Lung-derived mediators induce cytokine production in downstream organs via an NF-κB-dependent mechanism.

In the setting of acute lung injury, levels of circulating inflammatory mediators have been correlated with adverse outcomes. Previous studies have demonstrated that injured, mechanically ventilated lungs represent the origin of the host inflammatory response; however, mechanisms which perpetuate systemic inflammation remain uncharacterized. We hypothesized that lung-derived mediators generated by mechanical ventilation (MV) are amplified by peripheral organs in a "feed forward" mechanism of systemic inflammation. Herein, lung-derived mediators were collected from 129X1/SVJ mice after 2 hours of MV while connected to the isolated perfused mouse lung model setup. Exposure of liver endothelial cells to lung-derived mediators resulted in a significant increase in G-CSF, IL-6, CXCL-1, CXCL-2, and MCP-1 production compared to noncirculated control perfusate media (P < 0.05). Furthermore, inhibition of the NF-κB pathway significantly mitigated this response. Changes in gene transcription were confirmed using qPCR for IL-6, CXCL-1, and CXCL-2. Additionally, liver tissue obtained from mice subjected to 2 hours of in vivo MV demonstrated significant increases in hepatic gene transcription of IL-6, CXCL-1, and CXCL-2 compared to nonventilated controls. Collectively, this data demonstrates that lung-derived mediators, generated in the setting of MV, are amplified by downstream organs in a feed forward mechanism of systemic inflammation.

Mediators released from LPS-challenged lungs induce inflammatory responses in liver vascular endothelial cells and neutrophilic leukocytes.

The systemic inflammatory response plays an important role in the progression of acute lung injury (ALI) to multiple organ dysfunction syndrome (MODS). However, the role of lung-derived inflammatory mediators in induction of the inflammatory response in remote organs is poorly understood. To address the above, we investigated the effects of lung inflammation on induction of inflammatory response(s) in the liver in vitro. Inflammation in mouse lungs was induced by intranasal administration of lipopolysaccharide (LPS; 1 mg/ml) followed by mechanical ventilation using the isolated perfused mouse lung method to obtain and characterize lung perfusate from the pulmonary circulation. LPS administration to mouse lungs resulted in an increased release of inflammation-relevant cytokines and chemokines into the perfusate (Luminex assay) compared with the saline-controls. Subsequently, primary mouse liver vascular endothelial cells (LVEC) or mouse polymorphonuclear leukocytes (PMN) in vitro were stimulated with the perfusate obtained from saline- or LPS-challenged lungs and assessed for various inflammation-relevant end points. The obtained results indicate that stimulation of LVEC with perfusate obtained from LPS-challenged lungs results in 1) reactive oxygen species (ROS) production; 2) activation of NF-kappaB; and 3) expression of E-selectin, ICAM-1, and VCAM-1 and a subsequent increase in PMN rolling and adhesion to LVEC. In addition, perfusate from LPS-challenged lung induced activation of PMN with respect to increased ROS production and upregulation of cell surface levels of adhesion molecules MAC-1 and VLA-4. Heat-inactivation of the perfusate obtained from LPS-challenged lungs was very effective in suppressing increased proadhesive phenotype (i.e., E-selectin and ICAM-1 expression) in LVEC, whereas targeted inhibition (immunoneutralization) of TNF-alpha and/or IL-6 in LPS-lung perfusate had no effect. Taken together, these findings indicate that multiple proinflammatory mediators (proteinaceous in nature) released from inflamed lungs act synergistically to induce systemic activation of circulating PMN and promote inflammatory responses in liver vascular endothelial cells.

Effects of alveolar surfactant aggregates on T-lymphocyte proliferation.

