Phase II studies of nebulised Arikace in CF patients with Pseudomonas aeruginosa infection.

RATIONALE: Arikace is a liposomal amikacin preparation for aerosol delivery with potent Pseudomonas aeruginosa killing and prolonged lung deposition. OBJECTIVES: To examine the safety and efficacy of 28 days of once-daily Arikace in cystic fibrosis (CF) patients chronically infected with P aeruginosa. METHODS: 105 subjects were evaluated in double-blind, placebo-controlled studies. Subjects were randomised to once-daily Arikace (70, 140, 280 and 560 mg; n=7, 5, 21 and 36 subjects) or placebo (n=36) for 28 days. Primary outcomes included safety and tolerability. Secondary outcomes included lung function (forced expiratory volume at one second (FEV1)), P aeruginosa density in sputum, and the Cystic Fibrosis Quality of Life Questionnaire-Revised (CFQ-R). RESULTS: The adverse event profile was similar among Arikace and placebo subjects. The relative change in FEV1 was higher in the 560 mg dose group at day 28 (p=0.033) and at day 56 (28 days post-treatment, 0.093L±0.203 vs -0.032L±0.119; p=0.003) versus placebo. Sputum P aeruginosa density decreased >1 log in the 560 mg group versus placebo (days 14, 28 and 35; p=0.021). The Respiratory Domain of the CFQ-R increased by the Minimal Clinically Important Difference (MCID) in 67% of Arikace subjects (560 mg) versus 36% of placebo (p=0.006), and correlated with FEV1 improvements at days 14, 28 and 42 (p<0.05). An open-label extension (560 mg Arikace) for 28 days followed by 56 days off over six cycles confirmed durable improvements in lung function and sputum P aeruginosa density (n=49). CONCLUSIONS: Once-daily Arikace demonstrated acute tolerability, safety, biologic activity and efficacy in patients with CF with P aeruginosa infection.

A survey on the temporal and spatial distribution of perchlorate in the Potomac River.

Samples of river water and treated drinking water were obtained from eight sites along the Potomac River between western Maryland and Washington DC. Samples were collected each month from October 2007 to September 2008 and analyzed for perchlorate by ion chromatography/mass spectrometry. Data on anions were also collected for seven of the twelve months. Data were analyzed to identify spatial and temporal patterns for the occurrence of perchlorate in the Potomac. Over the year of sampling, the largest monthly increase occurred from June to July, with levels then decreasing from July to September. Samples from the period between December and May had lower perchlorate concentrations, relative to the remainder of the study year. Spatially, higher levels of perchlorate were found at sites located in west-central Maryland, the eastern panhandle of West Virginia, and central northern Virginia, with levels decreasing slightly as the Potomac approaches Washington DC. Within the sampling boundaries, river (untreated) water perchlorate concentrations ranged from 0.03 µg L(-1) to 7.63 µg L(-1), averaged 0.67 ± 0.97 µg L(-1) over the year-long period and had a median value of 0.37 µg L(-1). There was no evidence that any of the existing drinking water treatment technologies at the sampling sites were effective in removing perchlorate. There were no correlations found between the presence of perchlorate and any of the anions or water quality parameters examined in the source water with the exception of a weak positive correlation with water temperature. Results from the summer (June-August) and fall (September-November) months sampled in this study were generally higher than from the winter and spring months (December-May). All but one of the locations had annual average perchlorate levels below 1 µg L(-1); however, 7 of the 8 sites sampled had river water perchlorate detections over 1 µg L(-1) and 5 of the 8 sites had treated water detections over this level.

Bronchiolitis obliterans syndrome and survival following lung transplantation for patients with sarcoidosis.

