Publications

Current guidelines recommend beta blockers for patients after myocardial infarction (MI). Novel therapies for heart failure should be tested in combination with this medication before entering clinical trials. In this methodologic study, we sought to describe the time course of systolic and diastolic parameters of cardiac performance over a 6-wk period in closed-chest model of swine MI treated with a beta blocker. Myocardial infarction in pigs (n = 10) was induced by 90-min balloon occlusion of the left anterior descending coronary artery. Echocardiography and pressure-volume data were collected before and at 1 and 6 wk after MI; histopathology was assessed at 6 wk. Left-ventricular (LV) volume increased significantly over 6 wk, with significant decreases in ejection fraction, wall motion index, stroke work, rate of pressure development (dP/dt(max)), preload recruitable stroke work, and mechanical efficiency. Impairment of diastolic function was manifested by a significant increase in the exponential beta coefficient of the LV end-diastolic pressure-volume relation and reduction of LV pressure decay. At 6 wk, histopathologic analysis showed that the size of the infarct area was 16.3% +/- 4.4%, and the LV mass and myocyte cross-sectional area in both the infarct border and remote zones were increased compared with those of noninfarcted pigs (n = 5). These findings suggest a dynamic pattern of remodeling over time in a closed-chest ischemia-reperfusion swine model of acute MI on beta-blocker therapy and may guide future studies.

OBJECTIVE

To evaluate the effect of HIV infection on longitudinal changes in kidney function and to identify independent predictors of kidney function changes in HIV-infected individuals.

DESIGN

A prospective cohort.

METHODS

Cystatin C was measured at baseline and at the 5-year follow-up visit of the Study of Fat Redistribution and Metabolic Change in HIV infection in 554 HIV-infected participants and 230 controls. Control participants were obtained from the Coronary Artery Risk Development in Young Adults study. Glomerular filtration rate (eGFRcys) was estimated using the formula 76.7 x cysC(-1.19).

RESULTS

Compared with controls, HIV-infected participants had a greater proportion of clinical decliners (annual decrease in eGFRcys > 3 ml/min per 1.73 m2; 18 versus 13%, P = 0.002) and clinical improvers (annual increase in eGFRcys > 3 ml/min per 1.73 m2; 26 versus 6%, P < 0.0001). After multivariable adjustment, HIV infection was associated with higher odds of both clinical decline (odds ratio 2.2; 95% confidence interval 1.3, 3.9, P = 0.004) and clinical improvement (odds ratio 7.3; 95% confidence interval 3.9, 13.6, P < or = 0.0001). Among HIV-infected participants, a decrease in HIV viral load during follow-up was independently associated with clinical improvement; conversely, higher baseline and an increase in viral load during follow-up were associated with clinical decline. No individual antiretroviral drug or drug class appeared to be substantially associated with clinical decline or improvement.

CONCLUSION

Compared with controls, HIV-infected persons were more likely both to have clinical decline and clinical improvement in kidney function during 5 years of follow-up. The extent of viremic control had a strong association with longitudinal changes in kidney function.

Nephrogenic systemic fibrosis (NSF) is a disease of thickened, hard, hyperpigmented skin lesions with or without systemic fibrosis occurring in patients with renal insufficiency and associated with the administration of gadolinium-containing contrast. The pathogenesis of this disease is unclear, and there is no definitive treatment. We describe a 71-yr-old patient with stable chronic lymphocytic leukemia (CLL), end-stage renal disease (ESRD), and NSF who presented with hypercalcemia in 2006. Before onset of renal insufficiency in 2002, serum calcium, phosphorus, and PTH levels were normal. In 2004, the patient began hemodialysis, and he was diagnosed with NSF in 2005, shortly after undergoing an MRI with gadolinium contrast administration. Over the next 6 mo, albumin-corrected serum total calcium levels rose from 9.9 to 13.1 mg/dl (normal range, 8.5-10.5 mg/dl) with normal serum phosphorus levels. On admission in September 2006, 1,25-dihydroxyvitamin D [1,25(OH)(2)D] levels were elevated at 130.7 pg/ml (normal range, 25.1-66.1 pg/ml). Biopsy of an NSF lesion showed increased 25-hydroxyvitamin D(3)-1-alpha hydroxylase (CYP27B1) immunostaining compared with the biopsy from a normal control. This is the first reported association of NSF with hypercalcemia caused by elevated 1,25(OH)(2)D levels. This metabolic disturbance should be sought in future cases to determine a connection between NSF, 1,25(OH)(2)D metabolism, and CYP27B1 activation in the skin, which may shed light on the pathogenesis of this unusual local and systemic fibrosing disorder.

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.