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Purpose: To determine the effect of the timing of the medicine clerkship on academic performance in different racial-ethnic student groups., Method: Performance was measured by the average assessment of clinical preceptors, an OSCE (objective structured clinical examination), and the NBME (National Board of Medical Examiners) medicine subject examination. Outcomes were analyzed by student racial-ethnicity and clerkship sequence., Results: Of the 650 students who took the clerkship over four years, 6.9% were African American, 34.6% were Asian-Pacific Islander, 9.1% were Hispanic and 49.4% were white. African American and Hispanic students were in the earliest clerkship sequence 46.7% and 30.5% of the time, respectively, compared to 20% of Asian-Pacific Islanders and 27.4% of white students. Academic performance improved with time and varied among the racial-ethnic groups. All groups achieved higher scores in the NBME medicine examination later in the year but scores of African American and Hispanic students increased to a greater degree than other students., Conclusion: Sometimes, a "few points" on the NBME medicine examination can affect students' final grades and alter their attractiveness to competitive residency training programs. All students, but African American and Hispanic students, in particular, can significantly improve their scores in the NBME medicine examination by taking the clerkship later in the year. Students should be counseled regarding the timing effect and methods to neutralize the disparity should be considered.

The benefit of antimicrobial therapy for patients with an acute exacerbation of chronic bronchitis (AECB) remains controversial for two main reasons. First, the distal airways of patients with chronic bronchitis are persistently colonised, even during clinically stable periods, with the same bacteria that have been associated with AECB. Second, bacterial infection is only one of several causes of AECB. These factors have led to conflicting analyses on the role of bacterial agents and the response to antimicrobial therapy of patients with AECB. An episode of AECB is said to be present when a patient with chronic obstructive pulmonary disease (COPD) experiences some combination of increased dyspnoea, increased sputum volume, increased sputum purulence and worsening lung function. While the average COPD patient experiences 2 - 4 episodes of AECB per year, some patients, particularly those with more severe airway obstruction, are more susceptible to these attacks than others. Bacterial agents appear to be particularly associated with AECB in patients with low lung function and those with frequent episodes accompanied by purulent sputum. Non-typeable Haemophilus influenzae, Streptococcus pneumoniae and Moraxella catarrhalis account for up to 50% of episodes of AECB. Gram-negative bacilli are more likely to occur in patients with more severe lung disease. Antibiotics have been used to ameliorate AECB, to prevent AECB and to prevent the long-term loss of lung function that characterises COPD. Numerous prevention trials have been conducted with fairly consistent results; antibiotics do not lessen the number of episodes of AECB but do reduce the number of days lost from work. Most antibiotic trials have studied the impact of treatment on episodes of AECB and results have been inconsistent, largely due to patient selection and end point definition. In patients with severe airway obstruction, especially in the presence of purulent sputum, antibiotic therapy significantly shortens the duration of symptoms and can be cost-effective. Over the past 50 years, virtually all classes of antimicrobial agents have been studied in AECB. Important considerations include penetration into respiratory secretions, spectrum of activity and antimicrobial resistance. These factors limit the usefulness of drugs such as amoxicillin, erythromycin and trimethoprim-sulfamethoxazole. Extended-spectrum oral cephalosporins, newer macrolides and doxycycline have demonstrated efficacy in clinical trials. Amoxicillin-clavulanate and flouoroquinolones should generally be reserved for patients with more severe disease. A number of investigational agents, including ketolides and newer quinolones, hold promise for treatment of AECB.

Background: A large portion of the elderly population of the United States fails to receive an annual influenza vaccination. Minorities may receive disproportionately fewer vaccinations. The objectives of this study were to (a) estimate the levels of influenza vaccination among noninstitutionalized, U.S. citizens, 65 years and older, (b) examine the immunization levels among minority racial and ethnic groups relative to various majority groupings, and (c) explore potential factors that may contribute to disparities in vaccination levels., Methods: We analyzed data from the 1996 Medical Expenditure Panel Survey to compare influenza vaccination levels of different racial and ethnic groups among 2,309 persons aged 65 years and older., Results: Whites had 68.0% (+/- SE 1.5%) current influenza vaccination, Hispanics 61.7% (+/- SE 4.1%), and blacks 47.3% (+/- SE 4.3%). Blacks differed significantly compared to whites. Adjustment for potential confounders such as increased health risk, age distribution, perceived health status, family size, poverty level, and the number of ambulatory visits to a health care provider failed to change this difference substantially., Conclusions: In 1996, among elderly noninstitutionalized, U.S. citizens, blacks relative to whites were less likely to have current influenza vaccinations. This relationship remained significant even after adjustments for potential confounding variables., (Copyright 2002 American Health Foundation and Elsevier Science (USA).)