BACKGROUND: End-stage sarcoidosis is characterized by severe pulmonary fibrosis and is often poorly responsive to medical therapy. Lung transplantation, therefore, may be the only treatment option. Currently, there are few studies evaluating long-term outcomes following transplantation for these patients. Our aim was to evaluate post-transplant morbidity and survival of patients with sarcoid compared to recipients transplanted for idiopathic pulmonary fibrosis (IPF). METHODS: We retrospectively examined 300 lung transplant recipients using a dedicated database. Over a 10-year period, 15 (5.0%) patients with sarcoidosis and 48 (16%) patients with IPF were identified. Primary outcome measures included rate and time to onset of bronchiolitis obliterans syndrome (BOS) and survival. RESULTS: Recipients in the sarcoid group were younger and predominantly female compared to recipients in the IPF group. Five of 15 (33%) sarcoid patients developed BOS versus 15 of 48 (31%) IPF patients (p=1.0). There was no significant difference in the time to BOS onset. Median survival was 1,365 days for the sarcoid group and 1,593 days for the IPF group (Hazard Ratio 0.94 by Kaplan-Meier analysis; [95% CI] 0.33-2.67; p = 0.90). CONCLUSIONS: We observe similar long term outcomes following lung transplantation for sarcoid and IPF recipients. Transplantation remains a treatment option for end-stage sarcoidosis, as BOS and survival rates are comparable to IPF.

Management of congenital abnormalities of the donor lung.

Congenital abnormalities were encountered in three donor lungs. A donor tracheal bronchus was incorporated into the right bronchial anastomosis. Anomalous pulmonary venous return of the right upper lobe to the superior vena cava and the left upper lobe to the innominate vein were managed by bridging the anomalous veins to the left atrial cuff with autologous pericardium and donor iliac vein, respectively.

A clinical inflammatory syndrome attributable to aerosolized lipid-DNA administration in cystic fibrosis.

Immunologic reactivity to lipid-DNA conjugates has traditionally been viewed as less of an issue than with viral vectors. We performed a dose escalation safety trial of aerosolized cystic fibrosis transmembrane conductance regulator (CFTR) cDNA to the lower airways of eight adult cystic fibrosis patients, and monitored expression by RT-PCR. The cDNA was complexed to a cationic lipid amphiphile (GL-67) consisting of a cholesterol anchor linked to a spermine head group. CFTR transgene was detected in three patients at 2-7 days after gene administration. Four of the eight patients developed a pronounced clinical syndrome of fever (maximum of 103.3EF), myalgias, and arthralgia beginning within 6 hr of gene administration. Serum IL-6 but not levels of IL-8, IL-1, TNF-alpha, or IFN-gamma became elevated within 1-3 hr of gene administration. No antibodies to the cationic liposome or plasmid DNA were detected. We found that plasmid DNA by itself elicited minimal proliferation of peripheral blood mononuclear cells taken from study patients, but led to brisk immune cell proliferation when complexed to a cationic lipid. Lipid and DNA were synergistic in causing this response. Cellular proliferation was also seen with eukaryotic DNA, suggesting that at least part of the immunologic response to lipid-DNA conjugates is independent of unmethylated (E. coli-derived) CpG sequences that have previously been associated with innate inflammatory changes in the lung.

Association of reactive nitrogen species metabolites, myeloperoxidase, and airway inflammation in lung transplants.

BACKGROUND: We have previously reported that patients who had single or double lung transplants had higher concentrations than controls of nitrite and nitrate, which are metabolites of reactive nitrogen species (RNS), in bronchoalveolar lavage fluid (BALF) and serum. METHODS: This study investigates implications of RNS metabolites as markers of airway inflammation in a distinct group of lung transplant patients (n = 40). All patients underwent spirometry, routine surveillance transbronchial lung biopsies, and bronchoalveolar lavage as required by clinical protocol. Four normal controls also had bronchoscopy for measurement of BALF nitrite (NO2-) and nitrate (NO3-). BALF NO2- and NO3-, myeloperoxidase (MPO), protein, and urea were assayed. Total nitrite (NO2- plus enzymatically reduced NO3-) and urea were measured in serum. RESULTS: BALF RNS metabolites were mainly NO3-. Forced expiratory volume in 1 s (FEV1) obtained near bronchoscopy was compared with best postoperative FEV1. Total nitrite in transplant patients' BALF and serum were 3.8 +/- 0.2 and 49 +/- 5 microM, respectively. Total nitrite in controls' BALF and serum were 2.2 +/- 0.7 and 19 +/- 2 microM, respectively (P < 0.05 compared with transplant values). Serum total nitrite correlated (Pearson product moment) with percentage of neutrophils in BALF (R = 0.650, P < 0.0001), MPO (R = 0.431, P = 0.0055), change in FEV1 from baseline (deltaFEV1) (R = -0348, P = 0.0298), and days after transplantation (R = 0.345, P = 0.0294). None of the associated variables, airway inflanmmation (quantified as a score, "B"), deltaFEV1, serum, or BALF total nitrite, were explained by infection. Univariate analysis of airway inflammation in patients showed that it was associated with BALF neutrophils, deltaFEV1, and serum total nitrite. CONCLUSIONS: Serum nitrite appears to reflect the degree of airway inflammation in this lung-transplant study group.

