Publications

STUDY OBJECTIVE

To examine obstructive sleep apnea (OSA) as a risk factor for work disability.

PATIENTS AND SETTING

Consecutive patients referred to the University of California San Francisco Sleep Disorders Center with suspected OSA (n = 183).

DESIGN

All patients underwent overnight polysomnography after completing a written survey which assessed work disability due to sleep problems, occupational characteristics and excessive daytime sleepiness (EDS) defined as an Epworth Sleepiness Scale score > 10.

RESULTS

Among 150 currently employed patients, 83 had OSA on polysomnography (apnea-hypopnea index > or = 5). Compared with patients in whom both OSA and EDS were absent, patients with the combination of OSA and EDS were at higher risk of both recent work disability (adjusted odds ratio [OR], 13.7; 95% confidence interval [CI], 3.9-48) and longer-term work duty modification (OR, 3.6; CI, 1.1-12). When either OSA or EDS were absent, the strength of the association with work disability was less than when both OSA and EDS were present. When OSA was examined without respect to EDS, patients with OSA were at increased risk of recent work disability relative to patients without OSA (OR 2.6; 95% CI 1.2-5.8), but the association of OSA with longer-term work duty modification did not meet standard criteria for statistical significance (OR = 2.0, 95% CI 0.8-5.0).

CONCLUSIONS

The combination of OSA and EDS contributes to work disability, and OSA by itself contributes to recent work disability. These findings should highlight to employers and clinicians the importance of OSA in the workplace to encourage patients to be screened for OSA, particularly in situations of decreased productivity associated with EDS.

BACKGROUND

The diagnosis of and criteria for the evaluation of asbestos-related disease impairment remains controversial after decades of research. Assessing agreement among experts who study pneumoconiosis, and diagnose and treat patients with asbestos-related respiratory conditions may be the first step in clarifying clinical and forensic/administrative issues associated with asbestos-related pulmonary conditions.

METHODS

We conducted a Delphi study, an iterative method of obtaining consensus among a group of experts. An expert panel was identified using an objective, nonbiased algorithm, based on the number of asbestos-related disease publications authored during the preceding 10-year period. Identified experts were invited to participate by accessing an Internet site. Each expert was presented statements developed by the authors regarding the diagnosis or treatment of asbestos-related disease; experts then ranked their degree of agreement or disagreement utilizing an 11-level modified Likert scale for each statement. Each expert was asked to justify their selection and to suggest references in support of their opinion. The Wilcoxon signed rank test and the interquartile range were used to define "consensus." The results of the collective Likert rankings, deidentified comments, and suggested references as well as the initial consensus results were then provided to the participating experts. Each panel member then ranked their extent of agreement with a modified statement for which consensus was not achieved. The process was repeated three times.

RESULTS

Consensus was achieved on all but 9 of 32 statements.

CONCLUSIONS

Consensus was not achieved for nine statements. These statements may be topics for future research.

Since the current standards for drug approval were established nearly half a century ago, no drug has been approved for the treatment of systemic lupus erythematosus (SLE). Despite this sobering history, interest in drug development for SLE has heightened in the past few years. This enthusiasm has been fueled in large part by the success of biologic therapy for rheumatoid arthritis and other autoimmune diseases. Unfortunately, despite considerable clinical trial activity, this interest has not yet translated into the discovery of an effective treatment for SLE. This article provides an analysis of the major clinical trials in SLE, and offers an interpretation of the results that could illuminate the path forward.

OBJECTIVE

HIV-seropositive patients are at higher risk for atherosclerosis than HIV-seronegative persons. This has been variably attributed to antiretroviral drug toxicity, immunodeficiency, and/or HIV-associated inflammation. To evaluate the contributions of these factors to HIV-associated atherosclerosis, we assessed carotid artery intima-media thickness in a diverse cohort of HIV-seronegative and seropositive adults, including a unique group of HIV-infected patients who were untreated, had undetectable viral loads, and had preserved CD4 T-cell counts (HIV controllers).

METHODS AND RESULTS

Carotid intima-media thickness was measured in 494 participants, including 33 HIV controllers and 93 HIV-seronegative controls. HIV controllers had higher intima-media thickness than seronegative controls even after adjustment for traditional risk factors (P = 0.003). Intima-media thickness in controllers was similar to antiretroviral-untreated patients with detectable viremia. Across all participants, intima-media thickness was strongly associated with the presence of HIV disease rather than viral load or CD4 T-cell count. C-reactive protein was higher in HIV controllers than HIV-seronegative persons. Antiretroviral drug exposure was also associated with higher intima-media thickness.

CONCLUSIONS

Increased atherosclerosis with HIV infection can occur in the absence of antiretroviral therapy, detectable viremia, or overt immunodeficiency. Chronic inflammation - which is higher in controllers than in HIV-uninfected persons - may account for early atherosclerosis in these patients.

