compromise before transplant. Multivariate analysis indicated that higher pretransplant lung function scores are associated with a significant increased risk for developing early respiratory failure (category II hazard ratio [HR], 1.4; category III HR, 2.2; category IV HR, 3.1; p < 0.001) and death (category II HR, 1.2; category III HR, 2.2; category IV HR, 2.7; p < 0.005).Conclusions: These results suggest that not only does compromised pretransplant lung function contribute to the risk for development of early respiratory failure and mortality but this risk may be estimated before transplant by grading the extent of FEV(1) and DL(CO) compromise. [ABSTRACT FROM AUTHOR]

Thomson scattered light is polarized in the same orientation as the incident laser beam at low electron temperatures (T e ). At high T e , part of the spectrum begins to become randomly polarized due to relativistic reasons. First measurements of the depolarized Thomson scattering spectrum were obtained from Joint European Torus (JET) pulses in 2016. This paper builds upon these initial measurements with the data obtained during 2021. These new measurements improve upon first results, in particular, by obtaining spectral measurements of the depolarized spectrum. The recent JET campaign was well suited to these measurements with long and hot plasmas. The resulting data are averaged over many plasmas and laser pulses to obtain a measurement of the amount of "p" and "s" scattered light as a function of T e . This experimentally obtained d(p/s)/dT e is then fitted and found to show reasonable agreement with the theoretically predicted depolarized fraction. Error estimates on the measured "p/s" have been obtained and show that the measurements are meaningful. This is good news for ITER for which the intention is to use this measurement as a check on T e determined by the core plasma Thomson scattering diagnostic by using conventional spectral measurement techniques.

MAST-U is equipped with a Super-X divertor, which aims to reduce heat flux to the target and promote detachment. Measurements of plasma electron density and temperature in the Super-X chamber offer insight into the processes at work in this type of divertor. First data have been obtained from the MAST-U divertor Thomson scattering diagnostic designed to measure these quantities. Following a Raman scattering calibration in nitrogen, the diagnostic operated over a number of plasma pulses in the first physics campaign. Electron density and temperature measurements have been taken in attached and detached conditions as the strike leg moved through the field of view of the diagnostic. The system operated with a dedicated 30 Hz laser with timing synchronized to seven similar lasers installed in the core Thomson system. Electron densities in the range of 1 × 10 18 -5 × 10 19 m -3 have been measured by the system throughout these regimes. Although the system was specified to measure from 1 to 40 eV, electron temperatures in the Super-X divertor in the first campaign were low, and measurement down to 0.5 eV has been critical, particularly close to the detachment front. This generation of polychromator has been designed with increased stray light rejection compared to those used in the core system. This has proved successful with very low levels of stray light observed.

A new divertor Thomson scattering system has been developed for the MAST-U tokamak. The diagnostic will produce electron density and temperature profiles along the Super-X strike leg. The existing polychromator design has been adapted for low temperature measurements. A new 1061 nm channel with 2 nm bandwidth has been added to enable measurements down below the previous ∼5 eV limit on the core system. The optical filters used in the system have OD6 light rejection alongside a 1064.1 nm laser line filter to reduce stray light in the digitized channels. A new averaging technique has been applied to the scattered signal traces to improve the core Thomson data in the scrape-off layer. The technique reduces the systematic noise level in this region. This leads to a reduction in the error values for electron density and temperature measurements and, in particular, the digitizer noise. The technique has been applied to produce a radial profile for a number of L-mode MAST discharges down to very low densities of ∼1 × 10 18 m -3 .

Objective: Audiology patients frequently experience psychosocial difficulties created by their hearing loss or exacerbated by the loss. Clinicians are not always attuned to the unstated emotional undercurrents which may signal a need for further discussion or referral. This article aims to heighten audiologists' vigilance towards patient well-being., Design: A series of case vignettes with sample dialogue demonstrate the need for heightened clinical awareness of confounding consequences patients may grapple with and possible responses to these issues., Conclusions: Beyond hearing loss, contributing detractors to patient well-being can be difficult to recognise for clinicians, and exploration and discussions may feel challenging to broach. A heightened vigilance within patient care calls upon audiologists to be alert for concerns or conditions beyond hearing loss that may be threatening our patients or further decreasing the quality of their lives and that of their families.