Background: Colonization and infection with vancomycin-resistant Enterococcus faecium (VREF) has been associated with the use of vancomycin and other antibiotics in individual patients. The objective of this study was to determine the association of VREF with the aggregate usage of antibiotics on nursing units in a hospital., Methods: This was a retrospective correlation study. A usage ratio was calculated for each parenteral antibiotic on each nursing unit as the per-bed usage by weight of that antibiotic divided by its average usage throughout the hospital. An average usage ratio (AUR) for each nursing unit was calculated as the mean of usage ratios of individual antibiotics. The AUR was used to compare the usage of antibiotics among nursing units in the hospital. The incidence of VREF infections on individual nursing units in a Veterans Affairs Medical Center was correlated with the usage of parenteral antibiotics separately and in aggregate in univariate and multivariate regression analyses., Results: The AUR was strongly and positively correlated with the recovery of VREF on individual nursing units. By univariate analyses, increasing use of each antibiotic tested was associated with isolation of VREF but only clindamycin remained significant in the multivariate model. However, usage of various antibiotics was highly interrelated, and only clindamycin usage was significantly correlated with usage of all other antibiotics studied. Intensive care and acute care units and units with fewer patient beds were more likely to have patients with VREF infection than were subacute care units (p < 0.003) or larger units (p < 0.01)., Conclusions: VREF infections were associated with greater aggregate antibiotic use on nursing units. Determination of antibiotic usage ratios may provide a convenient and useful tool for examining the association of antibiotic usage with other nosocomial infections.

New therapies for vancomycin-resistant Enterococcus faecium (VREF) infections are urgently needed. We describe the treatment of 15 patients with VREF infection with quinupristin/dalfopristin (RP 59500), a new injectable streptogramin antibiotic. Primary infections treated were bacteremia (4), urinary tract (4), intraabdominal (5), otitis externa (1), and meningitis (1). Minimum inhibitory concentrations for quinupristin/dalfopristin ranged from 0.5 microgram/ml or less to 2 micrograms/ml, and minimum bactericidal concentrations were greater than 64 micrograms/ml for all VREF isolates tested. Peak serum inhibitory titers following infusion of quinupristin/dalfopristin ranged from 1:8 to 1:64; all bactericidal titers were less than 1:2. Development of resistance to quinupristin/dalfopristin during therapy was not observed. The only drug-related adverse effect noted was phlebitis in 4 patients; all had received quinupristin/dalfopristin by peripheral venous infusion. Three patients had clinical and bacteriologic cures. Relapses occurred in 5 patients with recovery of VREF from infected sites in post-treatment cultures. Ten patients died of severe underlying disease; VREF was believed to contribute directly to the death of only 1 patient. While evaluation of clinical efficacy was complicated by the severity of underlying disease in patients with VREF infection, our experience suggests that quinupristin/dalfopristin is a safe and potentially useful agent for the treatment of VREF infections.

Aspiration bronchopneumonia occurs in most patients undergoing prolonged mechanical ventilation. These pneumonias adversely affect lung function and release bacteria into the systemic circulation via the lungs' lymphatics. Through this mechanism, clinically occult pneumonias may initiate activation of systemic inflammation, leading to the syndrome of multiple organ failure.

The influence of topical antimicrobial prophylaxis (TAP) on colonization of oropharynx and trachea was studied in patients receiving and not receiving prophylaxis. Twenty-two patients in Intensive Care Unit (ICU) I (Group 1) received TAP (tobramycin, colistin, and amphotericine B in oropharynx and stomach). Simultaneous to Group 1, 21 patients (Group 2) not receiving TAP were studied in ICU I. A control group of patients admitted to another, identical, ICU (ICU II), where no TAP was administered, were studied simultaneously (Group 3a, n = 23). A second control group (Group 3b, n = 31), was formed by collecting data from patients admitted to ICU I in Period II. Patients receiving TAP were less frequently colonized than patients not receiving prophylaxis. Moreover, of the patients not receiving TAP, those staying in the ICU where TAP was administered (Group 2) were less frequently colonized than patients in another ICU (Group 3). Of the patients not colonized on admission, those staying in the ICU where TAP was administered remained free of colonization for a longer time. In the ICU where no TAP was administered, more patients were colonized simultaneously and cross-acquisition occurred more frequently. TAP significantly influenced colonization of oropharynx and trachea in patients receiving and not receiving prophylaxis within the same ICU as compared with patients not receiving prophylaxis in another identical ICU.

Many hazardous waste sites contain chemicals that cause serious disease in humans. However, adverse effects are uncommon. Evidence for harm comes principally from epidemiologic studies in which proof of exposure usually is lacking.

The adult respiratory distress syndrome is a major cause of morbidity and mortality in critical care patients. Lung injury in this syndrome is frequently associated with lung infection. The combined insults result in an influx of neutrophils and damage to the pulmonary epithelium. We investigated whether active neutrophil elastolytic activity was present in the bronchoalveolar fluid in baboons with mild or moderate hyperoxic lung injury and infection. Group A (N = 7) was exposed for 6 days to FIO2 = 0.8 and then inoculated by intratracheal bolus with Pseudomonas aeruginosa strain DGI-R130 (PA); the FIO2 was reduced to 0.5. Group B (N = 6) was exposed to similar concentrations of inspired oxygen but inoculated with buffered saline. Antibiotics included parenteral penicillin and topical gentamicin and polymyxin B. All 3 were given continuously in group B but stopped 24 h prior to PA inoculation in group A. Bronchoalveolar lavage fluid was collected 1 week before oxygen administration, when the FIO2 was reduced (day 6 or 7) and prior to necropsy (day 11). Hemodynamic, pulmonary function, microbiological, and biochemical variables were studied. Injured, infected animals (group A) had significant elevations of mean pulmonary artery pressure and decreases in total lung capacity and PaO2 compared both to baseline and to group B at day 11. At autopsy, group A had significant increases of bronchoalveolar lavage fluid (BALF) neutrophils and bacterial pathogens. Elastase levels in BALF (equal to 0 at baseline) rose to 136 +/- 98 ng/ml in group A vs. 6 +/- 14 ng/ml in group B. The elastase was inhibited by inhibitors of serine proteases including ones specific for neutrophil elastase. On Sephacryl S-300 chromatography the elastase activity eluted near human alpha 2-macroglobulin and separated from other proteolytic activity. These studies demonstrate a significant level of elastase in BALF from injured, infected baboons compared to injured, uninfected animals.