The effects of alveolar large aggregate (LA) and small aggregate (SA) surfactant subfractions isolated from healthy adult rats on mitogen-stimulated proliferative responses of human peripheral blood mononuclear cells (PBMC) was examined. Various concentrations of total surfactant suppressed proliferation of stimulated lymphocytes by up to 95% of mitogen-stimulated cells alone. LA subfractions of total surfactant had no effect on proliferation, whereas SA significantly enhanced the lymphocyte proliferation at lower concentrations (7.8 microg/ml) compared to mitogen-stimulated cells alone. Higher concentrations of SA (62.5 microg/ml) inhibited lymphocyte proliferation. This concentration-dependent effect of SA on proliferation of PBMC was also present when cells were stimulated with various lectins including anti-CD3, concanavalin A and phytohemagglutinin. Analysis of the supernatant of mitogen-stimulated cell cultures treated with inhibitory concentrations of SA showed decreased amounts of interleukin (IL)-2, compared to cells alone, which could be reversed by adding exogenous IL-2 to the cell cultures with the SA. These results suggest that alveolar surfactant subfractions have distinct functions within the alveoli, both biophysically and with respect to their effects on the host's immunomodulatory responses.

Trends in hospital emergency department utilization: United States, 1992-99.

OBJECTIVES: This report describes trends in hospital emergency department (ED) visits in the United States. Statistics are presented for overall utilization, case mix of patients, services provided, and outcome measures. METHODS: The data presented in this report were collected from the National Hospital Ambulatory Medical Care Survey (NHAMCS) from 1992 through 1999. To make the data points more reliable for trend analysis, the data were combined to provide 2-year annual averages for 1993-94, 1995-96, and 1997-98. The survey in 1992 was especially large so it was used alone. The 1999 data are the most recent year available and are presented separately. RESULTS: The volume of ED visits in the United States increased by 14% from 1992 through 1999, from 89.8 million to 102.8 million annually. This increase is mainly due to an increase in visits for illness-related as opposed to injury-related conditions. Although the population rate for ED visits did not significantly increase over this time period (rates between 35.7 and 37.9 visits per 100 persons), the rate for illness-related visits rose from 21.0 to 24.0 visits per 100 persons (p < 0.01). The most dramatic increases were observed in the overall visit rate for black persons 65 years of age and over, which rose by 59% from 45.4 visits per 100 persons in 1992 to 72.2 in 1999. For black seniors, both illness and injury-related visit rates increased at a much higher rate compared with trends for white seniors. CONCLUSION: Increased volume of ED encounters for persons 45 years of age and over was associated with a greater proportion of illness conditions presenting to the ED and the use of more services, medications, and mid-level providers.

National Hospital Ambulatory Medical Care Survey: 1997 outpatient department summary.

OBJECTIVE: This report describes ambulatory care visits to hospital outpatient departments in the United States. Statistics are presented on selected hospital, clinic, patient, and visit characteristics. METHODS: The data presented in this report were collected from the 1997 National Hospital Ambulatory Medical Care Survey (NHAMCS). NHAMCS is part of the ambulatory care component of the National Health Care Survey that measures health care utilization across various types of providers. NHAMCS is a national probability sample survey of visits to hospital outpatient and emergency departments of non-Federal, short-stay, and general hospitals in the United States. Sample data are weighted to produce annual estimates. RESULTS: During 1997, an estimated 77.0 million visits were made to hospital outpatient departments in the United States, an overall rate of 28.9 per 100 persons. Visit rates did not vary by age. Black persons had higher rates of visits than white persons. Of all visits made to hospital outpatient departments in 1997, 34.1 percent and 27.8 percent, respectively, listed private insurance and Medicaid as the primary expected source of payment, and 20.1 percent were made by patients belonging to a health maintenance organization. There were an estimated 7.1 million injury-related outpatient department visits during 1997.

National Hospital Ambulatory Medical Care Survey: 1996 outpatient department summary.

OBJECTIVE: This report describes ambulatory care visits to hospital outpatient departments in the United States. Statistics are presented on selected patient and visit characteristics. METHODS: The data presented in this report were collected from the 1996 National Hospital Ambulatory Medical Care Survey (NHAMCS). NHAMCS is part of the ambulatory care component of the National Health Care Survey that measures health care utilization across various types of providers. NHAMCS is a national probability survey of visits to hospital outpatient and emergency departments of non-Federal, short-stay, and general hospitals in the United States. Sample data were weighted to produce annual estimates. RESULTS: During 1996, an estimated 67.2 million visits were made to hospital outpatient departments in the United States, about 25.4 visits per 100 persons. Overall, visits rates did not vary by age. Females and black persons had higher rates of visits than males and white persons, respectively. There were an estimated 6.8 million injury--related outpatient department visits during 1996.

