Publications

OBJECTIVE

To investigate the frequency and outcomes of ventilated patients with newly acquired large burdens of Pseudomonas aeruginosa and to test the hypothesis that large quantities of bacteria are associated with adverse patient outcomes.

DESIGN

A prospective, single-center, observational, cohort study.

SETTING

Medical-surgical intensive care units in a tertiary care university hospital.

PATIENTS

All adult patients requiring > or = 48 hrs of mechanical ventilation and identified as having newly acquired P. aeruginosa in their lower respiratory tracts between October 2002 and April 2006.

INTERVENTIONS

None.

MEASUREMENTS AND MAIN RESULTS

Daily surveillance cultures of endotracheal aspirates were performed on patients intubated > or = 48 hrs; 69 patients with newly acquired P. aeruginosa were enrolled. Daily P. aeruginosa quantification of endotracheal aspirates was performed; clinical signs of infection were noted. Of 45 patients with high P. aeruginosa burdens (> or = 1,000,000 colony-forming units/mL in endotracheal aspirates; > or = 10,000 colony-forming units/mL in bronchoalveolar-lavage), 17 (37.8%) patients did not meet clinical criteria for ventilator-associated pneumonia and had a statistically significant higher risk of death (adjusted hazard ratio, 37.53; 95% confidence interval, 3.79-371.96; p = 0.002) when compared with the patients who had P. aeruginosa ventilator-associated pneumonia. When excluding the ten patients who had ventilator-associated pneumonia attributed to bacteria other than P. aeruginosa or attributed to multiple bacteria including P. aeruginosa, the risk of death remained statistically significant (adjusted hazard ratio, 23.98; 95% confidence interval: 2.49-230.53; p = 0.006). Furthermore, more patients with high P. aeruginosa burdens secreted the type III secretion facilitator protein, PcrV (p = 0.01).

CONCLUSIONS

A group of patients with large burdens of P. aeruginosa who did not meet clinical criteria for ventilator-associated pneumonia had an increased risk of death when compared with patients who had high P. aeruginosa burdens and met ventilator-associated pneumonia criteria. Patients with high P. aeruginosa burden seemed to possess more virulent strains.

Human obesity has a strong genetic component. Most genes that influence an individual's predisposition to gain weight are not yet known. However, the study of extreme human obesity caused by single gene defects has provided a glimpse into the long-term regulation of body weight. These monogenic obesity disorders have confirmed that the hypothalamic leptin-melanocortin system is critical for energy balance in humans, because disruption of these pathways causes the most severe obesity phenotypes. Approximately 20 different genes and at least three different mechanisms have been implicated in monogenic causes of obesity; however, they account for fewer than 5% of all severe obesity cases. This finding suggests that the genetic basis for human obesity is likely to be extremely heterogeneous, with contributions from numerous genes acting by various, yet undiscovered, molecular mechanisms.

In this study we examined the ability of interferon-gamma (IFN-gamma) to regulate mammary epithelial cell growth and gene expression, with particular emphasis on two genes: Maspin (a member of serine protease inhibitor superfamily), and the lysosomal aspartyl endopeptidase cathepsin D (CatD). The protein products of these genes are critically involved in regulation of multitude of biological functions in different stages of mammary tissue development and remodeling. In addition, the expression of Maspin is down-regulated in primary breast cancer and is lost in metastatic disease, while CatD is excessively produced and aberrantly secreted by breast cancer cells. We report that IFN-gamma receptors are expressed in mammary epithelial cells, and receptor engagement by IFN-gamma transduces the IFN-gamma signal via Stat-1 resulting in decreased vacuolar pH. This change in vacuolar pH alters CatD protein processing and secretion concurrent with increased Maspin secretion. In addition, IFN-gamma exerts a suppressive effect on cell growth and proliferation, and induces morphological changes in mammary epithelial cells. Our studies also reveal that breast cancer cells, which are devoid of Maspin, are refractory to IFN-gamma with respect to changes in vacuolar pH and CatD. However, Maspin transfection of breast cancer cells partially sensitizes the cells to IFN-gamma's effect, thus providing new therapeutic implications.

PURPOSE

Although chronic obstructive pulmonary disease (COPD) has a major impact on physical health, the specific impact of COPD on physical functional limitations has not been characterized clearly. We aimed to elucidate the physical functional limitations that are directly attributable to COPD compared to a matched referent group without the condition.