Pseudomonas aeruginosa was inoculated into the lungs of normal and oxygen-exposed hamsters. Air-breathing animals developed focal bronchopneumonias but viable organisms were not recovered from the lungs after 3 days; bacteremia was not detected but P. aeruginosa was isolated from the livers of 3 of 12 animals with positive lung cultures. Pseudomonas aeruginosa infection shortened the survival time of oxygen-breathing hamsters, and organisms persisted in the lungs during oxygen exposure. Focal bronchopneumonias were uncommon in animals inoculated after 4 days of oxygen exposure; the predominant histopathologic finding was accentuation of diffuse alveolar damage and increased numbers of scattered neutrophils. Pseudomonas aeruginosa was recovered from the livers of 15 of 18 oxygen-exposed animals in which lung colony counts exceeded 10(3)/lung; only 8 of these animals had demonstrable bacteremia. The concentration of elongation factor-2 in the livers and lungs of oxygen-exposed animals was reduced as colony counts of P. aeruginosa increased in the lungs of infected animals, suggesting exotoxin A activity in these organisms. These findings suggest that bacterial superinfection of injured lungs may account for both worsening lung function and impaired function of other organs.

Nosocomial bacterial pneumonia as a complication of acute, diffuse lung injury may be difficult to distinguish clinically from other pathologic processes. To determine the reliability of findings commonly used to diagnose pneumonia in this setting, we compared clinical predictions of bacterial pneumonia with postmortem histology. Pneumonia was present histologically in 58 percent of the study patients, 36 percent of whom had been thought to have only lung injury. Among patients who had only diffuse lung injury histologically, 20 percent were thought to have pneumonia by clinical evaluation. Overall, 29 percent of cases were misdiagnosed. Improved diagnostic techniques will be required before the efficacy of preventive or therapeutic measures for pneumonia in the setting of acute, diffuse lung injury can be accurately determined.

Human pulmonary alveolar macrophages (PAM) from 30 patients with a variety of pulmonary diseases were tested for their ability to undergo cryopreservation. The cells were cryopreserved and stored under liquid nitrogen for intervals of 2, 4, 6, 8, or 12 wk, then assayed for viability (using the trypan dye exclusion method as well as the NADH-dependent cytochrome c reductase (cytochrome c) assay) and cellular function (as documented by the measurement of in vitro aryl hydrocarbon hydroxylase (AHH) induction by benzanthracene (BA) and by quantitation of PAM particulate phagocytosis). These results demonstrated no decrease in PAM viability after 2 wk of cryopreservation compared with that of the control cells (p greater than 0.30, paired, 2-tailed t test). However, PAM viability decreased slightly compared with the 0-time (p less than 0.003 in all instances) when cells were stored for intervals of 4, 6, 8, or 12 wk. In addition, cells demonstrated no further decrease in viability after being cryopreserved for as long as 12 wk, thawed, and cultured for as long as 48 h compared with the 0-time control cells (p greater than 0.10 in all instances). Similarly, when AHH induction was fluorometrically quantitated in PAM cultured for 24 h, there was no decrease in BA-induced AHH levels after a 2-wk cryopreservation period. However, AHH levels decreased slightly compared with those in the 0-time control cells (p less than 0.004), when PAM were stored for longer intervals of 4, 6, or 8 wk. The phagocytic activity of cryopreserved PAM was also quantitated using amorphous silica as a substrate.(ABSTRACT TRUNCATED AT 250 WORDS)

Bleomycin was administered intrabronchially to four baboons in doses of 1 mg/kg for four consecutive weeks. At necropsy 6 months later, the lesions produced differed markedly from those resulting from parenteral administration of bleomycin and consisted of diffuse foci of inflammation and fibrosis of the lung parenchyma associated with small airway lesions. Airway lesions were found in respiratory bronchioles and consisted of bronchiolar wall inflammation, hyperplasia of smooth muscles, and epithelia bronchiolization of adjacent alveolated structures. Many bronchioles were obliterated by the fibrotic process. Biochemical measurements confirmed the histologic appearance of increased lung collagen in three of four animals. These findings indicate that obstruction of small airways by processes which cause lung fibrosis may be separable physiologically from processes which affect only the lung parenchyma.

Pulmonary fibrosis induced by bleomycin is associated with accumulation of collagen and elastin in the lungs. The excess connective tissue proteins persist despite resolution of inflammation after cessation of treatment. In the present study, mild lung injury was produced in 9 juvenile baboons by twice-weekly injections of bleomycin to a total dose of 66 units/kg. Treated animals showed losses in body weight, lung volume, and diffusing capacity. Right middle lobectomies were performed in 3 animals shortly after cessation of bleomycin. Only minimal histologic changes were present, but lobar connective tissue protein concentrations and the rate of collagen synthesis were increased. Biopsies obtained in 3 additional animals 3 months later revealed similar changes. All animals were killed 6 months after cessation of treatment. Mild fibrosis was present, and lobar contents of collagen and elastin, as well as synthetic rates of collagen and elastin, remained elevated. Accumulation of lung connective tissue proteins in this model was associated with increased rates of synthesis that persisted after discontinuance of the drug.

