Danazol-induced augmentation of serum alpha 1-antitrypsin levels in individuals with marked deficiency of this antiprotease.

Individuals with serum alpha1-antitrypsin levels below 80 mg/dl are clearly at risk for the development of accelerated panacinar emphysema. One possible approach to the therapy of this disorder would be to raise serum levels of this major antiprotease to establish protease-antiprotease homeostasis within the lung parenchyma. Because danazol, an impeded androgen, elevates levels of C1 inhibitor in patients deficient of that serum antiprotease, we hypothesized that this agent might also increase alpha1-antitrypsin levels in patients with alpha1-antitrypsin deficiency. To evaluate this concept, seven patients with severe emphysema associated with alpha1-antitrypsin deficiency (six PiZ and 1 M(Duarte)Z) and one asymptomatic individual (PiSZ) received 600 mg of danazol daily for 30 d. Five of the six PiZ patients responded to danazol therapy with significant increases in serum alpha1-antitrypsin levels (mean increase of 37%; P < 0.03). The two individuals who were heterozygous for the Z protein increased their serum levels by 85% (PiM(Duarte)Z) and 87% (PiSZ), respectively. These increases in serum alpha1-antitrypsin antigen were accompanied by commensurate increases in serum trypsin inhibition. Crossed immunoelectrophoresis showed no alterations of the microheterogeneity of the alpha1-antitrypsin or the presence of protease-antiprotease complexes in serum during danazol therapy. These data demonstrate that serum alpha1-antitrypsin levels can be augmented by danazol therapy in PiZ individuals as well as those heterozygotes with severe deficiency of alpha1-antitrypsin. The clinical relevance of these increases in serum alpha1-antitrypsin remains speculative, but these findings suggest that danazol may provide a means of improving the protease-antiprotease balance in these individuals and thus impede the progression of their lung disease.

Urinary levels of bombesin-like peptides in asymptomatic cigarette smokers: a potential risk marker for smoking-related diseases.

Bombesin-like peptides (BLP) produced by pulmonary neuroendocrine cells have many physiological actions which are relevant to the pathobiology of cigarette smoking. The objectives of this study were to determine whether cigarette smokers excrete increased levels of BLP in their urine compared with nonsmokers, to determine the relationship between BLP levels in urine and bronchoalveolar lavage (BAL) fluid, and whether urinary BLP levels are merely a reflection of exposure to cigarette smoke. Simultaneous BAL fluid and urine samples were obtained from ten clinically normal smokers and 22 normal nonsmoker volunteers. Urine samples were also obtained from 39 normal smokers and 30 normal nonsmokers who did not have BAL performed. BLP levels were measured in urine and BAL fluid using an enzyme-linked immunoassay. Expired air content of carbon monoxide, which reflects recent exposure to cigarette smoke, was determined in 34 of the clinically normal smokers and correlated with urinary BLP levels. We found that, in addition to having increased BLP levels in BAL fluid (P = 0.04), asymptomatic cigarette smokers also have increased BLP levels in their urine compared with normal nonsmokers (P = 0.007). Of note, a subgroup of smokers have markedly increased BLP levels which do not overlap with the nonsmokers. Urinary BLP levels correlated with expired air content of carbon monoxide (r = 0.49, P less than 0.01). However, not all smokers with increased expired air content of carbon monoxide exhibited increased BLP levels. Finally, all smokers with detectable BLP levels in BAL fluid had detectable urinary BLP levels, and there was a positive correlation between BLP levels in urine and BAL fluid (r = 0.625, P less than 0.001). We conclude that a subgroup of asymptomatic cigarette smokers exhibited increased BLP levels, measurable in both urine and BAL fluid, which precede the onset of clinically detectable disease and which are not strictly dependent on smoking intensity. We speculate that smokers with increased BLP levels may have a greater risk for smoking-related diseases.

Human tissue engineering allows the identification of active miRNA regulators of glioblastoma aggressiveness.