Background and Purpose: With the growth in the aging population, and shortage of primary care providers, telehealth programs are needed to optimize healthy independent living for older adults. The purpose of this study was to evaluate a nurse-led intervention program delivered through a telepresence robot to promote healthy lifestyles and address chronic illness management among older adults living independently in a retirement community. Telepresence robots provide two-way video-mediated communication with remote in-home navigation., Design and Methods: Satisfaction and technology evaluation ratings of the Telehealth Community Health Assistance Team (T-CHAT) program, as well as qualitative data from open-ended questions, were obtained from 26 older adults and 7 nurse practitioner students., Findings: On a scale from 1 = strongly disagree to 5 = strongly agree, satisfaction ratings were positive for usefulness (M = 3.90), ease of use (M = 4.16), and acceptability (M = 4.06). Technology evaluation ratings were high for all sessions (M = 4.35). Older adults and nurse practitioner students were highly complementary of the program. Areas for improvement were identified., Conclusions: The T-CHAT program demonstrated high ratings for satisfaction (usefulness, ease of use, acceptability) and for evaluation of the telepresence robot technology. Further refinement of the T-CHAT program is warranted, as is testing outcomes of this potentially viable mode of healthcare delivery., Clinical Relevance: Robotics is the wave of the future and provides an innovative mode of delivery to address health promotion and chronic illness management in older adults. Satisfaction and technology evaluation of robotic technology is paramount prior to implementation of such programs into practice., (© 2018 Sigma Theta Tau International.)

The purpose of this study was to test feasibility of the Telehealth Community Health Assistance Team (T-CHAT), a nurse-led intervention delivered through a telepresence robot designed to promote healthy independent living among older adults. Using a quasi-experimental design, 21 older adults were divided into a T-CHAT group (n = 11) or a waitlist control group (n = 10). The T-CHAT group received 3 weekly health coaching sessions from a nurse practitioner student through the telepresence robot. Data trends were analyzed using two-way repeated measures analysis of covariance (ANCOVA) with baseline values as co-variates; effect sizes using partial eta squared (η 2 ). Medium to large improvements in unhealthy days, depressive symptoms, sleep, quality of life, and confidence/self-efficacy were found favoring the T-CHAT group. Recruitment and retention strategies were successful, with lessons learned for future studies. Further research is warranted to refine and test efficacy of the T-CHAT program to promote healthy independent living among older adults., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: To assess the utility of noise cancelation earphones (NCE) in audiometric evaluations., Design: Degree of noise reduction of Bose QuietComfort 15 NCE was assessed through probe-microphone measures and sound-field audiometry. Occlusion effects from NCE were assessed for potential effects on bone-conduction thresholds., Study Sample: Twenty participants were tested to determine average occlusion effect values during bone-conduction testing with and without NCE. Noise reduction values of the NCE were assessed on a single subject through probe-microphone measures and sound-field testing., Results: NCE sufficiently reduced ambient noise to levels acceptable for air-conduction testing as well as for bone-conduction testing for most patients when adding minimal adjustment to acceptable levels as outlined by the ANSI S3.1-1999 standard. In addition, NCE did not create a clinically significant change in the occlusion effect for bone-conduction testing., Conclusion: NCE placed over insert earphones provide a sound pressure level at the tympanic membrane that is below ANSI standards for routine air-conduction testing and result in sufficient ambient noise reduction for bone-conduction testing with most patients. There is no clinically significant occlusion effect from NCE during routine bone-conduction audiometry. These findings support the utility of using NCE for offsite audiometric testing.

Airway epithelial cells (AEC) are critical components of the inflammatory and immune response during exposure to pathogens. AECs in monolayer culture and differentiated epithelial cells in air-liquid interface (ALI) represent two distinct and commonly used in vitro models, yet differences in their response to pathogens have not been investigated. In this study, we compared the transcriptional effects of flagellin on AECs in monolayer culture versus ALI culture using whole-genome microarrays and RNA sequencing. We exposed monolayer and ALI AEC cultures to flagellin in vitro and analyzed the transcriptional response by microarray and RNA-sequencing. ELISA and RT-PCR were used to validate changes in select candidates. We found that AECs cultured in monolayer and ALI have strikingly different transcriptional states at baseline. When challenged with flagellin, monolayer AEC cultures greatly increased transcription of numerous genes mapping to wounding response, immunity and inflammatory response. In contrast, AECs in ALI culture had an unexpectedly muted response to flagellin, both in number of genes expressed and relative enrichment of inflammatory and immune pathways. We conclude that in vitro culturing methods have a dramatic effect on the transcriptional profile of AECs at baseline and after stimulation with flagellin. These differences suggest that epithelial responses to pathogen challenges are distinctly different in culture models of intact and injured epithelium.

