Publications

We recently reported that integrin α(v)β(3) is necessary for vascular barrier protection in mouse models of acute lung injury and peritonitis. Here, we used mass spectrometric sequencing of integrin complexes to isolate the novel β(3)-integrin binding partner IQGAP1. Like integrin β(3), IQGAP1 localized to the endothelial cell-cell junction after sphingosine-1-phosphate (S1P) treatment, and IQGAP1 knockdown prevented cortical actin formation and barrier enhancement in response to S1P. Furthermore, knockdown of IQGAP1 prevented localization of integrin α(v)β(3) to the cell-cell junction. Similar to β(3)-null animals, IQGAP1-null mice had increased pulmonary vascular leak compared with wild-type controls 3 days after intratracheal LPS. In an Escherichia coli pneumonia model, IQGAP1 knockout mice had increased lung weights, lung water, and lung extravascular plasma equivalents of (125)I-labeled albumin compared with wild-type controls. Taken together, these experiments indicate that IQGAP1 is necessary for S1P-mediated vascular barrier protection during acute lung injury and is required for junctional localization of the barrier-protective integrin α(v)β(3).

Naturally blond hair is rare in humans and found almost exclusively in Europe and Oceania. Here, we identify an arginine-to-cysteine change at a highly conserved residue in tyrosinase-related protein 1 (TYRP1) as a major determinant of blond hair in Solomon Islanders. This missense mutation is predicted to affect catalytic activity of TYRP1 and causes blond hair through a recessive mode of inheritance. The mutation is at a frequency of 26% in the Solomon Islands, is absent outside of Oceania, represents a strong common genetic effect on a complex human phenotype, and highlights the importance of examining genetic associations worldwide.

RATIONALE

Animal and human studies support the importance of the coagulation cascade in pulmonary fibrosis.

OBJECTIVES

In a cohort of subjects with progressive idiopathic pulmonary fibrosis (IPF), we tested the hypothesis that treatment with warfarin at recognized therapeutic doses would reduce rates of mortality, hospitalization, and declines in FVC.

METHODS

This was a double-blind, randomized, placebo-controlled trial of warfarin targeting an international normalized ratio of 2.0 to 3.0 in patients with IPF. Subjects were randomized in a 1:1 ratio to warfarin or matching placebo for a planned treatment period of 48 weeks. International normalized ratios were monitored using encrypted home point-of-care devices that allowed blinding of study therapy.

MEASUREMENTS AND MAIN RESULTS

The primary outcome measure was the composite outcome of time to death, hospitalization (nonbleeding, nonelective), or a 10% or greater absolute decline in FVC. Due to a low probability of benefit and an increase in mortality observed in the subjects randomized to warfarin (14 warfarin versus 3 placebo deaths; P = 0.005) an independent Data and Safety Monitoring Board recommended stopping the study after 145 of the planned 256 subjects were enrolled (72 warfarin, 73 placebo). The mean follow-up was 28 weeks.

CONCLUSIONS

This study did not show a benefit for warfarin in the treatment of patients with progressive IPF. Treatment with warfarin was associated with an increased risk of mortality in an IPF population who lacked other indications for anticoagulation.

OBJECTIVE

The objective of the study was to examine the association between lactation and maternal subclinical cardiovascular disease.

STUDY DESIGN

The Women and Infants Study of Healthy Hearts enrolled 607 mothers who delivered a singleton between 1997 and 2002. In 2007, participating mothers underwent measurements of carotid intima-media thickness, lumen diameter, adventitial diameter, and carotid-femoral pulse wave velocity. Multivariable linear and logistic regressions were used to estimate the associations between lactation and subclinical cardiovascular disease.

RESULTS

Compared with mothers who breastfed for 3 or more months after every birth, mothers who never breastfed exhibited a 0.13 mm larger lumen diameter (95% confidence interval, 0.04-0.22) and a 0.12 mm larger adventitial diameter (95% confidence interval, 0.02-0.22) in models adjusting for age, parity, birth outcome, sociodemographic variables, health-related behaviors, family history, gestational weight gain, early adult body mass index, current body mass index, C-reactive protein, blood pressure, cholesterol, triglyceride, high-density lipoprotein, glucose, and insulin levels.

CONCLUSION

Mothers who do not breastfeed have vascular characteristics associated with a greater risk of cardiovascular disease.

Approximately 1 in 10 primary care patients has major depressive disorder, and its presence is associated with poor health outcomes in numerous medical conditions. Using the case of Mr J, a 52-year-old man with depressive symptoms and several comorbid medical conditions, diagnosis and treatment of depression are discussed. Specific topics include evidence regarding appropriate depression screening and diagnosis, the importance of team-based care, patient self-management, exercise, structured psychotherapy, pharmacotherapy, monitoring of therapy, and indications for referral.