Glioblastoma multiforme (GBM) is among the most aggressive cancers associated with massive infiltration of peritumoral parenchyma by migrating tumor cells. The infiltrative nature of GBM cells, the intratumoral heterogeneity concomitant with redundant signaling pathways likely underlie the inability of conventional and targeted therapies to achieve long-term remissions. In this respect, microRNAs (miRNAs), which are endogenous small non-coding RNAs that play a role in cancer aggressiveness, emerge as possible relevant prognostic biomarkers or therapeutic targets for treatment of malignant gliomas. We previously described a tissue model of GBM developing into a stem cell-derived human Engineered Neural Tissue (ENT) that allows the study of tumor/host tissue interaction. Combined with high throughput sequencing analysis, we took advantage of this human and integrated tissue model to understand miRNAs regulation. Three miRNAs (miR-340, -494 and -1293) active on cell proliferation, adhesion to extracellular matrix and tumor cell invasion were identified in GBM cells developing within ENT, and also confirmed in GBM biopsies. The components of miRNAs regulatory network at the transcriptional and the protein level have been also revealed by whole transcriptome analysis and Tandem Mass Tag in transfected GBM cells. Notably, miR-340 has a clinical relevance and modulates the expression of miR-494 and -1293, emphasizing its biological significance. Altogether, these findings demonstrate that human tissue engineering modeling GBM development in neural host tissue is a suitable tool to identify active miRNAs. Collectively, our study identified miR-340 as a strong modulator of GBM aggressiveness which may constitute a therapeutic target for treatment of malignant gliomas.

Incidence and outcome of the respiratory distress syndrome in gram-negative sepsis.

Twenty cases of the adult respiratory distress syndrome (ARDS) in 86 cases of Gram-negative bacteremia were identified. Features of Gram-negative bacteremia associated with the development of ARDS included a history of cardiac disease, hypotension, and thrombocytopenia. The mortality of patients with and without ARDS was 90% and 55%, respectively. The association of hypotension and thrombocytopenia with the subsequent development of ARDS suggests the possible role of endotoxin-induced coagulopathy in this complication.

Diagnosis of adult respiratory distress syndrome associated with underlying severe emphysema.

Adult respiratory distress syndrome (ARDS) notably produces bilateral homogeneous alveolar infiltrates and decreased lung compliance. We encountered a patient whose severe underlying emphysema altered these distinctive clinical features. The chest roentgenogram showed bilateral infiltrates containing multiple radiolucencies that simulated a cavitary process. Also, lung-chest wall compliances measured during mechanical ventilation were higher than usually observed in patients with ARDS. We suggest that the pathologic features of the emphysematous lung with multiple blebs and decreased elastic recoil properties impart these unique findings. When ARDS develops in a patient with severe underlying emphysema, an atypical presentation may produce a confusing clinical picture.

Obstructive lung disease and low lung function in adults in the United States: data from the National Health and Nutrition Examination Survey, 1988-1994.

BACKGROUND: Obstructive lung disease (OLD) is an important cause of morbidity and mortality in the US adult population. Potentially treatable mild cases of OLD often go undetected. This analysis determines the national estimates of reported OLD and low lung function in the US adult population. METHODS: We examined data from the Third National Health and Nutrition Examination Survey (NHANES III), a multistage probability representative sample of the US population. A total of 20,050 US adults participated in NHANES III from 1988 to 1994. Our main outcome measures were low lung function (a condition determined to be present if the forced expiratory volume in 1 second-forced vital capacity ratio was less than 0.7 and the forced expiratory volume in 1 second was less than 80% of the predicted value), a physician diagnosis of OLD (chronic bronchitis, asthma, or emphysema), and respiratory symptoms. RESULTS: Overall a mean (SE) of 6.8% (0.3%) of the population had low lung function, and 8.5% (0.3%) of the population reported OLD. Obstructive lung disease (age-adjusted to study population) was currently reported among 12.5% (0.7%) of current smokers, 9.4% (0.6%) of former smokers, 3.1% (1.1%) of pipe or cigar smokers, and 5.8% (0.4%) of never smokers. Surprisingly, 63.3% (0.2%) of the subjects with documented low lung function had no prior or current reported diagnosis of any OLD. CONCLUSIONS: This study demonstrates that OLD is present in a substantive number of US adults. In addition, many US adults have low lung function but no reported OLD diagnosis, which may indicate the presence of undiagnosed lung disease.

Criteria for weaning from prolonged mechanical ventilation.