The utility of open lung biopsy following lung transplantation.

BACKGROUND: Most pulmonary complications associated with lung transplantation have non-specific clinical characteristics. Furthermore, common diagnostic modalities, including bronchoscopy with transbronchial biopsy (TBB), often do not render a definitive diagnosis. In this study, we reviewed our experience with open lung biopsy (OLB) following lung transplantation, specifically regarding its ability to safely provide clinically relevant information that affects therapeutic decisions. METHODS: From October 1989 to March 2000, 202 patients underwent lung transplantation at our institution. We reviewed the clinical course of the 42 patients who received 48 OLBs. Of these patients, we determined the pre-operative clinical condition, preceding TBB histologic information, OLB histology, treatment changes, and procedural complications as a result of the OLB. RESULTS: A new, clinically unsuspected diagnosis was made in 14 biopsies (29% of all OLB), and all of these resulted in therapy changes. Thirty-two biopsies (67% of all OLB) confirmed our clinical suspicions, and new therapy was initiated in 30 of these patients. Two patients (4% of all OLB) had non-diagnostic OLB. Four biopsies (8% of all OLB), including the 2 non-diagnostic OLBs, did not result in any therapy changes or initiation of new therapy. Complications occurred in 3 patients, all of whom had an air leak for >7 days. CONCLUSION: Open lung biopsy in lung transplant patients renders a new, unsuspected diagnosis in nearly one third of patients and leads to specific, directed therapy in the vast majority of patients. Open-lung biopsy can be performed safely and should be considered when diagnosis is uncertain in clinically deteriorating patients.

Recurrence of bronchioloalveolar carcinoma in transplanted lungs.

BACKGROUND: Bronchioloalveolar carcinoma is a distinctive subtype of typical adenocarcinoma of the lung that tends to metastasize widely throughout the lungs but less commonly elsewhere. Because conventional therapies for intrapulmonary metastatic bronchioloalveolar carcinoma are generally ineffective, we treated seven patients who had intrapulmonary metastatic bronchioloalveolar carcinoma with lung transplantation. METHODS: Seven patients with biopsy-proved bronchioloalveolar carcinoma and no evidence of extrapulmonary disease received transplants of either one or two cadaveric lungs. At transplantation, all native lung tissue was removed and replaced with a donor lung or lungs. The patients received the usual post-transplantation care given at the institution. RESULTS: Four of the seven patients had recurrent bronchioloalveolar carcinoma within the donor lungs; the recurrences appeared from 10 to 48 months after transplantation. All recurrences were limited to the donor lungs. Histologic and molecular analyses showed that the recurrent tumors in three patients originated from the recipients of the transplants. CONCLUSIONS: Lung transplantation for bronchioloalveolar carcinoma is technically feasible, but recurrence of the original tumor within the donor lungs up to four years after transplantation was common.

Can chest CT decrease the use of preoperative bronchoscopy in the evaluation of suspected bronchogenic carcinoma?