This study examined the effect of fluid balance on survival in ARDS. Of the 213 patients entered into a prospective data collection study, we evaluated 113 patients who met strict criteria for ARDS. Multiple variables were analyzed for as long as 14 days after intubation including cardiac output, pulmonary capillary wedge pressure, mean blood pressure, intake minus output (I-O), cumulative intake minus output (cum I-O), and change in weight (delta wt). We found significant differences in cum I-O and delta wt between survivors and nonsurvivors on almost every day. Survivors lost weight and had a significantly lower cum I-O compared with nonsurvivors. Logistic regression was used to determine if delta wt and cum I-O could predict survival. Patients who lost 3 kg or more weight had a much higher survival than did those who gained 3 kg or more weight (67 and 0%, respectively, on Day 14). Similar results were obtained using comparably low and high values for cum I-O. The logistic regression equations demonstrated that weight loss and low cumulative I-O correlated with improved survival. Although cause and effect relationships are difficult to determine from these types of analyses, they can be used to formulate prospective studies and predict survival in patients.

Bacterial infections frequently,complicate pulmonary contusion and are the leading cause of death in such patients. This study evaluated the effects of pulmonary contusion alone and contusion associated with other factors on the ability to clear aerosolized bacteria from the lung. Lung bacterial clearance of Staphylococcus aureus and Klebsiella pneumoniae was studied in animals with isolated pulmonary contusion, or contusion associated with blood loss, rapid crystalloid infusion, or steroid administration. An isolated pulmonary contusion produced no impairment of the ability of the contused lung to clear either gram-negative or gram-positive organisms. The addition of acute blood loss and crystalloid infusion resulted in decreased clearance from the contused lung; steroid administration caused a marked depression in lung bacterial clearance from the noninjured lung as well. The canine model described allowed for study of regional differences in bacterial clearance. The data presented support several conclusions; (1) the contused lung is not more susceptible to bacterial infection than the normal lung: (2) acute blood loss renders the contused lung less able to clear bacteria; (3) crystalloid infusion markedly depresses lung bacterial clearance; and (4) steroids have a deleterious antibacterial effect on both contused and noncontused lungs.

A model of pneumonia due to Pseudomonas aeruginosa was produced in hamsters by an intratracheal bolus instillation of microorganisms. Sequential lung changes from 4 hr through 11 days were studied by morphologic and microbiologic methods. Hamsters inoculated with greater than 10(6) pseudomonads survived but consistently had histologic evidence of mild bronchopneumonia 24 hr postinoculation, whereas a severe bronchopneumonia and a 100% mortality were elicited with a 10(8) inoculum of organisms in 0.5 ml phosphate-buffered saline (PBS). An inoculum of 10(7) pseudomonads/0.5 ml PBS was then used to define the changes in the bacterial population in Pseudomonas pneumonia and to obtain serial histopathologic observations. Quantitative lung cultures obtained within 1 hr postinoculation demonstrated a mean of 10(6) colony forming units per lung, and none of the hamsters were bacteremic. However, by 24 hr bacterial counts had increased and all animals were bacteremic. Bacterial proliferation continued through 48 hr; however, the number of bacteremic animals had decreased. By 72 hr, bacterial counts had decreased with total Pseudomonas clearance noted by 120 hr. A striking polymorphonuclear leukocyte-rich alveolar exudate was present by 12 hr. Pseudomonas "vasculitis" was evident by 24 hr. The evolution of this vascular lesion correlated with the bacteremic state of the hamsters. By 11 days, resolution of the pneumonic process was seen. The macroscopic and microscopic features of this hamster model of Pseudomonas pneumonia are very similar to those reported in infected patients.

To determine the characteristics of the radiographic resolution of bacteremic Streptococcus pneumoniae pneumonia we examined serial chest roentgenograms in 72 patients. Consolidation disappeared in all patients by eight to 10 weeks; volume loss (9 per cent), plural disease (9 per cent), and stranding (19 per cent) often persisted beyond eight weeks. Resolution occurred earlier in patients less than 50 years old (P less than 0.05) and in the absence of alcoholism and underlying airways disease regardless of age (P less than 0.05). Delayed clearing occurred when these complicating factors were present in patients over 50. Lung cancer was not responsible for delayed resolution of pneumonia. We conclude that an appropriate interval for serial radiographic examinations after therapy for pneumococcal pneumonia is six weeks.

A correlation has previously been demonstrated between the in vitro adherence of Pseudomonas aeruginosa to upper respiratory tract epithelium of seriously ill patients and subsequent colonization of the respiratory tract by this opportunistic pathogen. Although the specific in vivo alterations in the cell surface that permit the adherence of P. aeruginosa have not been defined, we have demonstrated that P. aeruginosa adherence in vitro can be correlated with the loss of a protease-sensitive glycoprotein, fibronectin, from cell surface. The object of these studies was to correlate in vitro adherence of P. aeruginosa to buccal epithelial cells from patients with the levels of cell-surface fibronectin and of salivary proteases from the same patients, as well as to define the structure(s) on the bacterial surface important in the adherence process. A direct radioimmuno-binding assay was developed to measure cell-surface fibronectin, while protease activity in secretions was measured by 125I release from 125I-labelled insoluble fibrin matrices. Adherence of radiolabeled P. aeruginosa was directly related to decreased amounts of cell-surface fibronectin (P less than .001) and increased levels of salivary protease (P less than .001). Additionally, we demonstrated that pili may mediate the adherence of P. aeruginosa to buccal cells. This was shown by the ability of purified pili, when preincubated with buccal cells, to decrease the adherence of intact organisms from a mean of 30.6 organisms/cell to 5.7 organisms/cell (P less than .01).

