John W. Bloom

The Course and Prognosis of Different Forms of Chronic Airways Obstruction in a Sample from the General Population

We examined the course and prognosis in subjects selected from the general population who had chronic airflow obstruction at the time of their enrollment in a longitudinal epidemiologic study. Mortality and the rate of change in lung function were analyzed in relation to the initial clinical characteristics of the subjects. Twenty-seven subjects with symptoms and signs of asthma (Group I) had a higher survival rate and a much lower rate of decline in pulmonary function than the 45 subjects in Group III, whose clinical characteristics were more compatible with an emphysematous form of chronic obstructive pulmonary disease (COPD). The 10-year mortality among subjects in Group III (non-atopic smokers without a history of asthma) was close to 60 percent, whereas it was only 15 percent in Group I (atopic subjects or nonsmokers with known asthma). The mean overall rate of decline in forced expiratory volume in one second was 70 ml per year in Group III but less than 5 ml per year in Group I. Forty-five patients (Group II) who did not clearly fit into either Group I or III had intermediate values for survival and decline in pulmonary function. Previous data on mortality from COPD and the rate of progression of the condition, although compatible with our findings in patients who had an emphysematous form of disease, are not applicable to those with an asthmatic-bronchitic form. Better control of the progression of asthmatic bronchitis with therapy may explain its more favorable prognosis.

A Common Single Nucleotide Polymorphism in the CD14 Promoter Decreases the Affinity of Sp Protein Binding and Enhances Transcriptional Activity

CD14 is a pattern recognition receptor that plays a central role in innate immunity through recognition of bacterial lipoglycans, primarily LPS. Recently, our group has identified a common single nucleotide polymorphism, −159C→T, in the CD14 proximal promoter. Homozygous carriers of the T allele have a significant increase in soluble CD14, but a decreased total serum IgE. This epidemiologic evidence led us to investigate the molecular basis for the effects of CD14/−159C→T on CD14 regulation in monocytes and hepatocytes, the two major cell types known to express this gene in vivo. EMSA analysis showed that the T allele results in decreased affinity of DNA/protein interactions at a GC box that contains a binding site for Sp1, Sp2, and Sp3 transcription factors. In reporter assays, the transcriptional activity of the T allele was increased in monocytic Mono Mac 6 cells, which express low levels of Sp3, a member of the Sp family with inhibitory potential relative to activating Sp1 and Sp2. By contrast, both alleles were transcribed equivalently in Sp3-rich hepatocytic HepG2 cells. Our data indicate that the interplay between CD14 promoter affinity and the [Sp3]:[Sp1 + Sp2] ratio plays a critical mechanistic role in regulating transcription of the two CD14 alleles. Variation in a key gene of innate immunity may be important for the pathogenesis of allergy and inflammatory disease through gene-by-gene and/or gene-by-environment interactions.

Respiratory effects of non-tobacco cigarettes.

Data from the Tucson epidemiological study of airways obstructive disease on smoking of non-tobacco cigarettes such as marijuana were analysed to determine the effect of such smoking on respiratory symptoms and pulmonary function. Among adults aged under 40, 14% had smoked non-tobacco cigarettes at some time and 9% were current users. The prevalence of respiratory symptoms was increased in smokers of non-tobacco cigarettes. After tobacco smoking had been controlled for men who smoked non-tobacco cigarettes showed significant decreases in expiratory flow rates at low lung volumes and in the ratio of the forced expiratory volume in one second to the vital capacity. This effect on pulmonary function in male non-tobacco cigarette smokers was greater than the effect of tobacco cigarette smoking. These data suggest that non-tobacco cigarette smoking may be an important risk factor in young adults with respiratory symptoms or evidence of airways obstruction.

Video laryngoscopy improves intubation success and reduces esophageal intubations compared to direct laryngoscopy in the medical intensive care unit