Objective: The aim of the study was to determine whether infliximab use and other potential predictors are associated with decreased prevalence and severity of depression in pediatric patients with Crohn disease (CD)., Methods: A total of 550 (n = 550) youth ages 9 to 17 years with biopsy-confirmed CD were consecutively recruited as part of a multicenter randomized controlled trial. Out of the 550, 499 patients met study criteria and were included in the analysis. At recruitment, each subject and a parent completed the Children's Depression Inventory (CDI). A child or parent CDI score ≥  12 was used to denote clinically significant depressive symptoms (CSDS). Child and parent CDI scores were summed to form total CDI (CDIT). Infliximab use, demographic information, steroid use, laboratory values, and Pediatric Crohn's Disease Activity Index (PCDAI) were collected as the potential predictors of depression. Univariate regression models were constructed to determine the relations among predictors, CSDS, and CDIT. Stepwise multivariate regression models were constructed to predict the relation between infliximab use and depression while controlling for other predictors of depression., Results: Infliximab use was not associated with a decreased proportion of CSDS and CDIT after adjusting for multiple comparisons. CSDS and CDIT were positively associated with PCDAI, erythrocyte sedimentation rate, and steroid dose (P < 0.01) and negatively associated with socioeconomic status (SES) (P < 0.001). In multivariate models, PCDAI and SES were the strongest predictors of depression., Conclusions: Disease activity and SES are significant predictors of depression in youth with Crohn disease.

Accurate assessment of canine hearing is essential to decrease the incidence of hereditary deafness in predisposed breeds and to substantiate hearing acuity. The Brainstem Auditory Evoked Response (BAER) is a widely accepted, objective test used in humans and animals for estimation of hearing thresholds and deafness diagnosis. In contrast to humans, testing and recording parameters for determination of normal values for canine hearing are not available. Conflicting information concerning breed and head size effects on canine BAER tests are major contributors preventing this normalization. The present study utilized standard head measurement techniques coupled with BAER testing and recording parameters modeled from humans to examine the effect canine head size and breed have on BAER results. Forty-three adult dogs from fourteen different breeds had head size measurements and BAER tests performed. The mean latencies compared by breed for waves I, II, III, IV, and V were as follows: 1.46±0.49 ms, 2.52±0.54 ms, 3.45±0.41 ms, 4.53±0.83 ms and 5.53±0.43 ms, respectively. The mean wave I-V latency interval for all breeds was 3.69 ms. All dogs showed similar waveform morphology, structures, including the presence of five waves occurring within 11 ms after stimulus presentation and a significant trough occurring after Wave V. All of the waveform morphology for our subjects occurred with consistent interpeak latencies as shown by statistical testing. All animals had diagnostic results within the expected ranges for each wave latency and interwave interval allowing diagnostic evaluation. Our results establish that neither differences in head size nor breed impact determination of canine BAER waveform morphology, latency, or hearing sensitivity for diagnostic purposes. The differences in canine head size do not have a relevant impact on canine BAERs and are not clinically pertinent to management or diagnostic decisions., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Dog owners and handlers are naturally concerned when suspicion of hearing loss arises for their dogs. Questions frequently asked of the veterinarian center on warning signs of canine hearing loss and what can be done for the dog if hearing loss is confirmed. This article addresses warning signs of canine hearing loss, communication training and safety awareness issues, and the feasibility of hearing aid amplification for dogs., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Given the high incidence of deafness within several breeds of dogs, accurate hearing screening and assessment is essential. In addition to brainstem auditory evoked response (BAER) testing, 2 other electrophysiologic tests are now being examined as audiologic tools for use in veterinary medicine: otoacoustic emissions and the auditory steady state response (ASSR). To improve BAER testing of animals and ensure an accurate interpretation of test findings from one test site to another, the establishment of and adherence to clear protocols is essential. The ASSR holds promise as an objective test for rapid testing of multiple frequencies in both ears simultaneously., (Copyright © 2012 Elsevier Inc. All rights reserved.)

This study was designed to measure the sound output of four commonly used brands of forced-air dryers used by dog groomers in the United States. Many dog groomers have questions about the effect of this exposure on their hearing, as well as on the hearing of the dogs that are being groomed. Readings taken from each dryer at 1 meter (the likely distance of the dryer from the groomer and the dog) showed average levels ranging from 105.5 to 108.3 dB SPL or 94.8 to 108.0 dBA. Using the 90 dBA criterion required by the US Occupational Safety and Health Administration, dog groomers/bathers are at risk if exposure to the lowest intensity dryer (94.8 dBA) exceeds 4 hours per day. If the more stringent 85 dBA criterion and 3 dB tradeoff is applied, less than one hour of exposure is permissible in an 8 hour day. Cautions are recommended for any persons exposed to noise from forced-air dryers.

Underwater and in-air noise evaluations were completed in performance pool systems at Georgia Aquarium under normal operating conditions and with performance sound tracks playing. Ambient sound pressure levels at in-pool locations, with corresponding vibration measures from life support system (LSS) pumps, were measured in operating configurations, from shut down to full operation. Results indicate noise levels in the low frequency ranges below 100 Hz were the highest produced by the LSS relative to species hearing thresholds. The LSS had an acoustic impact of about 10 dB at frequencies up to 700 Hz, with a 20 dB re 1 μPa impact above 1000 Hz.

