Publications

BACKGROUND

Soluble intercellular adhesion molecule-1 (sICAM-1) is a transmembrane protein involved in the migration and adhesion of leukocytes to the vascular endothelium. While some studies indicate that elevated baseline sICAM-1 levels predict cardiovascular events, most of these studies were done in men; moreover, uncertainty exists regarding whether sICAM-1 levels predict vascular events consistent with acute thrombosis versus atherosclerotic disease progression.

METHODS AND RESULTS

In this prospective evaluation of 23,984 apparently healthy women, we measured sICAM-1 levels and followed participants for the development of cardiovascular (CVD) endpoints typically associated with atherosclerotic disease progression with resultant vessel narrowing (percutaneous transluminal angioplasty and coronary artery bypass grafting) and endpoints typically associated with vascular thrombosis and vessel occlusion (myocardial infarction (MI), ischemic stroke and death from a coronary cause). During a mean follow-up of 10 years, there were 741 events. For vascular events indicative of coronary atherosclerotic disease progression with luminal narrowing, Cox-proportional hazards models revealed an increase in vascular event rates from the lowest to highest quintile of baseline sICAM-1 after adjustment for CVD risk factors [hazard ratios (HR): 1.0, 1.4, 1.1, 1.6, 1.6, p(trend)=0.008]. By contrast, for endpoints reflective of acute vessel thrombosis, we found no association with sICAM-1 levels [HR for myocardial infarction: 1.0, 1.2, 0.9, 1.2, 1.0, p(trend)=0.7; HR for stroke (CVA): 1.0, 0.9, 1.0, 1.0, 1.1, p(trend)=0.6; HR for cardiovascular death: 1.0, 0.9, 0.7, 0.7, 0.8, p(trend)=0.7] except among smokers (RR=1.0, 1.4, 2.8, 3.8, 3.7, p=0.007).

CONCLUSIONS

Among women without a history of cardiovascular disease, sICAM-1 levels are predictive of CVD events that reflect coronary atherosclerotic disease progression and vessel narrowing, but not those events associated with acute thrombosis/vessel occlusion.

HIV-infected patients harbor approximately 10(5)-10(6) memory CD4 T-cells that contain fully integrated but transcriptionally silent HIV proviruses. While small in number, these latently infected cells form a drug-insensitive reservoir that importantly contributes to the life-long persistence of HIV despite highly effective antiviral therapy. In tissue culture, latent HIV proviruses can be activated when their cellular hosts are exposed to select proinflammatory cytokines or their T-cell receptors are ligated. However, due to a lack of potency and/or dose-limiting toxicity, attempts to purge virus from this latent reservoir in vivo with immune-activating agents, such as anti-CD3 antibodies and IL-2, have failed. A deeper understanding of the molecular underpinnings of HIV latency is clearly required, including determining whether viral latency is actively reinforced by transcriptional repressors, defining which inducible host transcription factors most effectively antagonize latency, and elucidating the role of chromatin in viral latency. Only through such an improved understanding will it be possible to identify combination therapies that might allow complete purging of the latent reservoir and to realize the difficult and elusive goal of complete eradication of HIV in infected patients.

PURPOSE

With improved patient survival from breast cancer, more interest has evolved regarding the symptoms women experience in association with breast cancer treatments. We studied the extent to which symptoms for women with incident breast cancer are addressed by their physicians and how symptom management varies with patient characteristics.

METHODS

As part of the Los Angeles Women's (LAW) Study, we categorized women from a population-based study of incident breast cancer (n = 1,219) as having an unmet need if she had at least one severe symptom (any of the following: nausea/vomiting, arm problems, hot flashes, vaginal dryness, difficulty sleeping) for which she did not receive the help she wanted. Multivariable analyses predicted having any unmet need as a function of patient demographic and health characteristics.