We retrospectively studied 11 instances of patients requiring prolonged mechanical ventilation. Their spontaneous ventilatory measurements were not useful in judging their ability to wean, since these measurements did not change from the period of unsuccessful weaning to the period of progressive weaning from the ventilator. An adverse factor score and a ventilator score were created to evaluate underlying medical and respiratory problems related to ability to wean. Each score and the sum of the two scores separated patients between unsuccessful and successful weaning periods. We also found that the course and the duration of the entire weaning process could be predicted once progressive weaning had begun. We conclude that the adverse factor score and ventilator score correlate with the ability of patients receiving prolonged mechanical ventilation to wean.

Outcome of 51 patients with roentgenographically occult lung cancer detected by sputum cytologic testing: a community hospital program.

BACKGROUND: Lung cancer is the most common fatal malignant neoplasm of both men and women. It is usually caused by tobacco smoke. However, at present there is no systematic approach to early diagnosis. The diagnosis of lung cancer is usually made by standard chest roentgenograms and biopsy by bronchoscopy or surgery. Survival rates at 5 years have remained 10% to 15% for the past 30 years with this conventional approach to diagnosis. METHODS: Fifty-one men and women, aged 46 to 81 years (mean age, 64.2 years), with roentgenographically occult cancer were identified in one community hospital by means of sputum cytologic testing. Cancers were diagnosed by means of one or more standard light fiberoptic bronchoscopic procedures with biopsies. RESULTS: Forty-four squamous cell carcinomas, three adenocarcinomas, two large-cell carcinomas, and two undifferentiated carcinomas were found. Forty-five (86%) were stage 0 or 1. Surgical cure was attempted in 27 patients, and there were three actuarial cancer deaths at 5 years and a total of nine deaths. Additionally, 19 patients received attempts at curative radiation therapy for various reasons, which were usually poor pulmonary or cardiac function or advanced age. Of both the 27 patients who underwent surgery and the 19 who were treated with radiation therapy (total, 46), the actuarial results by the life-table method included nine lung cancer deaths in 5 years and 21 deaths from all causes, giving an actuarial survival, including deaths from all causes, of 55%. CONCLUSION: Roentgenographically occult lung cancer can be found by sputum cytologic testing followed by fiberoptic bronchoscopy and biopsy at a time when cure is more likely than when it is diagnosed by conventional roentgenographic techniques (ie, 55% survival vs 10% to 15% survival). Sputum cytologic testing should be used as a case-finding tool, particularly in heavy smokers and those with occupational risks. This diagnostic approach to earlier diagnosis and intervention can be successful in a small community hospital.

Fulminant respiratory failure and death in a patient with idiopathic bronchiolitis obliterans.

A middle-aged man with fulminant respiratory failure was found to have idiopathic bronchiolitis obliterans with organizing pneumonia on lung biopsy specimen. His course was atypical in that it was not altered by steroid therapy and led to fulminant respiratory failure and death.

A randomized controlled trial comparing zileuton with theophylline in moderate asthma. The Zileuton Study Group.

BACKGROUND: Zileuton, a leukotriene pathway inhibitor, was compared with slowly absorbed theophylline in a randomized, double-blind study of patients with chronic asthma. The primary efficacy measure was improvement in forced expiratory volume in 1 second (FEV1). METHODS: Eligibility criteria included FEV1 of 40% to 80% of predicted, documented reversibility of airway disease, and age 18 to 60 years. Initially, the theophylline dosage was titrated to achieve trough concentrations of 8 to 15 micrograms/mL. After washout and 1-week placebo lead-in, patients were randomly assigned to 13 weeks of the appropriate theophylline dose or zileuton, 400 or 600 mg 4 times daily. The FEV1 was measured before the morning dose at 2-week intervals and serially after the dose on days 36 and 92. Patients kept daily diaries of asthma symptoms, beta-agonist usage, and peak expiratory flow rate; on days 36 and 92, they completed quality-of-life questionnaires. RESULTS: Of 471 eligible patients at 38 centers, 377 were randomly assigned to the study; 313 completed the study. On first-dose administration, all groups showed 11% to 13% improvement in FEV1 within 30 minutes. Patients who received zileuton, 400 mg, had significantly greater improvement at several points than did theophylline-treated patients. The range of long-term maximum improvement in FEV1 in the groups was 30% to 34% (P = .40 for zileuton 600 mg; P = .90 for zileuton 400 mg vs theophylline). Initially, the theophylline group improved significantly more in symptom scores, beta-agonist usage, and peak expiratory flow rate, but at maximal effect there was no significant difference. All groups showed significant improvement in quality of life. No overall differences were observed between the zileuton dosage groups. Adverse events were comparable in all groups. CONCLUSION: Zileuton appears as effective and safe as theophylline in patients with chronic asthma.