We studied the bactericidal capacity of the rat lung during the development of pneumococcal pneumonia. Pneumonia was produced in a lower lobe by the intrabronchial instillation of 10(4)Streptococcus pneumoniae cells in buffer. Lung bacterial counts progressively increased, reaching 10(7) per lung within 48 h, and the increase was associated with localized atelectasis and consolidation. Bacterial multiplication was inhibited with tetracycline at various intervals after infection, and the subsequent clearance of pneumococci was determined. Viable pneumococci were rapidly killed by lung defenses if bacterial multiplication was inhibited within 12 h of the onset of infection. No change occurred in the bacterial populationif tetracycline was delayed until 24 h after infection, indicating that pneumococcal killing by lung defenses had ceased. This effect could be reproduced with the addition of pneumococcal capsular polysaccharide to the inoculum, which produced a dose-related inhibition of pneumococcal clearance. The clearance of S. epidermidis was not impaired in the presence of pneumococcal pneumonia or by administration of exogenous capsular polysaccharide. These data indicate that pneumococcal pneumonia causes a marked impairment in lung antipneumococcal defenses within 24 h of the onset of infection. This acquired defect in antibacterial defenses may be due to the accumulation of pneumococcal capsular material in the lungs of infected animals.

Anaerobic pleuropulmonary infections are common in the setting of aspiration. Treatment is with penicillin or in mixed infections, penicillin and other appropriate antimicrobial agents. Four syndromes are commonly recognized. Simple pneumonitis resolves promptly with antibiotic therapy. If treatment is delayed, simple pneumonitis may evolve into a more fulminant process of necrotizing pneumonia with a significant mortality despite antibiotic therapy. Lung abscess, typically a subacute or chronic infection, responds well to antibiotic therapy so long as the cavity is drained via the communicating bronchus. Empyema requires surgical drainage by either closed or open thoracostomy if resolution is to be achieved.

Static deflation air and saline pressure-volume (PV) curves were performed on five normal excised baboon lungs, four with radiation-induced upper lobe fibrosis, and two with diffuse bleomycin-induced fibrosis. Curves were compared visually and using half-inflation pressures (h). When plotted as percent of observed vital capacity vs. transpulmonary pressure, the radiation-associated curves were similar in shape to control curves. Also, h values were not significantly different between the two groups. The bleomycin-associated curves, however, were shifted rightward and exhibited increased h values. PV curves were correlated with connective tissue data. Elastin concentration was increased in the irradiated upper lobes through loss of associated constituents. Elastin accumulated in the lower lobes of the irradiated animals through compensatory growth and in the bleomycin-associated lungs through excessive production. Collagen followed a similar but less dramatic trend. We conclude connective tissue accumulation may not lead to rightward shifted PV curves if accumulation is present in relatively noninflatable lung units, or as part of compensatory lung growth.

Lung repair after diffuse alveolar damage (DAD) may be modified by supportive therapy or the occurrence of complications. To provide a clinically relevant model of DAD, we studied the feasibility of long-term respiratory support of 5 normal baboons and 20 baboons with oleic-acid-induced lung injury. Oleic acid caused DAD, which evolved through exudative and reparative phases similar to those seen in human disease. Fibrotic residuals were present at 1 month but resolved by 6 months. Pulmonary function abnormalities, including reduction in total lung capacity and diffusing capacity, and hypoxemia occurred with DAD but resolved within 1 month. Bronchopulmonary infection with gram-negative bacilli was a common and frequently fatal complication. Revisions in management of the upper airway and the use of topical polymyxin B prevented this complication. Other complications included hemorrhagic gastritis, postextubation, upper airway obstruction, and pulmonary embolism. This model simulates many features of DAD in humans and should provide a valuable resource for future study.

Bacterial colonization of mucosal surfaces may be mediated by bacterial adherence to epithelial cells. To study the role of adherence in gram-negative bacillary colonization of the upper respiratory tract, we studied 32 noncolonized patients undergoing elective surgery. Adherence of Pseudomonas aeruginosa and 3 other bacilli to patients' buccal cells in vitro was studied pre- and postoperatively; results were correlated with occurrence of bacillary colonization of the oropharynx in vivo. Adherence of all species was similar. Preoperatively, mean +/- SD adherence was 4.3 +/- 2.0 Pseudomonas aeruginosa/cell. Postoperatively, adherence of Pseudomonas aeruginosa exceeded 8.3 (preoperative mean + 2 SD) bacilli/cell in 16 patients, 11 (69%) of whom became colonized. None of 16 patients whose cells adhered fewer than 8.3 bacilli/cell postoperatively became colonized. Buccal cell binding of 3H-concanavalin A was increased both pre- and postoperatively among patients who became colonized. Gram-negative bacillary colonization of the upper respiratory tract is associated with increased adherence of bacilli to buccal cells. Epithelial cell binding may provide the mechanism whereby ill patients are rendered susceptible to colonization.