Objective: To evaluate the degree of noise to which kenneled dogs were exposed in 2 typical kennels and to determine whether a measurable change in hearing might have developed as a result of exposure to this noise., Animals: 14 dogs temporarily housed in 2 kennel environments., Procedures: Noise levels were measured for a 6-month period in one environment (veterinary technical college kennel) and for 3 months in another (animal shelter). Auditory brainstem response testing was performed on dogs in the veterinary kennel 48 hours and 3 and 6 months after arrival. Temporal changes in the lowest detectable response levels for wave V were analyzed., Results: Acoustic analysis of the kennel environments revealed equivalent sound level values ranging between 100 and 108 dB sound pressure level for the 2 kennels. At the end of 6 months, all 14 dogs that underwent hearing tests had a measured change in hearing., Conclusions and Clinical Relevance: Results of the noise assessments indicated levels that are damaging to the human auditory system. Such levels could be considered dangerous for kenneled dogs as well, particularly given the demonstrated hearing loss in dogs housed in the veterinary kennel for a prolonged period. Noise abatement strategies should be a standard part of kennel design and operation when such kennels are intended for long-term housing of dogs.

Posterior cervical laminoforaminotomy is an effective treatment for cervical radiculopathy due to disc herniations or spondylosis. Over the last decade, minimally invasive (i.e., percutaneous) procedures have become increasingly popular due to a smaller incision size and presumed benefits in postoperative outcomes. We performed a systematic review of the literature and identified studies of open or percutaneous laminoforaminotomy that reported one or more perioperative outcomes. Of 162 publications found by our initial screening, 19 were included in the final analysis. Summative results indicate that patients undergoing percutaneous cervical laminoforaminotomy have lower blood loss by 120.7 mL (open: 173.5 mL, percutaneous: 52.8 mL, n = 670), a shorter surgical time by 50.0 minutes (open: 108.3 minutes, percutaneous: 58.3 minutes, n = 882), less inpatient analgesic use by 25.1 Eq (open: 27.6 Eq, percutaneous: 2.5 Eq, n = 356), and a shorter hospital stay by 2.2 days (open: 3.2 days, percutaneous: 1.0 days, n = 1472), compared with patients undergoing open procedures. However, the heterogeneous nature of published data calls into question the reliability of these summative results. Further structured trials should be conducted to better characterize the risks and benefits of percutaneous laminoforaminotomy.

Filamin A (FlnA) plays a critical role in cytoskeletal organization, cell motility and cellular signaling. FlnA utilizes different binding sites on a series of 24 immunoglobulin-like domains (Ig repeats) to interact with diverse cytosolic proteins and with cytoplasmic portions of membrane proteins. Mutations in a specific domain, Ig10 (FlnA-Ig10), are correlated with two severe forms of the otopalatodigital syndrome spectrum disorders Melnick-Needles syndrome and frontometaphyseal dysplasia. The crystal structure of FlnA-Ig10 determined at 2.44 Å resolution provides insight into the perturbations caused by these mutations.

Objective: Language impairment is a common symptom of Alzheimer disease (AD), and is thought to be related to semantic processing. This study examines the contribution of another process, namely visual perception, on measures of confrontation naming and semantic association abilities in persons with probable AD., Methods: Twenty individuals with probable mild-moderate Alzheimer disease and 20 age-matched controls completed a battery of neuropsychologic measures assessing visual perception, naming, and semantic association ability. Visual discrimination tasks that varied in the degree to which they likely accessed stored structural representations were used to gauge whether structural processing deficits could account for deficits in naming and in semantic association in AD., Results: Visual discrimination abilities of nameable objects in AD strongly predicted performance on both picture naming and semantic association ability, but lacked the same predictive value for controls. Although impaired, performance on visual discrimination tests of abstract shapes and novel faces showed no significant relationship with picture naming and semantic association. These results provide additional evidence to support that structural processing deficits exist in AD, and may contribute to object recognition and naming deficits., Conclusions: Our findings suggest that there is a common deficit in discrimination of pictures using nameable objects, picture naming, and semantic association of pictures in AD. Disturbances in structural processing of pictured items may be associated with lexical-semantic impairment in AD, owing to degraded internal storage of structural knowledge.

Th1 cells are implicated in numerous pulmonary inflammatory disorders, and adoptive transfer of alloreactive Th1 cells mediates lung injury and inflammation in mice. In response to Th1-mediated immune injury, CXCR3 ligands IP10 and MIG are markedly induced. Because Th1 cells express high levels of CXCR3, their recruitment and activity may be influenced by CXCR3 ligands. To examine the role of CXCR3 ligands, the authors inhibited CXCR3-ligand interaction by 2 approaches: (1) antibody ablation of CXCR3 ligands IP10 (CXCL10/interferon-gamma -inducible 10-kDa protein) and MIG (CXCL9/monokine-induced by interferon-gamma), and (2) use of cxcr3(-/-) mice. Antibody neutralization of IP10 and MIG reduced Th1-cell mediated lung inflammation but did not alter Th1-cell influx in the lung. In contrast, a lack of CXCR3 on host cells had no effect on Th1 cells influx or acute inflammation. In vitro, ablation of endogenous IP10 and MIG inhibited antigen-mediated Th1-cell proliferation. These results suggest that the influx of alloreactive Th1 cells into the lung does not require CXCR3 ligands, but that these chemokines do affect Th1-cell proliferation and activity within the affected tissue. Other CXCR3(+) leukocytes do not contribute to acute alloimmune injury.