National Hospital Ambulatory Medical Care Survey: 1998 emergency department summary.

OBJECTIVES: This report describes ambulatory care visits to hospital emergency departments in the United States. Statistics are presented on selected patient and visit characteristics. METHODS: The data presented in this report were collected from the 1998 National Hospital Ambulatory Medical Care Survey (NHAMCS). NHAMCS is part of the ambulatory care component of the National Health Care Survey that measures health care utilization across various types of providers. NHAMCS is a national probability survey of visits to hospital emergency and outpatient departments of non-Federal, short-stay, and general hospitals in the United States. Sample data are weighted to produce annual national estimates. RESULTS: During 1998, an estimated 100.4 million visits were made to hospital emergency departments (ED's) in the United States, about 37.3 visits per 100 persons. Persons 75 years and over had the highest rate of ED visits. There were an estimated 37.1 million injury-related ED visits during 1998, or 13.8 visits per 100 persons. Seventy-four percent of injury-related ED visits were made by persons under 45 years of age. Injury visit rates were higher for males than females in each age group under 45 years. According to ICD-9-CM classification, 77.2 percent of injury visits were unintentional. About 71 percent of the ED visits involved medication therapy, with pain relief drugs accounting for 31.5 percent of the medications mentioned. Acute upper respiratory infection was the leading illness-related diagnosis at ED visits.

National Hospital Ambulatory Medical Care Survey: 1995 outpatient department summary.

OBJECTIVE: This report describes outpatient department visits in the United States in 1995. Statistics are presented on selected patient and visit characteristics. METHODS: The data presented in this report were collected from the 1995 National Hospital Ambulatory Medical Care Survey (NHAMCS). NHAMCS is part of the ambulatory care component of the National Health Care Survey, which measures health care utilization across various types of providers. NHAMCS is a national probability survey of visits to outpatient departments and emergency departments of non-Federal, short-stay and general hospitals in the United States. Sample data were weighted to produce annual estimates. RESULTS: During 1995, an estimated 67.2 million visits were made to hospital outpatient departments in the United States, an overall rate of 25.7 visits per 100 persons. Overall, visit rates did not vary by age. Females and black persons had higher rates of visits than males and whites, respectively. There were an estimated 7.3 million injury-related outpatient department visits in 1995.

National Hospital Ambulatory Medical Care Survey: 1999 emergency department summary.

OBJECTIVES: This report describes ambulatory care visits to hospital emergency departments (ED's) in the United States. Statistics are presented on selected hospital, patient, and visit characteristics. Highlights of trends in ED utilization from 1992 through 1999 are also presented. METHODS: The data presented in this report were collected from the 1999 National Hospital Ambulatory Medical Care Survey (NHAMCS). NHAMCS is part of the ambulatory care component of the National Health Care Survey that measures health care utilization across various types of providers. NHAMCS is a national probability survey of visits to hospital emergency and outpatient departments of non-Federal, short-stay, and general hospitals in the United States. Sample data are weighted to produce annual national estimates. Trends are based on NHAMCS data for 1992, 1993-94, 1995-96, 1997-98, and 1999. RESULTS: During 1999, an estimated 102.8 million visits were made to hospital ED's in the United States, about 37.8 visits per 100 persons. The volume of ED visits increased by 14 percent from 1992 through 1999, though no trend was observed in the overall population-based visit rates. There was a significant increase in the visit rate for black persons 75 years of age and over. In 1999, persons 75 years of age and over had the highest ED visit rate and 41.5 percent of these patients arrived by ambulance. There were an estimated 37.6 million injury-related ED visits during 1999, or 13.8 visits per 100 persons. Seventy-four percent of injury-related ED visits were made by persons under 45 years of age. Injury visit rates were higher for males than females in each age group under 45 years. The case mix of visits at ED's changed since 1992, with a greater percent of visits presenting with illness rather than injury conditions. Abdominal pain, chest pain, fever, and headache were the leading patient complaints accounting for one-fifth of all visits. Acute upper respiratory infection was the leading illness-related diagnosis at ED visits. Increases were observed in visits where no complete diagnosis could be made (16.2 percent of visits in 1999). Diagnostic and/or screening services were provided at 89.0 percent of visits, procedures were performed at 42.5 percent of visits, and medications were provided at 72.5 percent of visits. Pain relief drugs accounted for 31.1 percent of the medications mentioned. Trend data from 1992 indicated that the use of medications at ED visits increased. In 1999, approximately 13 percent of ED visits ended in hospital admission. Facility-level data indicated that there is variation among hospital ED's with respect to case mix, number of services provided, and case disposition distributions, especially the percent admitted to the hospital.