A correlation has been demonstrated between the in vitro adherence of Pseudomonas aeruginosa to upper respiratory tract epithelium and colonization of the respiratory tract by this organism. Twenty patients with cystic fibrosis (CF) and 20 age-matched controls were examined in this study. All of the CF patients but none of the controls were colonized with P. aeruginosa at the time of study. P. aeruginosa adherence to isolated epithelial cells, as determined by an in vitro assay, was 19.1 +/- 1.1 bacteria per buccal epithelial cell in the CF patients and 2.3 +/- 0.3 bacteria per cell in the controls (P < 0.01). P. aeruginosa strains of the mucoid colony type adhered in significantly lower numbers to buccal epithelial cells than did strains of the rough colony type (1.8 + 0.1 versus 24.8 +/- 0.9, P < 0.001). This difference might explain the common observation that the initial pseudomonas colonization of the respiratory tract of CF patients is due to organisms of the rough colony type. We have further demonstrated that increased P. aeruginosa adherence in vitro varies directly with the loss of a protease-sensitive glycoprotein, fibronectin, from the cell surface, as well as increased levels of salivary proteases in CF patients. When examined by a direct radioimmune binding assay, buccal cells from CF patients possessed only 17% of the total cell surface fibronectin present on similar cells obtained from controls. Salivary protease levels, as measured by (125)I release from an (125)I-labeled insoluble fibrin matrix, were increased about threefold in CF patients versus controls. Thus, colonization of the respiratory tract by P. aeruginosa in CF patients correlates well with buccal cell adherence of this organism; increased adherence is associated with decreased amounts of fibronectin on respiratory epithelial cell surfaces and increased levels of salivary proteases.

Lung clearance of Diplococcus pneumoniae was markedly reduced in rats with acute hemorrhagic pulmonary edema produced by instillation of hydrochloric acid. Bacterial clearance was enhanced in both control and acid-instilled animals by pretreatment with a bacteriostatic antibiotic, tetracycline, 30 mg/kg. From these data the contributions of bacterial multiplication and bacterial elimination to net lung bacterial clearance were estimated. In control animals the constant for exponential bacterial elimination was -1.4283 (fractional clearance = 76% per h), and the doubling time for the pneumococcus was 170 min. In acid-instilled rats the elimination constant was -0.5336 (fractional clearance = 41% per h), and the doubling time of the pneumococcus was 47 min, approximating the doubling time of 42 min observed with pneumococci grown in broth. These results indicate that, in the case of pneumococci, both bacterial elimination and bacterial growth contribute to lung bacterial clearance in normal animals as well as animals with damaged lungs. In the present study changes in both parameters were required to explain the observed results in acid-instilled animals. The pulmonary pathogenicity of some bacterial species may be determined by their capacity for growth in the lung, since infection of the lung occurs when bacterial multiplication exceeds the rate of elimination of viable organisms.

Transtracheal instillation of clinical isolate Klebsiella pneumoniae serotype 1 (KP1) into the lungs of rats resulted in the production of a characteristic, chronic lobar pneumonia. To further examine this phenomenon, two variants of this organism were employed in this experimental model. These variants differed markedly in capsule size, colony morphology, and in virulence, as determined by mouse lethality tests. The ability of these strains to establish a lobar pneumonia in rats correlated with the virulence of the respective organisms as monitored by intraperitoneal injection in mice. The 50% lethal doses in mice were 4.9 x 10(1) colony-forming units (CFU) for the more virulent KP1 strain (KP1-O) and 1.42 x 10(5) CFU for the less virulent variant (KP1-T). In the rat lung model, marked lung pathology was evident by day 6 with a KP1-O inoculum of 5 x 10(2) CFU, whereas KP1-T caused little or no lung pathology when delivered transtracheally at a concentration of 7 x 10(6) CFU. Two relatively nonvirulent variants of K. pneumoniae serotype 2 were also used in this rat lung model and were found not to produce a lobar pneumonia even when delivered in large doses. These results indicate that a chronic lobar pneumonia can be established in a rat model if the appropriate organism is employed and the virulence of K. pneumoniae injected intraperitoneally into mice is an excellent indicator of an organism's potential to cause lobar pneumonia in rats.

Adult baboons were monitored during intravenous infusion of Soman (1,2,2-trimethylpropyl ester, phosphonofluoridate). Three groups of animals were studied. Two groups were anesthetized with sodium pentobarbital (initial dose, 20 mg/kg), instrumented for measurement of systemic blood pressure (BP), pulmonary artery pressure, cardiac output (CO), ECG, ventilatory flow, translaryngeal pressure (PTL), transdiaphragmatic pressure (Pdi), transpulmonary pressure (PTP), diaphragm EMG, and efferent phrenic nerve traffic (Eph). One group received no Soman and served as controls. In the other group, Soman was infused over 10 min at doses of 13.1, 8.21, 4.92, or 3.3 micrograms/kg. The onset of intoxication occurred within 7-8 min (before the end of the 10-min infusion), manifested by muscular fasciculations, stridorous breathing, copious secretions, and atrioventricular arrhythmias. Mean BP decreased to 30 mm Hg by the combination of decreased CO and decreased vascular resistance. There was a dose-related response in the onset and duration of these effects. Apnea occurred in most animals and coincided with cessation of the Eph signal. Stimulation of the diaphragm via the phrenic nerve following apnea yielded Pdi values unchanged from baseline, indicating an intact neuromuscular apparatus. All animals required ventilatory support. Some surviving animals exhibited severe behavior changes. The third group of animals was studied without anesthesia. Instrumentation was performed 3 days before using a tether system for the measurement of BP, CO, and ECG, and an arterial line for blood withdrawal. Soman was infused over 10 min at a dose of 13.1 micrograms/kg. The onset of intoxication occurred within 2-3 min, manifested by hyperactivity, severe muscle fasciculations which simulated grand-mal convulsions, stridorous respiratory sounds, copious secretions, and cardiac arrhythmias. Apnea and severe lactic acid acidosis developed in all animals and all required ventilatory assistance. None recovered spontaneous ventilation at the end of 4 hr.