Psychologic effects of continuous and nocturnal oxygen therapy in hypoxemic chronic obstructive pulmonary disease.

The Nocturnal Oxygen Therapy Trial (NOTT) showed previously that patients with hypoxemic chronic obstructive pulmonary disease (COPD) frequently suffered from neuropsychologic deficit and experienced disturbed mood, personality, and life quality. The present study has followed up 150 NOTT patients six months after they were randomized to continuous oxygen treatment (COT) or nocturnal oxygen treatment (NOT). Tested off oxygen, 42% showed modest neuropsychologic improvement after six months of therapy, and the rates for COT and NOT were comparable. A subsample (n = 37) was examined a third time, after 12 months of treatment. At this point patients receiving COT registered better neuropsychologic performance than those receiving NOT. Concurrently, the COT group began showing improved survival. Despite mild neuropsychologic improvement, patients reported little change in emotional status or life quality. It is concluded that prolonged oxygen treatment is associated with small but definite improvement in brain functioning among patients with hypoxemic COPD, and that COT might have some advantage over NOT in enhancing neuropsychologic functioning as well as survival.

Transdermal clonidine reduced some withdrawal symptoms but did not increase smoking cessation.

BACKGROUND: Clonidine may be useful in controlling tobacco withdrawal and in facilitating smoking cessation. This study was developed to test the efficacy of transdermal clonidine in promoting smoking cessation. METHODS: We conducted a five-center, double-blind, placebo-controlled, randomized controlled trial of transdermal clonidine in conjunction with a minimal behavioral intervention for smoking cessation. The intervention was based on the American Lung Association's Freedom From Smoking program. Self report of not smoking was validated with exhaled air carbon monoxide of less than 8 ppm and salivary cotinine of less than 20 ng/mL. Transdermal clonidine therapy began 1 week before the target quit date: 0.1 mg/24 h for the first 4 days increasing to 0.2 mg/24 h for the next 3 days, if the lower dose was tolerated. The highest tolerated dose was then continued for 6 weeks after target quit day. Withdrawal symptoms were measured daily for the first 7 days after target quit day. RESULTS: A total of 213 patients were enrolled (106 active drug and 107 placebo). During the study, 15.5% of patients had drug therapy discontinued due to adverse effects, 24.5% (26/106) taking active drug vs 8.4% (9/107) receiving placebo. There was a significant reduction in anxiety score from 3.0 to 2.4 (placebo vs active) and irritability score from 2.2 to 1.7 (placebo vs active) during the first week after cessation. There was no reduction in other withdrawal symptoms. The overall 12-week abstinence rate was 33.0% (35/106) in the active drug group vs 34.5% (37/107) in the placebo group (not significant). CONCLUSION: This study demonstrated some reduction in early withdrawal symptoms with the use of a clonidine transdermal patch, but no increase in cessation rate, 6 weeks after medication had been discontinued.

Outpatient oxygen therapy in chronic obstructive pulmonary disease. A review of 13 years' experience and an evaluation of modes of therapy.

Thirteen years' experience with home oxygen for patients with advanced chronic obstructive pulmonary disease are reviewed. Home oxygen is safe and relieves pulmonary hypertension and elevated RBC mass in some, but not all patients. Marked clinical improvement is the most important result of long-term home oxygen use, including reduced hospitalizations and return to gainful employment for a few patients. Chronic compensated carbon dioxide retention is well tolerated and adaptive in cases of severe chronic airflow obstruction. New oxygen concentrators are effective in correcting hypoxemia and may make home oxygen administration more convenient and less expensive.

Toscana virus meningitis case in Switzerland: an example of the ezVIR bioinformatics pipeline utility for the identification of emerging viruses.