IntroductionTracheal intubation in the Intensive Care Unit (ICU) can be challenging as patients often have anatomic and physiologic characteristics that make intubation particularly difficult. Video laryngoscopy (VL) has been shown to improve first attempt success compared to direct laryngoscopy (DL) in many clinical settings and may be an option for ICU intubations.MethodsAll intubations performed in this academic medical ICU during a 13-month period were entered into a prospectively collected quality control database. After each intubation, the operator completed a standardized form evaluating multiple aspects of the intubation including: patient demographics, difficult airway characteristics (DACs), method and device(s) used, medications used, outcomes and complications of each attempt. Primary outcome was first attempt success. Secondary outcomes were grade of laryngoscopic view, ultimate success, esophageal intubations, and desaturation. Multivariate logistic regression was performed for first attempt and ultimate success.ResultsOver the 13-month study period (January 2012-February 2013), a total of 234 patients were intubated using VL and 56 patients were intubated with DL. First attempt success for VL was 184/234 (78.6%; 95% CI 72.8 to 83.7) while DL was 34/56 patients (60.7%; 95% CI 46.8 to 73.5). Ultimate success for VL was 230/234 (98.3%; 95% CI 95.1 to 99.3) while DL was 52/56 patients (91.2%; 95% CI 81.3 to 97.2). In the multivariate regression model, VL was predictive of first attempt success with an odds ratio of 7.67 (95% CI 3.18 to 18.45). VL was predictive of ultimate success with an odds ratio of 15.77 (95% CI 1.92 to 129). Cormack-Lehane I or II view occurred 199/234 times (85.8%; 95% CI 79.5 to 89.1) and a median POGO (Percentage of Glottic Opening) of 82% (IQR 60 to 100) with VL, while Cormack-Lehane I or II view occurred 34/56 times (61.8%; 95% CI 45.7 to 71.9) and a median POGO of 45% (IQR 0 to 78%) with DL. VL reduced the esophageal intubation rate from 12.5% with DL to 1.3% (P = 0.001) but there was no difference in desaturation rates.ConclusionsIn the medical ICU, video laryngoscopy resulted in higher first attempt and ultimate intubation success rates and improved grade of laryngoscopic view while reducing the esophageal intubation rate compared to direct laryngoscopy.

A muscarinic receptor with high affinity for pirenzepine mediates vagally induced bronchoconstriction.

The nature of the putative muscarinic receptor subtypes involved in vagally mediated bronchoconstriction was examined in the rabbit model utilizing the classical muscarinic antagonist atropine and the selective antagonist pirenzepine. In vivo electrical stimulation of the cervical vagus nerves in anesthetized rabbits resulted in a reproducible increase in pulmonary resistance indicative of bronchoconstriction and a marked negative chronotropic effect on the heart. Both atropine and pirenzepine produced dose-related inhibition of these two vagal effects. Fifty percent inhibition of the vagally induced increase in pulmonary resistance was achieved with an infusion of pirenzepine that was only 8-fold greater than the equi-effective dose of atropine. In contrast, the dose of pirenzepine required to inhibit the vagally induced decrease in heart rate by 50% was 100-fold greater than the atropine dose. Thus, pirenzepine is markedly more potent in inhibiting vagally mediated bronchoconstriction than bradycardia. In vitro inhibition of methacholine-induced contraction of bronchial rings with atropine and pirenzepine yielded pA2 values of 8.86 and 6.88 respectively (95-fold potency ratio), demonstrating that the muscarinic receptors on airway smooth muscle cells that mediate contraction are not of the pirenzepine-sensitive subtype.

Bronchoscopic diagnosis of pulmonary coccidioidomycosis comparison of cytology, culture, and transbronchial biopsy

The results of all fiberoptic bronchoscopic examinations that detected Coccidioides immitis at two medical centers in an area endemic for coccidioidomycosis were retrospectively reviewed. Coccidioides immitis was detected by cytologic examination of fluid from either bronchial wash or bronchoalveolar lavage (BAL) fluid in eight (42%) of 19 HIV-infected patients and in 11 (31%) of 35 patients without HIV infection (P = 0.627). In all cases, the fluid samples grew C. immitis. The median time to positive identification of the fungus was 25 days. Preliminary identification of C. immitis, however, took a median of 3.5 days (range, 2-9 days) in 10 patients on whom these data were available. Transbronchial biopsy was performed simultaneously in eight cases, and C. immitis was identified by morphologic examination in all eight. These results indicate that cytologic examination of bronchial wash or BAL fluid from patients with and without HIV infection is diagnostic in less than half of cases of pulmonary coccidioidomycosis. Culture of the same fluid appears to be more sensitive than cytologic examination in establishing this diagnosis.

Glucocorticoid regulation of human eosinophil gene expression

Molecular analysis of steroid-regulated gene expression in freshly isolated human eosinophils is difficult due to the inherent high rate of spontaneous apoptosis and elevated levels of endogenous ribonucleases. To circumvent these limitations, we determined if the human eosinophilic cell line EoL-1 could serve as an in vitro model of glucocorticoid signaling. We found by optimizing growth conditions in low serum-containing media that dexamethasone (Dex) treatment of EoL-1 cells induced an apoptotic pathway that was inhibited by interleukin-5 (IL-5). Moreover, gene expression profiling using RNA from untreated EoL-1 cells and from freshly isolated human eosinophils identified 380 commonly expressed genes, including the eosinophil markers granule major basic protein, prostaglandin-endoperoxide synthase 1 and arachidonate 15-lipoxygenase. Expression profiling was performed using EoL-1 cells that had been treated with dexamethasone for 0, 4, 12, 24 and 48h identifying 162 genes as differentially expressed. Two of the most highly upregulated genes based on expression profiling were the transcription factor Ets-2 and the MHC Class II genes (Q, R, and P). Expression of these genes in EoL-1 cells was shown to be dexamethasone-induced at the RNA and protein levels which is consistent with the known function of Ets-2 in controlling cell cycle progression and the role of MHC Class II antigens in mediating eosinophil functions.