National Hospital Ambulatory Medical Care Survey: 1996 emergency department summary.

OBJECTIVES: This report describes ambulatory care visits to hospital emergency departments in the United States. Statistics are presented on selected patient and visit characteristics. METHODS: The data presented in this report were collected from the 1996 National Hospital Ambulatory Medical Care Survey (NHAMCS). NHAMCS is part of the ambulatory care component of the National Health Care Survey that measures health care utilization across various types of providers. NHAMCS is a national probability survey of visits to hospital emergency and outpatient departments of non-Federal, short-stay, and general hospitals in the United States. Sample data were weighted to produce annual estimates. RESULTS: During 1996, an estimated 90.3 million visits were made to hospital emergency departments (ED's) in the United States, about 34.2 visits per 100 persons. Persons 75 years and over had the highest rate of emergency department visits. There were an estimated 34.9 million injury-related emergency department visits during 1996, or 13.2 visits per 100 persons. There were 110,000 visits related to injuries caused by firearms, including 73,000 visits for gunshot wounds. Almost one-fifth of the injury visits were work-related for persons 18-64 years of age. Almost four-fifths of the ED visits involved medication therapy. Pain relief drugs accounted for almost 30 percent of the medications mentioned. Acute upper respiratory infection was the leading illness related diagnosis for ED visits.

National Hospital Ambulatory Medical Care Survey: 1998 outpatient department summary.

OBJECTIVE: This report describes ambulatory care visits to hospital outpatient departments in the United States. Statistics are presented on selected hospital, clinic, patient, and visit characteristics. METHODS: The data presented in this report were collected from the 1998 National Hospital Ambulatory Medical Care Survey (NHAMCS). NHAMCS is part of the ambulatory care component of the National Health Care Survey that measures health care utilization across various types of providers. NHAMCS is a national probability sample survey of visits to hospital outpatient and emergency departments of non-Federal, short-stay, and general hospitals in the United States. Sample data are weighted to produce annual estimates. RESULTS: During 1998, an estimated 75.4 million visits were made to hospital outpatient departments in the United States, an overall rate of 28.0 per 100 persons. Visit rates did not vary by age except in a comparison of the 15-24 year old group with the 75 years and over age group. Black persons had higher rates of visits than white persons as did women compared with men. Of all visits made to hospital outpatient departments in 1998, 33.8 percent and 25.9 percent, respectively, listed private insurance and Medicaid as the primary expected source of payment, and 21.9 percent were made by patients belonging to a health maintenance organization. There were an estimated 7.1 million injury-related outpatient department visits during 1998.

Hepatitis B virus transmission between children in day care.

We investigated two situations involving hepatitis B virus exposure among children in day care. In the first a 4-year-old boy who attended a day care center developed acute hepatitis B; another child at the center, who had a history of aggressive behavior (biting/scratching), was subsequently found to be a hepatitis B carrier. No other source of infection among family and other contacts was identified and no other persons at the center became infected. In the second situation a 4-year-old boy with frequently bleeding eczematous lesions was discovered to be a hepatitis B carrier after having attended a day care center for 17 months. Testing of contacts at the center revealed no transmission to other children or staff (representing 887 person months of exposure). Nationwide surveillance data showed that for the period 1983 to 1987, 161 children 1 to 4 years of age were reported with acute hepatitis B. After children with known hepatitis B risk factors were excluded, 25% (7 of 28) of children with known day care status were reported as day care attendees, a percentage comparable to national estimates of day care attendance by this age group. This is the first reported case of hepatitis B virus transmission between children in day care in the United States. Although it appears that day care transmission of hepatitis B is infrequent, further studies are needed to define the risk more accurately.