Toscana virus (TOSV) represents a frequent cause of viral meningitis in the Mediterranean Basin that remains neglected in neighbouring countries. We report a documented TOSV meningitis case in a traveller returning from Tuscany to Switzerland. While routine serological and PCR assays could not discriminate between TOSV and Sandfly fever Naples virus infection, a high-throughput sequencing performed directly on the cerebrospinal fluid specimen and analysed with the ezVIR pipeline provided an unequivocal viral diagnostic. TOSV could be unequivocally considered as the aetiological agent, proving the potential of ezVIR to improve standard diagnostics in cases of infection with uncommon or emerging viruses.

Pulmonary manifestations of systemic lupus erythematosus: review of twelve cases of acute lupus pneumonitis.

Acute lupus pneumonitis was the presenting manifestation of systemic lupus erythematosus in six of 12 cases in this series. The clinical picture was characterized by severe dyspnea, tachypnea, fever and arterial hypoxemia. Radiographic findings included an acinar filling pattern which was invariably found in the lower lobes and was bilateral in 10 of the cases. Studies failed to reveal evidence of infection as a cause of the acute pulmonary infiltrates. All patients were treated with oxygen and corticosteroids; seven received azathioprine. Six patients survived and are clinically well 14 months to four years following their acute illness. Three of these patients have residual interstitial infiltrates with persistent pulmonary function test abnormalities indicating progression to chronic interstitial pneumonitis. Histologic sections of the lungs available from four patients revealed hyaline membranes and interstitial edema (four cases), acute alveolitis (two cases), arteriolar thrombosis (one case) and a prominent lymphocytic interstitial pneumonitis with organizing bronchiolitis (one case).

Circadian variations in chronic asthma and chronic obstructive pulmonary disease.

Patients with airway obstruction of all types show circadian variation of airflow. This article reviews the results of studies that suggest both possible mechanisms for this phenomenon and strategies for its treatment. The strategies discussed include the use of sustained-release beta-agonists and a once-a-day theophylline preparation, Uniphyl tablets, that is especially effective in asthmatic patients when administered in the evening. Also presented is a summary of future directions in the planning and implementation of individualized therapeutic strategies for patients with advanced chronic obstructive airways disease.

Future trends in the management of asthma and chronic obstructive pulmonary disease.

The strategic approach to the management of asthma and reversible chronic obstructive pulmonary disease employs the use of bronchodilators, corticosteroids, and other agents. A stepped therapeutic approach based upon inhaled beta agonists, long-acting oral methylxanthines and practical steroid strategies is valuable for most patients with reversible asthma and a considerable number of patients with advanced chronic obstructive pulmonary disease. The goals of therapy are a complete or acceptable relief of symptoms and the achievement of the highest possible level of human function, maximal improvement in airflow, and minimal or no side effects from the pharmacologic agents used. The response to therapy from each agent should be carefully assessed by objective measurements of one-second forced expiratory volume and forced vital capacity using simple, practical spirometers. Future trends in asthma therapy include new inflammatory mediator blockers, combined pharmacologic strategies, and other new agents. Future trends in chronic obstructive pulmonary disease include the early identification and intervention with drugs that could reduce or minimize nonspecific bronchial hyperreactivity.

Theophylline levels and clinical response in asthmatic adults receiving long-term Uniphyl.

Serum theophylline levels were measured in response to a single daily dose of Uniphyl in asthmatic adults who had previously received sustained-release theophylline preparations (usually Theo-Dur). Nine men and 20 women between the ages of 20 and 75 with a one-second forced expiratory volume (FEV1) of 30 to 75 percent of predicted and with at least 15 percent improvement in FEV1 following an inhaled beta-adrenergic agonist were enrolled. Patients with coexisting major organ system dysfunction were excluded. Maintenance prednisone in a dosage of 20 mg or less each morning and inhaled corticosteroids were allowed. The five-week study included a baseline week when the usual sustained-release theophylline was continued; theophylline blood levels were determined at six to 10 hours on the fifth day. Patients then switched to an equivalent dose of Uniphyl with single morning dosing. FEV1 and serum theophylline levels were observed weekly as during the baseline period. Side effects were carefully monitored throughout the study. Concurrent therapy included inhaled beta agonist in 28, oral prednisone in 11, and beclomethasone in one. Serum theophylline levels were remarkably stable during the four Uniphyl weeks and averaged 15 micrograms/ml. During this time, a small improvement in FEV1 occurred in weeks 2 and 4 (p less than 0.05). Only two patients reported substantial side effects--nervousness and slight morning dizziness--which responded to a downward adjustment of Uniphyl dosage. This study indicated that, in asthmatic patients previously receiving twice-daily theophylline therapy, switching to a daily single dose of Uniphyl maintained stable blood levels with a very low incidence of side effects and a modest improvement to FEV1 at the time of the normal serum peak of theophylline. This study suggests that Uniphyl can replace twice-daily theophylline dosing, which may result in improved patient compliance.