Lipopolysaccharide binding protein (LBP) function is dependent on circulating LBP levels. Disturbance of LBP transcription regulation may influence the risk for clinical events. In a nested case-control study using a single nucleotide polymorphism haplotype tagging (tagSNP) approach, we assessed whether genetic variation in the LBP gene influences the risk for Gram-negative (GN) bacteremia after allogeneic hematopoietic cell transplantation (HCT), then validated the association in a prospective cohort by correlating genetic variation with basal serum LBP levels and mortality. Presence of the tagSNP 6878 C allele among patients was associated with a 2-fold higher risk for GN bacteremia (odds ratio = 2.15; 95% confidence interval [CI], 1.31-3.52, P = .002). TagSNP 6878 was in strong linkage disequilibrium with 3 SNPs in the LBP promoter, one of which was SNP 1683 (r(2) = 0.8), located in a CAAT box that regulates LBP promoter efficiency. SNP 1683 was associated with higher median basal serum LBP levels (TT 8.07 microg/mL; TC 10.40 microg/mL; CC 17.39 microg/mL; P = .002), and a 5-fold increase in GN bacteremia related mortality after HCT (hazard ratio = 4.83; 95% CI, 1.38-16.75, P = .013). These data suggest that transcriptional regulation of the LBP gene contributes to the risk for developing GN bacteremia and death after HCT.

Innate immunity is involved in the biology of graft versus host disease and common airway diseases. We screened 15 genes in this pathway using a linkage disequilibrium-based approach to identify potential candidate genes that may be involved in the development of airflow obstruction after hematopoietic cell transplantation. Sixty-nine single-nucleotide polymorphisms were selected for assessment in a discovery cohort (n = 363). Significant associations were validated in a validation cohort (n = 209). Expression of the candidate gene was demonstrated by detecting gene transcript and protein in malignant and normal small airway epithelial cells. In the discovery cohort, 133 patients developed significant airflow decline. Four patient and donor bactericidal/permeability-increasing (BPI) haplotypes were associated with a 2-fold to 3-fold increased risk of developing significant airflow decline (P values, .004-.038). This association was confirmed in the validation cohort, which had 66 patients with significant airflow decline, with 9 significant haplotypes (P values, .013-.043). BPI gene transcript and protein were detected in airway epithelial cells. These results suggest mutations in the BPI gene significantly influence the risk of developing rapid airflow decline after hematopoietic cell transplantation and may represent a novel therapeutic target for this form of airway disease.

Lung function decline is a well-recognized occurrence after myeloablative hematopoietic stem cell transplantation (HCT) that has not been studied after nonmyeloablative conditioning regimens. We examined the lung function of patients before and after 2-Gy total body irradiation-based nonmyeloablative and myeloablative preparative regimens. Before HCT, at day 100, and 1 year after HCT, nonmyeloablative patients had lower 1-second forced expiratory volume (FEV1), forced vital capacity, total lung capacity, residual volume, and carbon monoxide diffusion capacity. However, after transplantation, the risk for experiencing a >20% per year decrease of FEV 1 was significantly lower for nonmyeloablative than myeloablative patients >50 years of age (odds ratio, 0.3; 95% confidence interval, 0.1-0.8; P = .01). Lower pretransplantation FEV 1 was associated with a higher mortality rate for both groups, with the highest mortality risk among patients with a pretransplantation FEV 1 <60% (nonmyeloablative: hazard ratio, 3.9; 95% confidence interval, 1.9-8.0; myeloablative: hazard ratio, 7.2; 95% confidence interval, 2.5-21.2). These results suggest that despite having worse lung function, patients who receive the 2-Gy total body irradiation-based nonmyeloablative regimen will likely experience less pulmonary toxicity than patients who receive a myeloablative regimen, and this may have important clinical implications when deciding on a conditioning regimen for patients >50 years of age with compromised pretransplantation lung function.