Evaluation of exogenous surfactant treatment strategies in an adult model of acute lung injury.

Two exogenous surfactant preparations [Survanta and bovine lipid extract surfactant (BLES)] were evaluated in saline lavage-injured adult sheep with two different delivery methods (instillation vs. aerosolization). Instilled BLES resulted in the greatest improvement in lung function, followed by aerosolized Survanta and then instilled Survanta. Aerosolized BLES was ineffective. Total surfactant recovery and distribution patterns were similar for Survanta and BLES for each delivery method tested. There were significant differences, however, in the proportion of surfactant recovered in the alveolar wash relative to the lung tissue between the groups at killing. Moreover, the ratio of poorly functioning small surfactant aggregates to superior functioning large aggregates isolated from alveolar wash samples correlated with the physiological responses. The calculated contribution of secreted endogenous surfactant to the total alveolar phospholipid pool at killing was significantly greater for the aerosolized Survanta group compared with the aerosolized BLES group. This finding suggested that there were differences in the interaction of the exogenous surfactants and their alveolar environments. We conclude that the response to exogenous surfactant in acute lung injury depends not only on the preparation used but also on how the surfactants are delivered to the injured lung.

Mechanical ventilation of isolated septic rat lungs: effects on surfactant and inflammatory cytokines.

The effects of mechanical ventilation (MV) on the surfactant system and cytokine secretion were studied in isolated septic rat lungs. At 23 h after sham surgery or induction of sepsis by cecal ligation and perforation (CLP), lungs were excised and randomized to one of three groups: 1) a nonventilated group, 2) a group subjected to 1 h of noninjurious MV (tidal volume = 10 ml/kg, positive end-expiratory pressure = 3 cmH(2)O), or 3) a group subjected to 1 h of injurious MV (tidal volume = 20 ml/kg, positive end-expiratory pressure = 0 cmH(2)O). Nonventilated sham and CLP lungs had similar compliance, normal lung morphology, surfactant, and cytokine concentrations. Injurious ventilation decreased compliance, altered surfactant, increased cytokines, and induced morphological changes compared with nonventilation in sham and CLP lungs. In these lungs, the surfactant system was similar in sham and CLP lungs; however, tumor necrosis factor-alpha and interleukin-6 levels were significantly higher in CLP lungs. We conclude that injurious ventilation altered surfactant independent of sepsis and that the CLP lungs were predisposed to the secretion of larger amounts of cytokines because of ventilation.

Timing of exogenous surfactant administration in a rabbit model of acute lung injury.

The purpose of this study was to evaluate early vs. late administration of exogenous surfactant in an adult rabbit model of acute lung injury. Lung injury was induced by repetitive whole lung saline lavage and subsequent mechanical ventilation. Bovine lipid extract surfactant was instilled either 1 (Early) or 4 h (Late) after the last lavage. Animals were monitored for 7 h after the last lavage. Although arterial PO2 values increased significantly immediately after treatment in both the Early and Late groups, this improvement was not sustained in the Late group. There was also a higher incidence of pneumothoraxes in the Late group vs. both the Early group and a nontreated control group. The ratio of poorly functioning small surfactant aggregates to superior functioning large aggregates was higher in the Late group compared with the Early group. Morphological analysis revealed that early surfactant treatment prevented the progression of lung injury over time. We conclude that administration of exogenous surfactant at an early time point in lung injury resulted in superior responses compared with later treatments.

Alveolar environment influences the metabolic and biophysical properties of exogenous surfactants.

Several factors have been shown to influence the efficacy of exogenous surfactant therapy in the acute respiratory distress syndrome. We investigated the effects of four different alveolar environments (control, saline-lavaged, N-nitroso-N-methylurethane, and hydrochloric acid) on the metabolic and functional properties of two exogenous surfactant preparations: bovine lipid extract surfactant and recombinant surfactant-associated protein (SP) C drug product (rSPC) administered to each of these groups. The main difference between these preparations was the lack of SP-B in the rSPC. Our results demonstrated differences in the large aggregate pool sizes recovered from each of the experimental groups. We also observed differences in SP-A content, surface area cycling characteristics, and biophysical activities of these large aggregate forms after the administration of the two exogenous surfactant preparations. We conclude that the alveolar environment plays a critical role, influencing the overall efficacy of exogenous surfactant therapy. Thus further preclinical studies are warranted to investigate the specific factors within the alveolar environment that lead to the differences observed in this study.

