Longitudinal Follow-Up of Participants With Tobacco Exposure and Preserved Spirometry.

Importance: People who smoked cigarettes may experience respiratory symptoms without spirometric airflow obstruction. These individuals are typically excluded from chronic obstructive pulmonary disease (COPD) trials and lack evidence-based therapies.

Objective: To define the natural history of persons with tobacco exposure and preserved spirometry (TEPS) and symptoms (symptomatic TEPS).

Treating COVID-19: Evolving approaches to evidence in a pandemic.

The rapid pace of the COVID-19 pandemic precluded traditional approaches to evaluating clinical research and guidelines. We highlight notable successes and pitfalls of clinicians' new approaches to managing evidence amidst an unprecedented crisis. In "Era 1" (early 2020), clinicians relied on anecdote and social media, which democratized conversations on guidelines, but also led clinicians astray.

Autoregulation of insulin receptor signaling through MFGE8 and the αvβ5 integrin.

The role of integrins, in particular αv integrins, in regulating insulin resistance is incompletely understood. We have previously shown that the αvβ5 integrin ligand milk fat globule epidermal growth factor like 8 (MFGE8) regulates cellular uptake of fatty acids. In this work, we evaluated the impact of MFGE8 on glucose homeostasis.

"Silent" Presentation of Hypoxemia and Cardiorespiratory Compensation in COVID-19.

Severe hypoxemia presents variably, and sometimes silently, without subjective complaints of dyspnea. The adequacy of cardiovascular compensation for oxygen delivery to tissues should be a focus in all hypoxemic patients.

500 Million Alveoli from 30,000 Feet: A Brief Primer on Lung Anatomy.

The lungs are a complex organ that fulfill multiple life-sustaining roles including transfer of oxygen and carbon dioxide between the ambient environment and the bloodstream, host defense, and immune homeostasis. As in any biological system, an understanding of the underlying anatomy is prerequisite for successful experimental design and appropriate interpretation of data, regardless of the precise experimental model or procedure in use. This chapter provides an overview of human lung anatomy focused on the airways, the ultrastructure or parenchyma of the lung, the pulmonary vasculature, the innervation of the lungs, and the pulmonary lymphatic system.

Cell division cycle 7 kinase is a negative regulator of cell-mediated collagen degradation.

Although extensive work has delineated many of the mechanisms of extracellular matrix (ECM) production, far less is known about pathways that regulate ECM degradation. This is particularly true of cellular internalization and degradation of matrix, which play an underappreciated role in ECM metabolism and lung fibrosis. For example, genetic perturbation of this pathway leads to exacerbated fibrosis in experimental animal models.

α8β1 integrin regulates nutrient absorption through an Mfge8-PTEN dependent mechanism.

Coordinated gastrointestinal smooth muscle contraction is critical for proper nutrient absorption and is altered in a number of medical disorders. In this work, we demonstrate a critical role for the RGD-binding integrin α8β1 in promoting nutrient absorption through regulation of gastrointestinal motility. Smooth muscle-specific deletion and antibody blockade of α8 in mice result in enhanced gastric antral smooth muscle contraction, more rapid gastric emptying, and more rapid transit of food through the small intestine leading to malabsorption of dietary fats and carbohydrates as well as protection from weight gain in a diet-induced model of obesity.

Mfge8 promotes obesity by mediating the uptake of dietary fats and serum fatty acids.

Fatty acids are integral mediators of energy storage, membrane formation and cell signaling. The pathways that orchestrate uptake of fatty acids remain incompletely understood. Expression of the integrin ligand Mfge8 is increased in human obesity and in mice on a high-fat diet, but its role in obesity is unknown.

Functional genomic screen identifies novel mediators of collagen uptake.

Tissue fibrosis occurs when matrix production outpaces matrix degradation. Degradation of collagen, the main component of fibrotic tissue, is mediated through an extracellular proteolytic pathway and intracellular pathway of cellular uptake and lysosomal digestion. Recent studies demonstrate that disruption of the intracellular pathways can exacerbate fibrosis.

Always cleave up your mess: targeting collagen degradation to treat tissue fibrosis.

Pulmonary fibrosis is a vexing clinical problem with no proven therapeutic options. In the normal lung there is continuous collagen synthesis and collagen degradation, and these two processes are precisely balanced to maintain normal tissue architecture. With lung injury there is an increase in the rate of both collagen production and collagen degradation.

Mfge8 suppresses airway hyperresponsiveness in asthma by regulating smooth muscle contraction.

Airway obstruction is a hallmark of allergic asthma and is caused primarily by airway smooth muscle (ASM) hypercontractility. Airway inflammation leads to the release of cytokines that enhance ASM contraction by increasing ras homolog gene family, member A (RhoA) activity. The protective mechanisms that prevent or attenuate the increase in RhoA activity have not been well studied.

Mfge8 diminishes the severity of tissue fibrosis in mice by binding and targeting collagen for uptake by macrophages.

Milk fat globule epidermal growth factor 8 (Mfge8) is a soluble glycoprotein known to regulate inflammation and immunity by mediating apoptotic cell clearance. Since fibrosis can occur as a result of exaggerated apoptosis and inflammation, we set out to investigate the hypothesis that Mfge8 might negatively regulate tissue fibrosis. We report here that Mfge8 does decrease the severity of tissue fibrosis in a mouse model of pulmonary fibrosis; however, it does so not through effects on inflammation and apoptotic cell clearance, but by binding and targeting collagen for cellular uptake through its discoidin domains.

Isoflurane inhibits growth but does not cause cell death in hippocampal neural precursor cells grown in culture.

Background: Isoflurane causes long-term hippocampal-dependent learning deficits in rats despite limited isoflurane-induced hippocampal cell death, raising questions about the causality between isoflurane-induced cell death and isoflurane-induced cognitive function. Neurogenesis in the dentate gyrus is required for hippocampal-dependent learning and thus constitutes a potential alternative mechanism by which cognition can be altered after neonatal anesthesia. The authors tested the hypothesis that isoflurane alters proliferation and differentiation of hippocampal neural progenitor cells.

A prospective study of primary surrogate decision makers' knowledge of intensive care.

Objectives: We sought to determine 1) primary surrogate decision makers' knowledge of their family members' intensive care and resuscitation status; 2) whether characteristics such as low education level and lack of English language fluency were associated with poor knowledge of intensive care; 3) surrogates' ratings of intensive care unit team communication; and 4) barriers to communication.

Design: Prospective study.

Setting: Medical intensive care units of a county hospital located in an urban area.