The pretransplant pulmonary function test plays an important role in the management of noninfectious pulmonary complications after hematopoietic stem cell transplantation (HCT). Although these tests are widely used as standard preoperative assessments in the nontransplant population, common conditions associated with the HCT patient requires that particular attention be given to interpretation of pulmonary function testing (PFT) results, such as comparison of serial pulmonary function tests and evaluation of the diffusion capacity. Although their utility in helping to predict the likelihood of developing post transplant pulmonary complications and mortality is not well established, current data indicate that pretransplant PFTs are important as a reference for the interpretation of post transplant PFTs and for identifying patients at high risk for developing pulmonary complications and/or mortality after HCT. Future studies of pretransplant pulmonary function should consider the advances in HCT, so that pretransplant PFTs will become a useful tool in pretransplant risk assessment and help the transplant oncologist to determine the most appropriate conditioning regimen for a patient with compromised lung function.

The clinical significance of early airflow decline after myeloablative allogeneic hematopoietic SCT is uncertain. We performed a retrospective cohort analysis to determine if airflow decline by day 100 is associated with later development of transplant-related airflow obstruction (AFO) and increased mortality risk. Overall, 750 (40%) patients had airflow decline by day 100. Development of airflow decline by day 100 was associated with an increased risk for AFO at 1 year (relative risk 2.6, 95% confidence interval 2.1-3.1) but not with an increase in mortality risk (hazard ratio (HR) 0.86, P=0.05). However, patients with the fastest rate of decline between day 100 and 1 year (12.5% per year +/-24) had the highest mortality risk (HR 3.2, P<0.001). In conclusion, airflow measurements made on day 100 do not predict the rate of airflow decline between day 100 and 1 year, and therefore are not useful as a single measurement for determining mortality risk associated with development of AFO. Closer monitoring of the rate of airflow decline during the first year may facilitate the timely detection and treatment of early airflow decline and prevent the development of fixed AFO and increased mortality risk after hematopoietic stem cell transplant.

Trafficking of lymphocytes to lung is a critical component of pulmonary immune defense and surveillance. Selectins, expressed on vascular endothelium, regulate T lymphocyte emigration into tissues, such as skin, but the role of the selectins in trafficking of T cells to lung has not been well characterized. Here, we used a model of lung inflammation induced by adoptive transfer of alloreactive Th1 cells to analyze the role of P- and E-selectin in Th1 cell trafficking to lung in vivo. We found that both P- and E-selectin play an important role in Th1 lymphocyte migration to lung. We confirmed that the Th1 cells express P-selectin glycoprotein ligand-1, which was functional in binding to P- and E-selectin in vitro. However, our studies reveal that a ligand distinct from P-selectin glycoprotein-1 also binds these selectins in vitro and appears to play a physiologic role in in vivo emigration of Th1 lymphocytes into the lung.

The incidence, etiology, outcome, and risk factors for developing pneumonia late after hematopoietic stem cell transplantation (SCT) were investigated in 1359 patients transplanted in Seattle. A total of 341 patients (25% of the cohort) developed at least one pneumonic episode. No microbial or tissue diagnosis (ie clinical pneumonia) was established in 197 patients (58% of first pneumonia cases). Among the remaining 144 patients, established etiologies included 33 viral (10%), 31 bacterial (9%), 25 idiopathic pneumonia syndrome (IPS, 7%), 20 multiple organisms (6%), 19 fungal (6%), and 16 Pneumocystis carinii pneumonia (PCP) (5%). The overall cumulative incidence of first pneumonia at 4 years after discharge home was 31%. The cumulative incidences of pneumonia according to donor type at 1 and 4 years after discharge home were 13 and 18% (autologous/syngeneic), 22 and 34% (HLA-matched related), and 26 and 39% (mismatched related/unrelated), respectively. Multivariate analysis of factors associated with development of late pneumonia after allografting were increasing patient age (RR 0.5 for <20 years, 1.2 for >40 years, P=0.009), donor HLA-mismatch (RR 1.6 for unrelated/mismatched related, P=0.01), and chronic graft-versus-host disease (GVHD; RR 1.5, P=0.007). Our data suggest that extension of PCP prophylaxis may be beneficial in high-risk autograft recipients. Further study of long-term anti-infective prophylaxis based on patient risk factors after SCT appear warranted.

Despite advances in the management of myeloablative allogeneic hematopoietic stem cell transplants, airflow obstruction (AFO) remains a significant complication. We conducted a 12-year study to examine the recent epidemiology of AFO and its associated mortality. Using the rate of percent predicted FEV1 decline after transplant, we defined AFO as a more than 5% per year decline in percent predicted FEV1 with the lowest post-transplant FEV1/FVC ratio less than 0.8. New obstruction was more frequent than previous estimates (26% overall, 32% among patients with chronic graft-versus-host disease [GVHD]) and was significantly associated with older age at transplant, lower pretransplant FEV1/FVC ratio, history of both acute and chronic GVHD, and respiratory viral infection within the first 100 days after transplant. AFO was associated with significant attributable mortality rates of 9% at 3 years, 12% at 5 years, and 18% at 10 years after transplant, which were much higher for the subpopulation of patients with chronic GVHD (22% at 3 years, 27% at 5 years, and 40% at 10 years). These results suggest that the incidence of AFO may have been underestimated previously, and its presence significantly increases the mortality of long-term survivors of myeloablative allogeneic hematopoietic stem cell transplant patients.