BACKGROUND: Fiberoptic bronchoscopy (FOB) is frequently used to diagnose and stage bronchogenic carcinoma (BC). However, the value of FOB in diagnosis/staging BC presenting as a pulmonary nodule or mass (PNM) is controversial. Since chest CT is usually obtained in these patients, it may be used in patient selection for preoperative FOB. OBJECTIVE: Evaluation of the role of chest CT in determining the predictive value of FOB in diagnosing/staging a PNM, by comparing the results of CT and bronchoscopy. DESIGN: Retrospective review of chest CTs and medical records. PATIENTS: Consecutive patients with BC between 1992 and 1994 who had diagnostic FOB and CT in our institution, but without radiographic evidence of (1) pulmonary atelectasis, (2) endobronchial tumor or narrowing of the central airways, and (3) the PNM abutting the central airways. RESULTS: Sixty-four patients met the selection criteria. The size of the PNM ranged from 1.5 to 10 cm; the size was < or = 4 cm in 62 patients. FOB provided a diagnosis in 22 patients. Bronchoscopy detected endobronchial lesions in 11 patients (17%); 3 had lesions in more than one lobe. In three patients, the PNM was <3 cm. The radiographically undetected endobronchial tumor increased the tumor stage in only two patients. The "CT bronchus" sign had a positive and negative predictive value of 75% and 68%, respectively. CONCLUSIONS: (1) In this study, CT failed to detect endobronchial tumor in 11 of 64 patients (17%). Because of the implications of a new staging system, more studies are necessary before abandoning staging FOB. (2) The CT bronchus sign has a very high positive and negative predictive value in the use of diagnostic FOB and should be used to guide the method of biopsy of a PNM.

Wegener's granulomatosis upper respiratory tract and pulmonary radiographic manifestations in 30 cases with pathogenetic consideration.

Although the radiographic manifestations and pathologic features of Wegener's granulomatosis have been well described, their relationship to two variants of anti-neutrophil cytoplasmic antibodies (c- and p-ANCA) remains unclear. The purposes of this study are to analyze the radiographic and pathologic findings in 30 patients with Wegener's granulomatosis and to correlate c- and p-ANCA with such findings. Major histologic findings included parenchymal necrosis, necrotizing vasculitis, and granulomatous inflammations. Nodular lesions were more often associated with arteritis whereas patchy fluffy lesions associated with hemorrhagic capillaritis. ANCAs, particularly c-ANCA, instead of p-ANCA, were present in a high percentage of patients tested. These findings suggest that c-ANCA could play an important pathogenetic role in Wegener's granulomatosis which showed dual pathologic processes: vasculitis and granulomatous inflammation manifested radiographically as either nodular or pneumonia-like lesions, whereas p-ANCA was more often associated with patchy fluffy lung lesions as the consequence of hemorrhagic capillaritis.

Pulmonary manifestations of Goodpasture's syndrome. Antiglomerular basement membrane disease and related disorders.

Goodpasture's syndrome, or antiglomerular basement membrane disease, is a disorder in which lungs and kidneys are affected by the binding of anti-GBM antibodies, leading to pulmonary hemorrhage and glomerulonephritis with rapidly progressive renal insufficiency. Recent advances in the understanding of disease pathogenesis and diagnosis and treatment have significantly improved our ability to recognize the syndrome, distinguish it from other similar disorders, and offer successful treatment. This article focuses on the pathogenetic features, clinical manifestations, diagnostic strategies, and therapeutic principles of anti-GBM disease.

Determining the collateral effects of peer tutor training on a student with severe disabilities.

In one experiment and two case studies, we evaluated the impact of training peer tutors without disabilities to provide effective instructional procedures with a student with severe disabilities who exhibited aberrant behaviors in the classroom. Peer tutors received training on how to provide appropriate commands and specific praise statements, as well as to decrease negative statements. In the experiment, two peer tutors were taught these skills in a multiple baseline design. Two case studies further clarified the impact of the peer tutor training. In Case Study 1, one peer tutor received training on the three skills concurrently and data were assessed in an AB design. In Case Study 2, one peer tutor was trained prior to working with the student to determine if a peer tutor who had no prior history with the student could work effectively with minimal disruptions from the onset. Data were also measured on the student's aberrant behaviors and his compliance before, during, and after training the peer tutors. Results indicated that the peer tutors learned to provide appropriate commands and specific praise and to reduce negative statements. More important, as a collateral effect of the training program, the student's aberrant behaviors decreased and his compliance to requests improved.

Restenosis following subclavian artery angioplasty for treatment of coronary-subclavian steal syndrome: definitive treatment with Palmaz-stent placement.