METHODS

We used the Function, Living, Outcomes, and Work (FLOW) cohort study of adults with COPD (n=1202) and referent subjects matched by age, sex, and race (n=302) to study the impact of COPD on the risk of a broad array of functional limitations using validated measures: lower extremity function (Short Physical Performance Battery [SPPB]), submaximal exercise performance (Six Minute Walk Test [SMWT]), standing balance (Functional Reach Test), skeletal muscle strength (manual muscle testing with dynamometry), and self-reported functional limitation (standardized item battery). Multivariate analysis was used to control for confounding by age, sex, race, height, educational attainment, and cigarette smoking.

RESULTS

COPD was associated with poorer lower extremity function (mean SPPB score decrement for COPD vs referent -1.0 points; 95% CI, -1.25 to -0.73 pts) and less distance walked during the SMWT (-334 feet; 95% CI, -384 to -282 ft). COPD also was associated with weaker muscle strength in every muscle group tested, including both the upper and lower extremities (P<.0001 in all cases) and with a greater risk of self-reported functional limitation (OR 6.4; 95% CI, 3.7 to 10.9).

CONCLUSIONS

A broad array of physical functional limitations were specifically attributable to COPD. COPD affects a multitude of body systems remote from the lung.

BACKGROUND

Despite extensive evidence that air pollution affects childhood asthma, state-level and national-level tracking of asthma outcomes in relation to air pollution is limited.

OBJECTIVES

Our goals were to evaluate the feasibility of linking the 2001 California Health Interview Survey (CHIS), air monitoring, and traffic data; estimate associations between traffic density (TD) or outdoor air pollutant concentrations and childhood asthma morbidity; and evaluate the usefulness of such databases, linkages, and analyses to Environmental Public Health Tracking (EPHT).

METHODS

We estimated TD within 500 feet of residential cross-streets of respondents and annual average pollutant concentrations based on monitoring station measurements. We used logistic regression to examine associations with reported asthma symptoms and emergency department (ED) visits/hospitalizations.

RESULTS

Assignment of TD and air pollution exposures for cross-streets was successful for 82% of children with asthma in Los Angeles and San Diego, California, Counties. Children with asthma living in high ozone areas and areas with high concentrations of particulate matter < 10 microm in aerodynamic diameter experienced symptoms more frequently, and those living close to heavy traffic reported more ED visits/hospitalizations. The advantages of the CHIS for asthma EPHT include a large and representative sample, biennial data collection, and ascertainment of important socio-demographic and residential address information. Disadvantages are its cross-sectional design, reliance on parental reports of diagnoses and symptoms, and lack of information on some potential confounders.

CONCLUSIONS

Despite limitations, the CHIS provides a useful framework for examining air pollution and childhood asthma morbidity in support of EPHT, especially because later surveys address some noted gaps. We plan to employ CHIS 2003 and 2005 data and novel exposure assessment methods to re-examine the questions raised here.

BACKGROUND

A previous American College of Chest Physicians Consensus Statement on asthma in the workplace was published in 1995. The current Consensus Statement updates the previous one based on additional research that has been published since then, including findings relevant to preventive measures and work-exacerbated asthma (WEA).

METHODS

A panel of experts, including allergists, pulmonologists, and occupational medicine physicians, was convened to develop this Consensus Document on the diagnosis and management of work-related asthma (WRA), based in part on a systematic review, that was performed by the University of Alberta/Capital Health Evidence-Based Practice and was supplemented by additional published studies to 2007.

RESULTS

The Consensus Document defined WRA to include occupational asthma (ie, asthma induced by sensitizer or irritant work exposures) and WEA (ie, preexisting or concurrent asthma worsened by work factors). The Consensus Document focuses on the diagnosis and management of WRA (including diagnostic tests, and work and compensation issues), as well as preventive measures. WRA should be considered in all individuals with new-onset or worsening asthma, and a careful occupational history should be obtained. Diagnostic tests such as serial peak flow recordings, methacholine challenge tests, immunologic tests, and specific inhalation challenge tests (if available), can increase diagnostic certainty. Since the prognosis is better with early diagnosis and appropriate intervention, effective preventive measures for other workers with exposure should be addressed.

CONCLUSIONS

The substantial prevalence of WRA supports consideration of the diagnosis in all who present with new-onset or worsening asthma, followed by appropriate investigations and intervention including consideration of other exposed workers.