Tissue inhibitors of metalloproteinases (TIMPs) are multifunctional proteins that have the capacity to modify cellular activities and to modulate matrix turnover. We demonstrate that TIMP-1 messenger RNA (mRNA) and protein expression are selectively and markedly increased in a murine model of bleomycin-induced pulmonary fibrosis. Northern analysis showed that lung steady-state TIMP-1 mRNA levels increased 14-fold after bleomycin administration compared with control mice. Expression of the genes for TIMP-2, TIMP-3, and interstitial collagenase (matrix metalloproteinase-13) was unaltered in the injured lung. In situ hybridization demonstrated that TIMP-1 gene induction was spatially restricted to areas of lung injury. Metalloproteinase inhibitory activity of relative molecular mass of ~ 21 to 28 kD, corresponding to the molecular weights for TIMP-1 and TIMP-2, was identified in lung extracts of bleomycin-injured mice by reverse zymography. Western analysis demonstrated that TIMP-1 protein levels in bronchoalveolar lavage fluid (BALF) of bleomycin-treated mice increased 220- and 151-fold at Days 4 and 28, respectively, compared with control mice. TIMP-2 immunoreactive protein in the BALF increased 20- and 103-fold relative to controls at Days 4 and 28, respectively. These results demonstrate that TIMP-1 gene expression is selectively increased, and that the expression of TIMP-1 and TIMP-2 is differentially regulated in bleomycin-induced pulmonary fibrosis. The profound and durable increase in TIMP-1 and TIMP-2 proteins suggests an important regulatory role for these antiproteases in the inflammatory and fibrotic responses to bleomycin-induced lung injury.

Lipopolysaccharide (LPS) has been implicated in the pathogenesis of graft-versus-host disease (GVHD). The toll-like receptor (TLR)-4 has been recently identified as a major receptor for LPS. Mutations of TLR4 have been associated with LPS hyporesponsiveness. We hypothesized that TLR4 mutations reduce the risk of acute GVHD in allogeneic marrow transplant recipients. In a preliminary study to determine the frequency of TLR4 mutations and their possible association with GVHD, we tested 237 patients and their HLA-identical sibling donors for 2 TLR4 polymorphisms. All patients received methotrexate and cyclosporine for GVHD prophylaxis. One or more mutants were detected in 10.8% of patients and 10.6% of donors. Multivariable logistic regression models were used to analyze the association between TLR4 mutations and probability (1-sided) of GVHD. The odds ratio (adjusted for advanced disease, total body irradiation dose, and patient age) for development of grades II to IV GVHD when a mutation was present in the recipient was 0.63 (95% confidence interval [CI], 0.25-1.60; P = .16). When a mutation was present in the donor, the adjusted odds ratio was 0.88 (95% CI, 0.36-2.17; P = .40). When a mutation was present in both recipient and donor, the odds ratio was 0.72 (95% CI, 0.22-2.32; P = .29). Among 24 patients with TLR4 mutations in either donor or recipient, 4 (16.7%) developed gram-negative bacteremia. Among 213 patients without mutations, 14 (6.6%) developed gram-negative bacteremia (P = .09). The data indicate that a reduced risk of acute GVHD is associated with TLR4 mutations and that TLR4 mutations may increase the risk for gram-negative bacteremia. However, these associations are not statistically significant in recipients of HLA-matched sibling marrow transplants who are prophylactically treated for infections and GVHD. A much larger study population would be needed to confirm the role of LPS in the pathogenesis of GVHD in humans.

T helper type 1 (Th1) cells are important effectors in a number of immune-mediated lung diseases. We recently described a murine model of lung injury induced by adoptive transfer of cloned alloreactive Th1 cells. To investigate mechanisms that result in injury to the lung, we studied the in vivo distribution of (51)Cr-labeled Th1 cells. One hour after intravenous administration, >85% of injected radioactivity was left in the lung, and at 24 h, 40% of radioactivity was left in the lung. Adherence of Th1 cells in the lung was significantly inhibited by neutralizing antibody to lymphocyte function-associated antigen-1. Th1 cell adherence also was decreased in lungs of mice deficient in intercellular adhesion molecule-1 (ICAM-1). Th1 cell transfer further induced expression of ICAM-1 and vascular cell adhesion molecule-1 in the lung. Vascular cell adhesion molecule-1-immunoreactive protein was markedly induced in lung endothelium by alloreactive Th1 cells. These findings indicate that Th1 cells localize in normal lung by a mechanism involving lymphocyte function-associated antigen-1 and ICAM-1. Alloreactive cells further induce endothelial adhesion molecules that may facilitate recruitment of inflammatory cells to the lung and amplify Th1 cell-induced lung injury.

