Rationale and design of a randomized trial of home electronic symptom and lung function monitoring to detect cystic fibrosis pulmonary exacerbations: the early intervention in cystic fibrosis exacerbation (eICE) trial.

BACKGROUND: Acute pulmonary exacerbations are central events in the lives of individuals with cystic fibrosis (CF). Pulmonary exacerbations lead to impaired lung function, worse quality of life, and shorter survival. We hypothesized that aggressive early treatment of acute pulmonary exacerbation may improve clinical outcomes. PURPOSE: Describe the rationale of an ongoing trial designed to determine the efficacy of home monitoring of both lung function measurements and symptoms for early detection and subsequent early treatment of acute CF pulmonary exacerbations. STUDY DESIGN: A randomized, non-blinded, multi-center trial in 320 individuals with CF aged 14 years and older. The study compares usual care to a twice a week assessment of home spirometry and CF respiratory symptoms using an electronic device with data transmission to the research personnel to identify and trigger early treatment of CF pulmonary exacerbation. Participants will be enrolled in the study for 12 months. The primary endpoint is change in FEV1 (L) from baseline to 12 months determined by a linear mixed effects model incorporating all quarterly FEV1 measurements. Secondary endpoints include time to first acute protocol-defined pulmonary exacerbation, number of acute pulmonary exacerbations, number of hospitalization days for acute pulmonary exacerbation, time from the end of acute pulmonary exacerbation to onset of subsequent pulmonary exacerbation, change in health related quality of life, change in treatment burden, change in CF respiratory symptoms, and adherence to the study protocol. CONCLUSIONS: This study is a first step in establishing alternative approaches to the care of CF pulmonary exacerbations. We hypothesize that early treatment of pulmonary exacerbations has the potential to slow lung function decline, reduce respiratory symptoms and improve the quality of life for individuals with CF.

Immunophenotypic and gene expression analysis of monoclonal B-cell lymphocytosis shows biologic characteristics associated with good prognosis CLL.

Monoclonal B-cell lymphocytosis (MBL) is a hematologic condition wherein small B-cell clones can be detected in the blood of asymptomatic individuals. Most MBL have an immunophenotype similar to chronic lymphocytic leukemia (CLL), and 'CLL-like' MBL is a precursor to CLL. We used flow cytometry to identify MBL from unaffected members of CLL kindreds. We identified 101 MBL cases from 622 study subjects; of these, 82 individuals with MBL were further characterized. In all, 91 unique MBL clones were detected: 73 CLL-like MBL (CD5(+)CD20(dim)sIg(dim)), 11 atypical MBL (CD5(+)CD20(+)sIg(+)) and 7 CD5(neg) MBL (CD5(neg)CD20(+)sIg(neg)). Extended immunophenotypic characterization of these MBL subtypes was performed, and significant differences in cell surface expression of CD23, CD49d, CD79b and FMC-7 were observed among the groups. Markers of risk in CLL such as CD38, ZAP70 and CD49d were infrequently expressed in CLL-like MBL, but were expressed in the majority of atypical MBL. Interphase cytogenetics was performed in 35 MBL cases, and del 13q14 was most common (22/30 CLL-like MBL cases). Gene expression analysis using oligonucleotide arrays was performed on seven CLL-like MBL, and showed activation of B-cell receptor associated pathways. Our findings underscore the diversity of MBL subtypes and further clarify the relationship between MBL and other lymphoproliferative disorders.

Single-cell analysis reveals oligoclonality among 'low-count' monoclonal B-cell lymphocytosis.