RESULTS

The prevalence of unmet need varied by the type of symptom with the highest proportion of women receiving help for nausea and vomiting (0.91) and the lowest for vaginal dryness (0.48). Black women (OR = 3.61, 95% CI: [1.57, 8.31]), and Spanish-speaking Hispanic women (OR = 2.69, 95% CI: [1.22, 5.94]) were significantly more likely than white women to report an unmet need. More black and Hispanic women compared to white women cited the doctor not thinking treatment would benefit her (P = 0.02), not appreciating how much the problem bothered her (P = 0.03), not knowing about treatments (P < 0.0001), or insurance/cost barriers (P = 0.009) as reasons for her unmet need.

CONCLUSION

These results show the persistence of racial disparities in the receipt of appropriate care within the health care system.

Surfactant lines the alveolar surface and prevents alveolar collapse. Derangements of surfactant cause respiratory failure and interstitial lung diseases. The collectins, surfactant proteins A and D, are also important in innate host defense. However, surfactant regulation in the postnatal lung is poorly understood. We found that the epithelial integrin, alphavbeta6, regulates surfactant homeostasis in vivo by activating latent transforming growth factor (TGF)-beta. Adult mice lacking the beta-subunit of alphavbeta6 (Itgb6-/-) developed increased bronchoalveolar lavage phospholipids and surfactant proteins A and D, and demonstrated abnormal-appearing alveolar macrophages, reminiscent of the human disease pulmonary alveolar proteinosis. Using lung-specific expression of constitutively active TGF-beta1 in Itgb6-/- mice, we found that TGF-beta1 was sufficient to normalize these abnormalities. Tgfbeta1-deficient mice also demonstrated increased phospholipids and surfactant proteins A and D, but mice lacking the key TGF-beta signaling molecule, SMAD3, did not. Therefore, integrin-mediated activation of latent TGF-beta1 regulates surfactant constituents independent of intracellular SMAD3. In vivo increases in surfactant protein A and D were not associated with increases in mRNA for these proteins in alveolar tissue from Itgb6-/- mice. On the other hand, isolated alveolar macrophages from Itgb6-/- mice were defective in processing phospholipids in vitro, suggesting that reduced surfactant clearance contributes to altered surfactant homeostasis in these mice in vivo. These findings show that alphavbeta6 and TGF-beta1 regulate homeostasis of phospholipids and collectins in adult mouse lungs and may have implications for anti-fibrotic therapeutics that inhibit active TGF-beta in the lung.

We examined the hypothesis that insulin resistance in skeletal muscle promotes the development of atherogenic dyslipidemia, associated with the metabolic syndrome, by altering the distribution pattern of postprandial energy storage. Following ingestion of two high carbohydrate mixed meals, net muscle glycogen synthesis was reduced by approximately 60% in young, lean, insulin-resistant subjects compared with a similar cohort of age-weight-body mass index-activity-matched, insulin-sensitive, control subjects. In contrast, hepatic de novo lipogenesis and hepatic triglyceride synthesis were both increased by >2-fold in the insulin-resistant subjects. These changes were associated with a 60% increase in plasma triglyceride concentrations and an approximately 20% reduction in plasma high-density lipoprotein concentrations but no differences in plasma concentrations of TNF-alpha, IL-6, adiponectin, resistin, retinol binding protein-4, or intraabdominal fat volume. These data demonstrate that insulin resistance in skeletal muscle, due to decreased muscle glycogen synthesis, can promote atherogenic dyslipidemia by changing the pattern of ingested carbohydrate away from skeletal muscle glycogen synthesis into hepatic de novo lipogenesis, resulting in an increase in plasma triglyceride concentrations and a reduction in plasma high-density lipoprotein concentrations. Furthermore, insulin resistance in these subjects was independent of changes in the plasma concentrations of TNF-alpha, IL-6, high-molecular-weight adiponectin, resistin, retinol binding protein-4, or intraabdominal obesity, suggesting that these factors do not play a primary role in causing insulin resistance in the early stages of the metabolic syndrome.