Publications

STUDY DESIGN

Randomized controlled trial.

OBJECTIVE

To characterize the increase in gelatinase A (MMP2) activity after spinal cord injury (SCI) in the mouse model, and the effects of MMP2/MMP9 inhibition on apoptotic cells.

SUMMARY OF BACKGROUND DATA

Clinical consequences of SCI are due to a series of secondary injury cascades. Matrix metalloproteinases are thought play a key role in this, leading to apoptotic cell death.

METHODS

SCI via a drop tower in mice was used. MMP2 beta-gal reporter mice were used to quantify the level of MMP2 after SCI. In a follow-up experiment, mice which underwent SCI were randomized to daily SQ injections of MMP2/MMP9 inhibitor versus placebo. MMP2 levels were quantified and histology was performed with TUNEL and Luxol fast blue staining.

RESULTS

MMP2 transcription was significantly upregulated after SCI, by the beta-gal assay. Inhibition of MMP2/MMP9 activity after SCI led to statistically significant decreases in apoptosis within the zone of injury. There was a trend towards preservation of myelin by preserved luxol fast blue staining.

CONCLUSION

After SCI, MMP2 is upregulated along with neuron and glial cells apoptosis. The level of apoptosis could be reduced with MMP2/MMP9 inhibition. This supports MMP2 as cause for apoptosis after SCI with the potential for therapeutic intervention as apoptosis can be reduced with MMP2 inhibition.

OBJECTIVES

Although discussing a prognosis is a duty of physicians caring for critically ill patients, little is known about surrogate decision-makers' beliefs about physicians' ability to prognosticate. We sought to determine: 1) surrogates' beliefs about whether physicians can accurately prognosticate for critically ill patients; and 2) how individuals use prognostic information in their role as surrogate decision-makers.

DESIGN, SETTING, AND PATIENTS

Multicenter study in intensive care units of a public hospital, a tertiary care hospital, and a veterans' hospital. We conducted semistructured interviews with 50 surrogate decision-makers of critically ill patients. We analyzed the interview transcripts using grounded theory methods to inductively develop a framework to describe surrogates' beliefs about physicians' ability to prognosticate. Validation methods included triangulation by multidisciplinary analysis and member checking.

MEASUREMENTS AND MAIN RESULTS

Overall, 88% (44 of 50) of surrogates expressed doubt about physicians' ability to prognosticate for critically ill patients. Four distinct themes emerged that explained surrogates' doubts about prognostic accuracy: a belief that God could alter the course of the illness, a belief that predicting the future is inherently uncertain, prior experiences where physicians' prognostications were inaccurate, and experiences with prognostication during the patient's intensive care unit stay. Participants also identified several factors that led to belief in physicians' prognostications, such as receiving similar prognostic estimates from multiple physicians and prior experiences with accurate prognostication. Surrogates' doubts about prognostic accuracy did not prevent them from wanting prognostic information. Instead, most surrogate decision-makers view physicians' prognostications as rough estimates that are valuable in informing decisions, but are not determinative. Surrogates identified the act of prognostic disclosure as a key step in preparing emotionally and practically for the possibility that a patient may not survive.

CONCLUSIONS

Although many surrogate decision-makers harbor some doubt about the accuracy of physicians' prognostications, they highly value discussions about prognosis and use the information for multiple purposes.

BACKGROUND

Mortality risk in adult asthma is poorly understood, especially the interplay among race, disease severity, and health care access.

OBJECTIVE

To examine mortality risk factors in adult asthma.

METHODS

In a prospective cohort study of 865 adults with severe asthma in a closed-panel managed care organization, we used structured interviews to evaluate baseline sociodemographics, asthma history, and health status. Patients were followed up until death or the end of the study (mean, 2 years). We used Cox proportional hazards regression to evaluate the impact of sociodemographics, cigarette smoking, and validated measures of perceived asthma control, physical health status, and severity of asthma on the risk of death.

RESULTS

We confirmed 123 deaths (mortality rate, 6.7 per 100 person-years). In an analysis adjusted for sociodemographics and tobacco history, higher severity-of-asthma scores (hazard ratio [HR], 1.11 per 0.5-SD increase in severity-of-asthma score; 95% confidence interval [CI], 1.01-1.23) and lower perceived asthma control scores (HR, 0.91 per 0.5-SD increase in perceived asthma control score; 95% CI, 0.83-0.99) were each associated with risk of all-cause mortality. In the same adjusted analysis, African American race was not associated with increased mortality risk relative to white race (HR, 0.64; 95% CI, 0.36-1.14).

CONCLUSIONS

In a large managed care organization in which access to care is unlikely to vary widely, greater severity-of-asthma scores and poorer perceived asthma control scores are each associated with increased mortality risk in adults with severe asthma, but African American patients are not at increased risk for death relative to white patients.