Monoclonal B-cell lymphocytosis (MBL) is a preclinical hematologic syndrome characterized by small accumulations of CD5(+) B lymphocytes. Most MBL share phenotypic characteristics with chronic lymphocytic leukemia (CLL). Although some MBL progress to CLL, most MBL have apparently limited potential for progression to CLL, particularly those MBL with normal absolute B-cell counts ('low-count' MBL). Most CLL are monoclonal and it is not known whether MBL are monoclonal or oligoclonal; this is important because it is unclear whether MBL represent indolent CLL or represent a distinct premalignant precursor before the development of CLL. We used flow cytometry analysis and sorting to determine immunophenotypic characteristics, clonality and molecular features of MBL from familial CLL kindreds. Single-cell analysis indicated four of six low-count MBL consisted of two or more unrelated clones; the other two MBL were monoclonal. 87% of low-count MBL clones had mutated immunoglobulin genes, and no immunoglobulin heavy-chain rearrangements of V(H) family 1 were observed. Some MBL were diversified, clonally related populations with evidence of antigen drive. We conclude that although low-count MBL share many phenotypic characteristics with CLL, many MBL are oligoclonal. This supports a model for step-wise development of MBL into CLL.

Smoking is associated with an age-related decline in exhaled nitric oxide.

Age-related declines in forced expiratory volume in one second are accelerated in smokers. Smoking is associated with decreased exhaled nitric oxide fraction (F(eNO)). The aim of the present study was to determine the impact of age on F(eNO) in otherwise healthy smokers and nonsmokers. F(eNO) and serum cotinine levels were measured in 994 healthy subjects aged 18-40 yrs. American Thoracic Society questionnaire data on smoking habits was used to validate serum cotinine levels as a surrogate marker for categorisation of smokers and nonsmokers in the cohort. Serum cotinine levels were a good discriminator of smokers (n = 99) and nonsmokers (n = 895). F(eNO) levels were significantly lower in otherwise healthy smokers compared with nonsmokers. There was an inverse correlation of serum cotinine levels with F(eNO). No correlation of age with F(eNO) was found in nonsmokers but an inverse correlation of F(eNO) with age in smokers was found. F(eNO) was significantly lower in smokers aged 21-40 yrs compared with nonsmokers aged 21-40 yrs, but was not lower in smokers aged 18-20 yrs compared with nonsmokers of the same age. Smoking was associated with decreased exhaled nitric oxide. The greatest smoking-related declines in exhaled nitric oxide occurred in older subjects. This suggests that smoking is associated with age-related declines in exhaled nitric oxide and justifies future mechanistic studies that address the impact of exhaled nitric oxide decline on lung function.

Naloxone requires circulating catecholamines to attenuate the cardiovascular suppression of endotoxic shock.

The opiate antagonist naloxone (NAL) improves cardiovascular performance in canine hemorrhagic and endotoxic shock. If the release of neural and adrenal catecholamines is attenuated, NAL does not produce the expected improvement in cardiovascular function in canine hemorrhagic shock. This study tests the hypothesis that an endorphin-catecholamine interaction at the heart is responsible for a part of the cardiovascular depression of endotoxic shock. Two groups of five dogs were instrumented to measure mean arterial pressure (MAP), the first derivative of left ventricular pressure over time (LV dP/dt max), cardiac output, and heart rate (HR); they were then subjected to bilateral adrenalectomy and given chlorisondamine to produce ganglionic blockade. At t = 0 min the dogs were given Escherichia coli endotoxin at 1 mg/kg (LD80). Group I animals received NAL at 2 mg/kg + 2 mg/kg.hr iv from t = 30 to t = 60. At t = 45 these animals were treated with epinephrine (EPI) at 20 micrograms/kg.hr iv until t = 60. Group II animals got EPI from t = 30 to t = 60 and NAL from t = 45 to t = 60 at the same doses as Group I. In Group I, NAL alone had no effect on MAP, LV dP/dt max, or HR. EPI significantly increased (P less than 0.002) cardiovascular parameters with MAP increasing from 52 +/- 7 to 159 +/- 14 mm Hg. In Group II, EPI produced a significant increase in all parameters, and the addition of NAL produced a further significant increase; MAP increased from 37 +/- 3 to 126 +/- 16 mm Hg with EPI and then to 175 +/- 11 mm Hg with NAL. These data support the above hypothesis and indicate that circulating catecholamines need to be present to allow naloxone to reverse the cardiovascular depression in endotoxic shock.