Publications

BACKGROUND

Asthma has been found to be among the most common conditions in the working age population and is among the most common causes of work limitation, but we could find no longitudinal studies of employment among persons with this condition.

METHODS

A panel of 601 persons with a diagnosis of asthma from random samples of northern California pulmonologists and allergy-immunologists were interviewed as many as three times at 18-month intervals by a trained survey worker to report on the severity of disease, demographic characteristics, and the extent of their employment. Their employment was then compared to that of a matched sample from the U.S. Bureau of the Census Current Population Survey.

RESULTS

Ninety-two percent of the persons with asthma had worked at some point prior to study enrollment. Among persons with onset during adulthood, only 29% of those who were not employed at disease onset were working at study enrollment, compared to 68% among those who were employed. Among the 420 persons interviewed three times, 75, 81, and 75%, respectively, were employed as of the three interviews. Among these 420, 66% were continuously employed and 15% were continuously not employed. The principal determinants of continuity of employment were demographic and employment characteristics, not medical ones. The employment rate and hours of work per week and per year of the persons with asthma were similar to the matched sample.

CONCLUSIONS

Asthma has not substantially impeded the employment of the persons with asthma we studied, with the exception that those who were not employed at disease onset continued to have low employment rates.

BACKGROUND

In general practice settings, the proportion of adult asthma attributable to occupational factors is not known.

OBJECTIVE

The goal of this study was to estimate the proportion of adult asthma cases that can be attributed to occupational factors initiating new disease onset and exacerbating preexisting disease.

METHODS

We performed a cross-sectional analysis of interview data for 150 adults with asthma recruited from a random sample of family practice specialists. We ascertained the asthma and work histories of the subjects and estimated the proportion with likely work-initiated asthma and work-related asthma recrudescence.

RESULTS

Seventy-four subjects (49%) reported adult-onset asthma while employed; an additional 25 (17%) reported recrudescence of previously quiescent childhood-onset asthma during employment. Of those with new-onset asthma while employed, 15 (10% of the study group; 95% confidence interval, 5 to 15%) were employed in occupations at increased risk of occupational asthma initiation on the basis of an independent job scoring matrix. Of those with asthma recrudescence in adulthood, seven (5% of the study group; 95% confidence interval, 2 to 8%) were employed in occupations at increased risk of exposures aggravating asthma.

CONCLUSIONS

Among adults with asthma treated in general practice settings, > 1 in 10 patients has a work history strongly suggestive of a potential relationship between exposure and disease.

The resident integral hepatic endoplasmic reticulum (ER) proteins, cytochromes P450 (P450s), turn over in vivo with widely varying half-lives. We and others (Correia et al., Arch. Biochem. Biophys. 297, 228, 1992; and Tierney et al., Arch. Biochem. Biophys. 293, 9, 1992) have previously shown that in intact animals, the hepatic P450s of the 3A and 2E1 subfamilies are first ubiquitinated and then proteolyzed after their drug-induced suicide inactivation. Our findings with intact rat hepatocytes and ER preparations containing native P450s and P450s inactivated via heme modification of the protein have revealed that the proteolytic degradation of heme-modified P450s requires a cytosolic ATP-dependent proteolytic system rather than lysosomal or ER proteases (Correia et al., Arch. Biochem. Biophys. 297, 228, 1992). Using purified cumene hydroperoxide-inactivated P450s (rat liver P450s 2B1 or 3A and/or a recombinant human liver P450 3A4) as models, we now document that these heme-modified enzymes are indeed ubiquitinated and then proteolyzed by the 26S proteasome, but not by its 20S proteolytic core. In addition, our studies indicate that the ubiquitination of these heme-modified P450s is preceded by their phosphorylation. It remains to be determined whether, in common with several other cellular proteins, such P450 phosphorylation is indeed required for their degradation. Nevertheless, these findings suggest that the membrane-anchored P450s are to be included in the growing class of ER proteins that undergo ubiquitin-dependent 26S proteasomal degradation.

Mechanism-based inactivation of liver microsomal cytochromes P450 3A (CYP 3A, P450s 3A) in vivo and/or in vitro, via heme modification of the protein, results in accelerated proteolytic degradation of the enzyme that is preceded by the ubiquitination of the protein, thereby implicating the ubiquitin-ATP-dependent 26S proteasomal system. In this study, this involvement is confirmed with the use of the proteasomal inhibitors aclarubicin and MG-132 as probes, in isolated rat hepatocytes treated with the P450 3A mechanism-based inactivator, 3,5-dicarbethoxy-2,6-dimethyl-4-ethyl-1, 4-dihydropyridine (DDEP). In addition, the findings reveal that during the course of this proteolysis, the endoplasmic reticulum (ER)-anchored DDEP-inactivated P450 3A is translocated from the ER to the cytosol in a brefeldin A-insensitive manner.

Unstable angina comprises a heterogeneous population of patients who present with a wide spectrum of underlying pathophysiology. The traditional treatment of these patients is based on both evidenced-based medicine as well as clinical experience. Despite the large population of patients admitted with this diagnosis, the scientific literature regarding its treatment is scarce. Therefore, the management of patients with unstable angina relies heavily on the clinical skills of the physician. One of the most important steps in this process involves risk stratification, especially in the current environment of cost containment. Those patients who are at low risk for adverse outcomes can be treated and evaluated safely as outpatients. Patients at high or moderate risk, however, should be treated intensively as inpatients. Although there appear to be many new promising therapies for unstable angina on the horizon, the traditional therapies still have a place. The use of aspirin in this population is well supported by the literature and appears to have a positive effect on mortality and cardiovascular events. The other traditional therapies, however, are not as well supported by the literature. They do appear to benefit the patient in terms of reducing symptoms, but their effects on reducing mortality and cardiovascular events are not clear. Therefore, the goal of medical therapy in this patient population should be to stabilize them so that they can proceed with an appropriate risk stratification procedure as soon as possible. This is especially true with performing coronary angiography or interventions because the risk of procedural complications is higher in patients with unstable angina and ongoing symptoms.

Solid tumors depend on angiogenesis for their growth. In a transgenic mouse model of pancreatic islet cell carcinogenesis (RIP1-Tag2), an angiogenic switch occurs in premalignant lesions, and angiogenesis persists during progression to expansive solid tumors and invasive carcinomas. RIP1-Tag2 mice were treated so as to compare the effects of four angiogenesis inhibitors at three distinct stages of disease progression. AGM-1470, angiostatin, BB-94, and endostatin each produced distinct efficacy profiles in trials aimed at preventing the angiogenic switch in premalignant lesions, intervening in the rapid expansion of small tumors, or inducing the regression of large end-stage cancers. Thus, anti-angiogenic drugs may prove most efficacious when they are targeted to specific stages of cancer.