Smoking during pregnancy remains a major public health concern and is associated with numerous adverse effects. Recently the clearance of nicotine and cotinine was shown to be substantially increased in pregnant women compared with nonpregnant controls. The present study investigated the usefulness of the rabbit for studying the molecular basis for the observed changes in nicotine and cotinine disposition during pregnancy. Nicotine was largely metabolized to cotinine in rabbit liver microsomes (approximately 50% of total metabolism); significant amounts of nicotine-N'-oxide and nornicotine also were detected. The conversion of nicotine to cotinine also was detected in rabbit placental and fetal liver microsomes, albeit at only a fraction of the rate found in adult rabbit liver microsomes. The major products of cotinine metabolism in rabbit liver microsomes were 5'-hydroxycotinine, cotinine-N'-oxide, and norcotinine. Differences between human and rabbit liver were most apparent for cotinine. The major human metabolite, 3'-hydroxycotinine, was formed at only low levels in rabbit liver microsomes. Pregnancy had no effect on the metabolism of nicotine or on the expression of CYP2A6 immunoreactive proteins in rabbit liver microsomes. These studies provide a complete quantitative assessment of nicotine metabolism in rabbit liver microsomes and suggest that the rabbit may not be an appropriate animal model to study the effects of pregnancy on nicotine and cotinine metabolism. However, a molecular understanding of these effects is essential for prediction of the pharmacological and toxicological consequences of smoking during pregnancy.

Asthma exacerbations can be triggered by viral infections or allergens. The Th2 cytokines IL-13 and IL-4 are produced during allergic responses and cause increases in airway epithelial cell mucus and electrolyte and water secretion into the airway surface liquid (ASL). Since ASL dehydration can cause airway inflammation and obstruction, ion transporters could play a role in pathogenesis of asthma exacerbations. We previously reported that expression of the epithelial cell anion transporter pendrin is markedly increased in response to IL-13. Herein we show that pendrin plays a role in allergic airway disease and in regulation of ASL thickness. Pendrin-deficient mice had less allergen-induced airway hyperreactivity and inflammation than did control mice, although other aspects of the Th2 response were preserved. In cultures of IL-13-stimulated mouse tracheal epithelial cells, pendrin deficiency caused an increase in ASL thickness, suggesting that reductions in allergen-induced hyperreactivity and inflammation in pendrin-deficient mice result from improved ASL hydration. To determine whether pendrin might also play a role in virus-induced exacerbations of asthma, we measured pendrin mRNA expression in human subjects with naturally occurring common colds caused by rhinovirus and found a 4.9-fold increase in mean expression during colds. Studies of cultured human bronchial epithelial cells indicated that this increase could be explained by the combined effects of rhinovirus and IFN-gamma, a Th1 cytokine induced during virus infection. We conclude that pendrin regulates ASL thickness and may be an important contributor to asthma exacerbations induced by viral infections or allergens.

BACKGROUND

Proventricular dilatation disease (PDD) is a fatal disorder threatening domesticated and wild psittacine birds worldwide. It is characterized by lymphoplasmacytic infiltration of the ganglia of the central and peripheral nervous system, leading to central nervous system disorders as well as disordered enteric motility and associated wasting. For almost 40 years, a viral etiology for PDD has been suspected, but to date no candidate etiologic agent has been reproducibly linked to the disease.

RESULTS

Analysis of 2 PDD case-control series collected independently on different continents using a pan-viral microarray revealed a bornavirus hybridization signature in 62.5% of the PDD cases (5/8) and none of the controls (0/8). Ultra high throughput sequencing was utilized to recover the complete viral genome sequence from one of the virus-positive PDD cases. This revealed a bornavirus-like genome organization for this agent with a high degree of sequence divergence from all prior bornavirus isolates. We propose the name avian bornavirus (ABV) for this agent. Further specific ABV PCR analysis of an additional set of independently collected PDD cases and controls yielded a significant difference in ABV detection rate among PDD cases (71%, n = 7) compared to controls (0%, n = 14) (P = 0.01; Fisher's Exact Test). Partial sequence analysis of a total of 16 ABV isolates we have now recovered from these and an additional set of cases reveals at least 5 distinct ABV genetic subgroups.

CONCLUSION

These studies clearly demonstrate the existence of an avian reservoir of remarkably diverse bornaviruses and provide a compelling candidate in the search for an etiologic agent of PDD.

OBJECTIVES

Morbidity and mortality due to liver disease and cirrhosis vary significantly by race/ethnicity in the United States. We examined the prevalence of liver disease risk factors among blacks, Mexican Americans, and whites, including elevated aspartate aminotransferase and alanine aminotransferase activity, infection with viral hepatitis B or hepatitis C, alcohol intake, obesity, diabetes, and metabolic syndrome.

METHODS

Data were obtained from the Fourth National Health and Nutrition Examination Survey (NHANES IV). A logistic regression was used to examine the association of race/ethnicity to liver disease risk factors, controlling for the demographic and socioeconomic variables.

RESULTS

Mexican-American men and women are the most likely to have elevated aminotransferase activity. Among men, Mexican Americans are more likely than whites to be heavy/binge drinkers, and blacks are more likely to have hepatitis B or hepatitis C. Among women, Mexican Americans are more likely than whites to be obese and diabetic, and less likely to be heavy/binge drinkers; blacks are more likely than whites to have hepatitis B or hepatitis C, be obese or diabetic, and less likely to be heavy/binge drinkers.

CONCLUSIONS

In this national sample, the prevalence of risk factors for liver disease varies by race/ethnicity. Mexican Americans and blacks have a greater risk of developing liver disease than their white counterparts. These findings are consistent with the observed racial/ethnic disparities in morbidity and mortality due to chronic liver disease and contribute to the efforts to identify the causes of these disparities. This information can be used by health professionals to tailor screening and intervention programs.