Effects of surfactant distribution and ventilation strategies on efficacy of exogenous surfactant.

The effects of both surfactant distribution patterns and ventilation strategies utilized after surfactant administration were assessed in lung-injured adult rabbits. Animals received 50 mg/kg surfactant via intratracheal instillation in volumes of either 4 or 2 ml/kg. A subset of animals from each treatment group was euthanized for evaluation of the exogenous surfactant distribution. The remaining animals were randomized into one of three ventilatory groups: group 1 [tidal volume (VT) of 10 ml/kg with 5 cmH2O positive end-expiratory pressure (PEEP)]; group 2 (VT of 5 ml/kg with 5 cmH2O PEEP); or group 3 (VT of 5 ml/kg with 9 cmH2O PEEP). Animals were ventilated and monitored for 3 h. Distribution of the surfactant was more uniform when it was delivered in the 4 ml/kg volume. When the distribution of surfactant was less uniform, arterial PO2 values were greater in groups 2 and 3 compared with group 1. Oxygenation differences among the different ventilation strategies were less marked in animals with the more uniform distribution pattern of surfactant (4 ml/kg). In both surfactant treatment groups, a high mortality was observed with the ventilation strategy used for group 3. We conclude that the distribution of exogenous surfactant affects the response to different ventilatory strategies in this model of acute lung injury.

Epidemiologic aspects of a St. Louis encephalitis outbreak in Fort Walton Beach, Florida in 1980.

From July 10 through August 4, 1980, five cases of St. Louis encephalitis (SLE) occurred in and near Fort Walton Beach on the Gulf Coast of northwest Florida. These were the first cases of SLE ever reported from the Florida panhandle. To determine the extent of SLE infection in the community, sera (n = 968) were collected from patients at the local hospital and county public health unit and tested for SLE virus antibody. The SLE attack rate was highest in a centrally located impoverished census tract. There was a trend toward decreasing seroprevalence with distance from the central area of the city. Overall, seroprevalence was higher in males (prevalence ratio = 2.7) and in all areas, seroprevalence increased with age. The serosurvey results suggest that SLE has been endemic in the Fort Walton Beach area.

Shedding of oocysts in immunocompetent individuals infected with Cryptosporidium.

In June 1985, we investigated an outbreak of cryptosporidiosis at a day-care center in Florida. Through day-care center-wide stool screening, 33% (28/84) of the children and 22% (4/18) of the staff members submitting stool specimens were found to have cryptosporidiosis. Children 12-35 months of age and their teachers were at highest risk. All but 1 of the Cryptosporidium-positive patients reported diarrhea, which lasted between 1-44 days. Serial stool specimens were obtained from 8 infected individuals (5 children and 3 adults). Duration of oocyst shedding ranged from 8 to more than 50 days and continued in 5 individuals after diarrhea ceased. No relationship was found between duration of oocyst shedding and the age of the patient or duration or severity of diarrhea. Results of the investigation indicate that infected individuals may continue to excrete oocysts and, therefore, may remain infectious for days or weeks after gastrointestinal symptoms disappear.

Use of physician assistants and nurse practitioners in primary care, 1995-1999.

Federal policies and state legislation encourage the use of physician assistants (PAs) and nurse practitioners (NPs) in primary care, although the nature of their work has not been fully analyzed. In this paper we analyze primary care physician office encounter data from the 1995-1999 National Ambulatory Medical Care Surveys. About one-quarter of primary care office-based physicians used PAs and/or NPs for an average of 11 percent of visits. The mean age of patients seen by physicians was greater than that for PAs or NPs. NPs provided counseling/education during a higher proportion of visits than did PAs or physicians. Overall, this study suggests that PAs and NPs are providing primary care in a way that is similar to physician care.