We report a case of progressive angina pectoris 4 years post coronary bypass surgery, in which the left internal mammary artery (LIMA) was grafted to the native left anterior descending coronary artery. The coronary-subclavian steal phenomenon was proven angiographically with retrograde reflux through the LIMA graft into the distal subclavian vessel, downstream from a critical stenosis at the origin of the subclavian artery. After initially successful angioplasty of the ostial subclavian lesion, restenosis and return of angina prompted repeat dilatation and placement of a Palmaz 154-M stent. Follow-up catheterization has demonstrated persistent patency at the stented site and absence of coronary steal.

Treatment regimen and side effects of treatment measures.

The severity of asthma can be judged by many features, including the need for medication and associated side effects. Since asthma has both acute and chronic characteristics, therapeutic regimens should be valuable as an instrument to define disease severity and the consequence of intervention. However, because of the variability of asthma severity within each patient, medication quantitation as an index of asthma severity is not without difficulty and limitation. Furthermore, the philosophy of asthma therapy has undergone changes over the past decade. Previously, anti-inflammatory therapy was reserved for only the most severely ill patients. Now, inflammation is recognized as a critical component of asthma, and all patients with active asthma (other than mild symptoms) are recommended to use anti-inflammatory therapy. Although there is little published experience with treatment regimens as an index of disease severity, those that have been used have found validity and reproducibility with this approach. In this paper, a scoring approach to medication use is recommended. Medication is classified into bronchodilator (beta-agonists, theophylline, and anticholinergic) or anti-inflammatory (corticosteroid and cromolyn sodium). Medication scores are given on either a per-use or a new-dosage basis. Furthermore, the eight medications are stratified according to potency (i.e., inhaled corticosteroid < oral corticosteroid < parenteral corticosteroid). From this approach, the severity of an individual patient's asthma can be quantitated, and this value can serve as one instrument to assess disease severity.

An evaluative study of a community health service development.

This paper describes a research study designed to evaluate a community health service development in one health authority in rural England. The study compared two types of primary care teams working towards the same objectives. Surveys of patients and staff in the health authority were conducted about a range of issues, defined by the original aims of the scheme. Measures were made of care received by people over 75 years of age, consumer satisfaction, staff experiences of the multi-disciplinary team, job satisfaction and liaison with social services personnel. Few differences existed between the two forms of care on all of these measures. This paper contains a discussion of the findings alongside an examination of the implications for future health service developments, particularly flagship enterprises such as nursing development units. The importance of well established baseline measurements is emphasized by both the research findings and the discussion.

Transforming growth factor beta within fibrotic scleroderma lungs.

PURPOSE, PATIENTS, AND METHODS: Since transforming growth factor beta (TGF beta) has been implicated as an important mediator of pulmonary fibrosis, we measured TGF beta protein and gene expression in alveolar epithelial lining fluid (ELF) of fibrotic scleroderma lungs sampled by bronchoalveolar lavage (BAL). TGF beta protein was qualitatively examined by Western blot analysis, and quantitatively by radioreceptor assays. Gene expression was evaluated in BAL mononuclear cells by Northern blot analysis with quantification of relative gene expression by densitometric analysis of the autoradiograms. RESULTS: Normal and scleroderma subjects had a 24-kd protein that comigrated with defined human TGF beta 1 and immunoreacted with anti-TGF beta antibody. The normal population had a significantly higher average TGF beta concentration (705 pM) compared with the scleroderma subjects (177 pM). The TGF beta 1 gene was expressed in amounts that did not significantly differ between the scleroderma and normal groups. On an individual subject basis, the TGF beta concentration variability did not correlate with variations in BAL cellularity or TGF beta 1 gene expression within the recovered mononuclear cells. CONCLUSIONS: It is concluded that both normal and fibrotic lungs have TGF beta 1 present at the alveolar epithelial surface. However, in the fibrotic scleroderma lungs, TGF beta protein content and gene expression were not increased at the alveolar epithelial surface. The simultaneous analysis of TGF beta protein content, gene expression, and cellular constituents within individual ELF specimens showed that the cellular components of the ELF do not appear to be major determinants of TGF beta protein concentration at the alveolar epithelial surface.