Critical care ultrasound training: A survey of US fellowship directors

PURPOSE The purpose of this study is to describe the current state of bedside ultrasound use and training among critical care (CC) training programs in the United States. MATERIALS AND METHODS This was a cross-sectional survey of all program directors for Accreditation Council for Graduate Medical Education accredited programs during the 2012 to 2013 academic year in CC medicine, surgical CC, pulmonary and critical care, and anesthesia CC. Availability, current use, and barriers to training in CC ultrasound were assessed. RESULTS Sixty of 195 (31%; 95% confidence interval [CI], 24%-38%) program directors responded. Most of the responding programs had an ultrasound system available for use (54/60, 90%; 95% CI, 79%-96%) and identified ultrasound training as useful (59/60, 98%; 95% CI, 91%-100%) but lacked a formal curriculum (25/60, 42%; 95% CI, 29%-55%) or trained faculty (mean percentage of faculty trained in ultrasound: pulmonary and critical care, 25%; surgical CC, 33%; anesthesia CC, 20%; CC medicine, 7%), and relied on informal teaching (45/60, 77%; 95% CI, 62%-85%). Faculty with expertise (53/60, 88%; 95% CI, 77%-95%), simulation training (60/60, 100%; 95% CI, 94%-100%), establishing and meeting required number of examinations (47/60, 78%; 95% CI, 66%-88%), and regular review sessions (49/60, 82%; 95% CI, 70%-90%) were identified as necessary to improve ultrasound training. Most responding programs (32/35 91%; 95% CI, 77%-98%) without a formal curriculum plan to create one in the next 5 years. CONCLUSIONS This study identified deficiencies in current training, suggesting a need for a formal curriculum for bedside ultrasound training in CC fellowship programs.

Glucocorticoid regulation of GM-CSF: evidence for transcriptional mechanisms in airway epithelial cells.

Inflammation plays a central role in the pathogenesis of asthma. Glucocorticoids are first-line anti-inflammatory therapy in the treatment of asthma and are effective inhibitors of inflammatory cytokines. Clinical data demonstrate that granulocyte-macrophage colony-stimulating factor (GM-CSF) production by airway epithelial cells may be an important target of inhaled glucocorticoid therapy. We examined the regulatory mechanisms of GM-CSF expression by interleukin-1β (IL-1β) and the synthetic glucocorticoid dexamethasone in the BEAS-2B human bronchial epithelial cell line. IL-1β stimulation resulted in a 15-fold induction of GM-CSF protein, which was associated with a corresponding 47-fold maximal induction of GM-CSF mRNA levels. Treatment with the transcriptional inhibitor actinomycin D before IL-1β stimulation completely abolished induction of GM-CSF mRNA, whereas incubation with cycloheximide had no effect. Taken together, these data demonstrate that IL-1β induction of GM-CSF is mediated through transcriptional mechanisms. Dexamethasone treatment of BEAS-2B cells produced an 80% inhibition of IL-1β-induced GM-CSF protein and a 51% inhibition of GM-CSF mRNA. GM-CSF mRNA was rapidly degraded in these cells, and dexamethasone treatment did not significantly affect this decay rate. We conclude that, in the BEAS-2B bronchial epithelial cell line, IL-1β induction and dexamethasone repression of GM-CSF expression are mediated predominantly through transcriptional mechanisms.

Pneumococcus‐specific immunoglobulin E in cigarette smokers

A relationship between elevated scrum immunoglobulin E levels and smoking has been demonstrated in epidemiological studies. Allergy skin test data suggest that the excess immunoglobulin E of smokers is not specific for aeroallergens. It is possible that the excess immunoglobulin E is specific for microorganisms that often infect the lower respiratory tract of smokers. To investigate this possibility we utilized a radio‐allergosorbent test assay for detecting serum immunoglobulin E specific for Streptococcus pneumoniae, an organism commonly isolated from the respiratory tract of smokers with chronic bronchitis. We assayed sera of thirty smokers and thirty nonsmokers for immunoglobulin E specific for Streptococcus pneumoniae. Individual sera were considered positive for pneumococcus‐specific immunoglobulin E if the binding was at least twice the non‐specific binding at the total immunoglobulin E concentration of the particular serum. Eleven of the thirty sera of smokers and two of the thirty nonsmokers were positive for pneumococcus‐specific immunoglobulin E. By chi‐square analysis of these data, the prevalence of pneumococcus‐specific immunoglobulin E was significantly greater in the smoking group compared with the non‐smoking group (P<0·02). These results suggest that the excess immunoglobulin E of smokers is, at least in part, specific for microorganisms that infect the airways.