Proinflammatory responses generated by T helper type 1 (Th1) cells may contribute significantly to immune-mediated lung injury. We describe a murine model of Th1 cell-induced lung injury in which adoptive transfer of alloreactive Th1 cells produces pulmonary inflammation characterized by mononuclear cell vasculitis, alveolitis, and interstitial pneumonitis. To investigate the link between activation of Th1 cells in the lung and inflammatory cell recruitment, we characterized cytokine and chemokine mRNA expression in Th1 cells activated in vitro and in lung tissue after adoptive transfer of Th1 cells. Activated Th1 cells per se express mRNA for interferon (IFN)-gamma and several members of the tumor necrosis factor family as well as the C-C chemokine receptor-5 ligands regulated on activation normal T cells expressed and secreted and macrophage inflammatory protein-1alpha and -1beta. Additional chemokine genes were induced in the lung after Th1 cell administration, most notably IFN-gamma-inducible protein (IP-10) and monokine induced by IFN-gamma (MIG). Remarkable increases in IP-10- and MIG-immunoreactive proteins were present in inflammatory foci lung and identified in macrophages, endothelium, bronchial epithelium, and alveolar structures. The findings suggest that IFN-gamma-inducible chemokines are an important mechanism for amplifying inflammation initiated by Th1 cells in the lung.

Background: Lung injury occurs frequently after allogeneic bone marrow transplantation in association with graft-versus-host disease, an immune response that involves both cellular and cytokine components. In a murine model, we recently showed that cloned alloreactive T helper (Th)1 cells can cause lung injury associated with increased production of tumor necrosis factor (TNF)-alpha by alveolar macrophages (J Immunol 1998; 161: 1913)., Methods: To evaluate the role of TNF-alpha in this model, we injected in vitro-activated Th1 cells into the following: (1) recipients deficient in receptors for TNF; (2) C57BL/6 control mice; (3) C57BL/6 mice, pretreated with soluble TNFRIIFc (a dimorphic high-affinity TNF antagonist); (4) mice expressing TNFRIIFc transgene under control of the surfactant apoprotein C promoter (SPCTNFRIIFc); and (5) wild-type littermate controls (C57BL/6) (n=3-6 mice/group)., Results: At 1 and 3 days after i.v. Th1 cell transfer, recipients were killed for analysis of lung histology, bronchoalveolar lavage (BAL) protein, and BAL cell counts. Control mice (wild type) at day 1 after injection had a mild to moderate mononuclear perivasculitis and increased interstitial cellularity. At day 3, lesions were more severe and perivasculitis also involved larger veins. TNFR-deficient mice had normal lung or minimal lung inflammation at day 1. At day 3, perivasculitis of medium-sized vessels was present, but there was no apparent involvement of larger veins. Results in mice treated with soluble TNFRIIFc and transgenic mice (SPCsTNFRIIFc) were similar to controls. BAL protein and BAL cell counts did not differ between any of the experimental groups., Conclusions: We conclude that lung inflammation induced by Th1 cells may be only delayed when TNF-alpha action is blocked. The persistence of abnormalities indicates that other proinflammatory pathways are involved in injury caused by these cells.

Perfluorochemical (PFC) liquids have both low surface tension and a high capacity to dissolve O2 and CO2, and have been shown to improve gas exchange and lung compliance in animal models of lung injury. We have previously demonstrated that perflubron and other PFC liquids enhance transgene expression in lungs of spontaneously breathing normal rodents after intratracheal instillation of either adenoviral or liposomal vectors followed by a single instillation of PFC liquid. We reasoned that PFC liquids may also be useful for enhancing transgene expression in abnormal lungs. GM-CSF knockout mice develop chronic accumulation of surfactant lipids and proteinaceous material in alveolar spaces and serve as a useful model of chronic alveolar filling. Intratracheal instillation of the adenoviral vector Adlac-Z resulted in patchy in situ distribution of beta-Gal activity, predominantly in larger proximal airways. In contrast, in mice instilled with Adlac-Z followed by instillation of a single dose of perflubron (10 ml/kg body weight), increased expression was observed in distal airway and alveolar epithelial cells. In particular, expression was observed in epithelial cells of debris-filled alveoli. Spectrophotometric measure of quantitative beta-Gal activity in lung homogenates demonstrated increased activity in lungs of mice receiving Adlac-Z plus perflubron compared with lungs of animals receiving Adlac-Z alone. These studies demonstrate that use of perflubron enhances transgene expression in lungs of animals with a chronic alveolar filling process. This approach may be applicable for gene delivery in diseases marked by chronic airway or alveolar filling such as cystic fibrosis.