BACKGROUND

Ethnic-specific interactions between different asthma medications are not well described.

OBJECTIVE

To determine whether the use of leukotriene modifiers is associated with the magnitude of bronchodilator responsiveness among Mexican American and Puerto Rican children with persistent asthma.

METHODS

A cross-sectional study of 84 Mexican American and 192 Puerto Rican children, with persistent asthma who were aged 8 to 16 years. Within each group, bronchodilator responsiveness to albuterol, objectively assessed via spirometry, was compared between participants using leukotriene modifiers and those not using leukotriene modifiers.

RESULTS

Leukotriene modifier use was associated with a clinically significant increase in percentage change in forced expiratory volume in 1 second of 11.8 (P < .001) in Puerto Rican children, but there was no significant change in percentage change in forced expiratory volume in 1 second (-3.2, P=.57) in Mexican American children. This finding persisted after controlling for the use of inhaled corticosteroids. In addition, among the Puerto Rican children, the association between leukotriene modifier use and augmented bronchodilator responsiveness was greatest in those younger than 12 years.

CONCLUSIONS

Among children with persistent asthma, use of leukotriene modifiers is associated with augmented bronchodilator responsiveness to albuterol in Puerto Ricans, but not Mexican Americans. This ethnic-specific, drug-drug interaction highlights the need for the further understanding of asthma pharmacogenetics among children from different ethnic groups to improve asthma outcomes.

Src signaling has been implicated in several malignancies including melanoma. The prevalence of Src activation in human melanoma and the effect of the newer Src inhibitors, dasatinib, and bosutinib (SKI-606), as single agents or in combination, on melanoma cell lines is not well established. In the melanoma cell lines, A-375, SK-Mel-5, and SK-Mel-28, activity of Src inhibitors was assessed alone or in combination with standard chemotherapy agents; 50% growth inhibitory concentration was determined by MTS assay and immunoblotting was used to measure Src activation and downstream signaling. Staining for Src activation was measured by Src-phosphotyrosine 416. Immunohistochemistry was performed on primary cutaneous, mucosal, and metastatic melanoma. Src inhibitors blocked the growth of melanoma cell lines; furthermore, Src inhibitor treatment was synergized with cisplatin but not temozolomide or paclitaxel. Treatment with dasatanib increased the levels of pS473 Akt in A-375 melanoma cells but not in the other two cell lines. Forty-eight percent (17 of 35) of all melanoma stained weakly, moderately, or strongly for pY416 Src: cutaneous 61% (eight of 13), mucosal 31% (four of 13), metastatic 55% (five of nine). Most positive biopsies stained weakly and only one metastatic melanoma specimen stained strongly for Src-phosphotyrosine 416. pY416 Src is expressed in cutaneous, mucosal, and metastatic melanoma in various degrees. Src inhibitors may be a promising therapy in melanoma, either by themselves or in combination with chemotherapy (especially with platinum compounds) or inhibitors of the Akt/PI3k pathway.

We performed a longitudinal analysis of 661 methicillin-resistant Staphylococcus aureus (MRSA) isolates obtained from patients in a long-term care facility. USA300 clone increased from 11.3% of all MRSA isolates in 2002 to 64.0% in 2006 (p<0.0001) and was mostly recovered from skin or skin structures (64.3% vs. 27.0% for non-USA300 MRSA; p<0.0001).

The insulin/IGF1 signaling pathways affect lifespan in several model organisms, including worms, flies and mice. To investigate whether common genetic variation in this pathway influences lifespan in humans, we genotyped 291 common variants in 30 genes encoding proteins in the insulin/IGF1 signaling pathway in a cohort of elderly Caucasian women selected from the Study of Osteoporotic Fractures (SOF). The cohort included 293 long-lived cases (lifespan > or = 92 years (y), mean +/- standard deviation (SD) = 95.3 +/- 2.2y) and 603 average-lifespan controls (lifespan < or = 79y, mean = 75.7 +/- 2.6y). Variants were selected for genotyping using a haplotype-tagging approach. We found a modest excess of variants nominally associated with longevity. Nominally significant variants were then replicated in two additional Caucasian cohorts including both males and females: the Cardiovascular Health Study and Ashkenazi Jewish Centenarians. An intronic single nucleotide polymorphism in AKT1, rs3803304, was significantly associated with lifespan in a meta-analysis across the three cohorts (OR = 0.78 95%CI = 0.68-0.89, adjusted P = 0.043); two intronic single nucleotide polymorphisms in FOXO3A demonstrated a significant lifespan association among women only (rs1935949, OR = 1.35, 95%CI = 1.15-1.57, adjusted P = 0.0093). These results demonstrate that common variants in several genes in the insulin/IGF1 pathway are associated with human lifespan.