Complications and consequences of endotracheal intubation and tracheotomy. A prospective study of 150 critically ill adult patients.

A prospective study of the complications and consequences of translaryngeal endotracheal intubation and tracheotomy was conducted on 150 critically ill adult patients. Adverse consequences occurred in 62 percent of all endotracheal intubations and in 66 percent of all tracheotomies during placement and use of the artificial airways. The most frequent problems during endotracheal intubation were excessive cuff pressure requirements (19 percent), self-extubation (13 percent) and inability to seal the airway (11 percent). Patient discomfort and difficulty in suctioning tracheobronchial secretions were very uncommon. Problems with tracheotomy included stomal infection (36 percent), stomal hemorrhage (36 percent), excessive cuff pressure requirements (23 percent) and subcutaneous emphysema or pneumomediastinum (13 percent). Complications of tracheotomy were judged to be more severe than those of endotracheal intubation. Follow-up studies of survivors revealed a high prevalence of tracheal stenosis after tracheotomy (65 percent) and significantly less after endotracheal intubation (19 percent)(p < 0.01). Thirty-nine of 41 (95 percent) patients with endotracheal intubation and 20 of 22 (91 percent) patients with tracheotomy had laryngotracheal injury at autopsy. Ulcers on the posterior aspect of the true vocal cords were found at autopsy in 51 percent of the patients who died after endotracheal intubation. There was no significant relationship between the duration of endotracheal intubation or tracheotomy and the over-all amount of laryngotracheal injury at autopsy, although patients with prolonged endotracheal intubation followed by tracheotomy had more laryngeal injury at autopsy (P = 0.06) and more frequent tracheal stenosis (P = 0.05) than patients with short-term endotracheal intubation followed by tracheotomy. Adverse effects of both endotracheal intubation and tracheotomy are common. The value of tracheotomy when an artificial airway is required for periods as long as three weeks is not supported by data obtained in this study.

Can moderate chronic obstructive pulmonary disease be diagnosed by historical and physical findings alone?

BACKGROUND: The value of the history and physical examination in diagnosing chronic obstructive pulmonary disease (COPD) is uncertain. This study was undertaken to determine the best clinical predictors of COPD and to define the incremental changes in the ability to diagnose COPD that occur when the physical examination findings and then the peak flowmeter results are added to the pulmonary history. SUBJECTS AND METHODS: Ninety-two outpatients with a self-reported history of cigarette smoking or COPD completed a pulmonary history questionnaire and received peak flow and spirometric testing. The subjects were independently examined for 12 physical signs by 4 internists blinded to all other results. Multivariate analyses identified independent predictors of clinically significant, moderate COPD, defined as a forced expiratory volume in 1 second (FEV1) less than 60% of the predicted value or a FEV1/FVC (forced vital capacity) less than 60%. RESULTS: Fifteen subjects (16%) had moderate COPD. Two historical variables from the questionnaire--previous diagnosis of COPD and smoking (70 or more pack-years)--significantly entered a logistic regression model that diagnosed COPD with a sensitivity of 40% and a specificity of 100%. Only the physical sign of diminished breath sounds significantly added to the historical model to yield a mean sensitivity of 67% and a mean specificity of 98%. The peak flow result (best cutoff value was less than 200 L/min) significantly added to the models of only one of the four physicians for a mean final sensitivity of 77% and a specificity of 95%. Subjects with none of the three historical and physical variables had a 3% prevalence of COPD; this prevalence was unchanged by adding the peak flow results. CONCLUSIONS: Diminished breath sounds were the best predictor of moderate COPD. A sequential increase in sensitivity and a minimal decrease in specificity occurred when the quality of breath sounds was added first to the medical history, followed by the peak flow result. The chance of COPD was very unlikely with a normal history and physical examination.