Recent evidence suggests that colonization of the upper respiratory tract by gram-negative bacilli is mediated by adherence to regional epithelial cells. Buccal epithelial cells were obtained for study from 12 seriously ill patients, all of whom were colonized with Pseudomonas aeruginosa. In comparison to cells from uncolonized controls, cells obtained from these patients attached significantly more P. aeruginosa organisms during incubation in vitro. Although the sialic acid content of colonized patients' cells was less than that of controls' cells, removal of sialic acid from normal cells with neuraminidase did not increase bacillary adherence. Trypsinization of normal cells increased bacillary adherence and significantly reduced the amount of fibronectin on the cell surface. Both trypsinized normal cells and cells recovered from seriously ill colonized patients attached large numbers of P. aeruginosa organisms in vitro and demonstrated decreased fibronectin on the cell surface by immunofluorescent staining. These findings suggest that the host alteration associated with increased susceptibility to adherence by P. aeruginosa is the loss of fibronectin from the cell surface.

Patients with the adult respiratory distress syndrome and multiple organ system failure have a high mortality rate despite extensive supportive therapy. We evaluated the role of multiple organ system failure and infection in 37 consecutive survivors of the syndrome, and 47 consecutive nonsurvivors on whom autopsies were done. Failure of the central nervous, coagulation, endocrine, gastrointestinal, and renal systems was common in all patients but was more frequent in those who died. Major infections occurred in 46 nonsurvivors and 22 survivors. All patients with bacteremia who had a clinically identified site of infection survived, whereas all patients with bacteremia without a clinically identified site of infection died. Autopsy results of the latter group showed infections requiring surgical drainage for complete therapy. Patients clinically septic but without bacteremia and without a clear site of infection were shown at autopsy to have pneumonia. Multiple organ system failure was more common in infected (93%) than noninfected (47%) patients. Vigorous evaluation and treatment of infection in patients with the adult respiratory distress syndrome may improve survival.

Bacterial infection in the adult respiratory distress syndrome (ARDS) is associated with the occurrence of multiple organ failures and death. We studied 108 infections in 129 patients with ARDS and evaluated the organisms responsible, the body sites involved, and the outcomes of therapy. Gram-negative bacilli represented 57% of the microbial pathogens and gram-positive cocci 36%. Only 7% of infections were caused by other organisms (fungi, viruses, Pneumocystis, Legionella). Gram-negative organisms were more common in the lung, abdomen, and pleura. Bacteremia was more common in abdominal infections (11 of 17, 67%) than in infections at other sites (18 of 65, 28%), (p less than 0.01); ;9 patients were bacteremic from clinically undetected sites. Ten of 17 (59%) patients with abdominal infections survived compared with 7 of 56 (13%) patients with lung infections (p less than 0.001). A retrospective review of in vitro organism susceptibility and the antibiotics administered revealed that the patients who received adequate antibiotic therapy did not have a higher survival rate (20 of 69, 29%) than those who received inadequate antibiotic therapy (3 of 13, 23%). These data suggest that further investigation of infections in patients with ARDS is required and that emphasis should be placed on pathogenesis, prevention, and host responses.

Pulmonary fibrosis was induced in eight baboons with bleomycin; five untreated animals were controls. After 45-65 U/kg of bleomycin, lung volumes and diffusing capacity were reduced, and static lung pressure-volume curves were shifted to the right. Right middle lobes were resected at this time in five bleomycin-treated and two control animals. Compared to controls, right middle lobes from bleomycintreated animals had increased weight and contained increased amounts of total protein, collagen, elastin, and DNA; synthesis of collagen and noncollagen protein were also elevated. Occasional alveolar septae were edematous and infiltrated by mononuclear inflammatory cells; a slight increase in collagen was demonstrable histologically. Four of six treated animals died with extensive diffuse interstitial fibrosis after 95 U/kg of bleomycin. Biochemical analyses revealed significantly elevated lobar contents of dry weight, protein, elastin, and collagen. Two animals survived 95 U/kg of bleomycin and were terminated 6 mo after treatment. In these animals, physiologic studies were indicative of restrictive lung disease, but lung histology was nearly normal. Lung weight, total protein, and DNA had returned to control values, but collagen and elastin were increased in amount and concentration. Bleomycin induces an intense inflammatory response in the lung. During this inflammation, connective tissue proliferation occurs in concert with proliferation of other tissue components. Cessation of bleomycin treatment is followed by resolution of inflammation manifested by decreases in tissue mass, cellular content, and nonconnective tissue protein. Collagen and elastin deposited during inflammation are less successfully removed during resolution, leading to a stage characterized by increased concentrations of these proteins. A similar sequence of tissue alterations may occur in idiopathic diffuse interstitial fibrosis of man in response to various lung injuries.

Almitrine bismesylate was studied for its effects on hypoxemia in 67 patients with chronic obstructive lung disease in a placebo-controlled, double-blind study. Arterial Po2 rose by 11.2 mm Hg (p less than 0.05) in 21 patients receiving 100 mg twice daily and by 6.0 mm Hg (p less than 0.05) in 22 patients receiving 50 mg twice daily. Arterial Pco2 decreased by 3.8 mm Hg (p less than 0.05) in the group receiving 100 mg twice daily but was unchanged in patients receiving 50 mg twice daily. Lung function was unaltered except for a slight increase in forced mid-expiratory flow in both dosage groups (p less than 0.05). The major side effect was the unexplained worsening of dyspnea, which occurred in 4 patients (19%) receiving 100 mg twice daily, 2 (9%) receiving 50 mg twice daily group, and 1 (4%) receiving placebo. Almitrine bismesylate improves arterial blood gas values in patients with chronic obstructive lung disease, apparently by reducing intrapulmonary ventilation-perfusion mismatching, and appears to be useful in the long-term management of these patients.

A rare complication, massive pulmonary hemorrhage, occurred in two patients who were receiving heparin for pulmonary thromboembolic disease. The site of pulmonary hemorrhage was not found at autopsy. The occurrence of profuse hemoptysis in both patients prior to anticoagulation suggests that this finding may be of value in predicting the risk of pulmonary hemorrhage in a given patient.

Bacterial pneumonia is a common complication of lung injury that can be an important determinant of outcome. We studied experimental lung injury produced in hamsters by injecting 20 mg/kg paraquat (PQ) intraperitoneally; control animals received saline vehicle. Three days later, Pseudomonas aeruginosa (PAO1), 10(8) organisms in 0.25 ml, or saline, 0.25 ml, was inoculated intratracheally. Lung and systemic antibacterial defenses were studied at death 24 h later. Paraquat alone produced focal interstitial pneumonitis and neutrophilic alveolitis, and resulted in a 12% (3 of 26) mortality. PAO1 alone caused focal pneumonias and no deaths. Animals receiving both agents (PAO1/PQ) had extensive diffuse alveolar damage characterized by alveolar hemorrhage, edema, influx of neutrophils, and vasculitis; 50% (16 of 32) died within 96 h of PQ injection. Mean lung counts of PAO1 at death were 7.6 X 10(4) colony forming units/g in PAO1 and 2.8 X 10(7) in PAO1/PQ animals (p less than 0.05). PAO1 colony counts in liver were increased nearly 100-fold in PAO1/PQ animals (p less than 0.05). Half-time of clearance of P. aeruginosa from the blood was prolonged in PAO1 and in PAO1/PQ animals (p less than 0.05) but not in PQ animals. Phagocytosis of Staphylococcus aureus by leukocytes lavaged from the lung was not impaired in any group compared with that in control animals, but intracellular killing was impaired in PAO1 and PAO1/PQ but not in PQ animals. Paraquat injury impairs lung antibacterial defenses by uncertain mechanisms. Superinfection of PQ-injured lungs by PAO1 appears responsible for defects in intrapulmonary and systemic antibacterial defenses.

Four patients with Mycobacterium kansaii pulmonary infection were followed without treatment for 10 to 14 years after diagnosis. Although spontaneous resolution of active disease occurred 5 years after diagnosis in one patient, slowly progressive disease in the absence of significant symptoms was documented in 3 patients during a 12-to-14-year follow-up period. Administration of antituberculous drugs resulted in rapid resolution of signs of active disease in these patients. These observations added to our limited knowledge of the natural history of M. kansasii disease.

Adherence of Pseudomonas aeruginosa organisms to the upper respiratory epithelium of seriously ill patients in vitro is correlated with subsequent colonization of the respiratory tract by this opportunistic pathogen. The role of pili in the attachment to epithelial cells of P. aeruginosa was studied in an in vitro system employing human buccal epithelial cells and P. aeruginosa pretreated by various means. Pretreatment of the bacteria with proteases, heat, or Formalin caused a significant decrease in adherence. A decrease when compared with controls was also noted in the adherence of P. aeruginosa organisms to buccal epithelial cells preincubated with purified pili prepared from the strain used for adherence testing; however, pili prepared from a heterologous strain failed to block adherence. Similar results were obtained in serological studies when antisera to purified pili prepared from the strain used for adherence testing decreased adherence, whereas heterologous antiserum to pili did not decrease adherence. From these results it appears that pili mediate the adherence of P. aeruginosa organisms to human buccal epithelial cells.

The records of 195 patients admitted to an intensive care unit with a diagnosis of sedative drug overdose were reviewed with special reference to respiratory complications. Endotracheal intubation with mechanical ventilation was required in 150 patients (77 per cent). Complications associated with mortality included difficult or traumatic intubation (P less than 0.001), initial hypotension (P less than 0.001), alveolar hypoventilation (P less than 0.02), and the presence of chest roentgenographic infiltrates (P less than 0.01). Infiltrates appeared on the chest roentgenograms of 72 patients (37 per cent) and were related to hypotension (P less than 0.05) and evidence of gastric aspiration (P less than 0.001). Eight of 9 deaths were due to progressive respiratory insufficiency, and bacterial pneumonia was documented at autopsy in 4 of 7 cases. High serum drug concentrations and the presence of shock or gastric aspiration on admission characterized the 9 patients (4.6 per cent) who died.