Flow Decay: A Novel Spirometric Index to Quantify Dynamic Airway Resistance.

BACKGROUND: Dynamic airway resistance from obstructive disease causes a concavity in the mid-expiratory portion of the spirometric flow-volume loop. We developed a simple model to measure the exponential decay in air flow during forced exhalation to quantify the extent of dynamic airway obstruction and facilitate the detection of obstructive airway diseases clinically. METHODS: We calculated flow decay as the slope of volume versus ln(1/flow) in mid-exhalation. We derived the normal range in a derivation group of healthy volunteers in whom spirometry had been performed repeatedly. We validated the derived upper limit of normal (mean + 2 × SD) by using it to distinguish a separate group of healthy subjects (n = 25) from subjects with independently diagnosed reversible airway obstruction (n = 31) and subjects with obstruction, hyperinflation, and air trapping (n = 62). RESULTS: In the derivation group (n = 7), the mean ± SD flow decay was 0.588 ± 0.107 L-1 (upper limit of normal = 0.802 L-1). Flow decay in 23 of 25 healthy subjects in the validation group was below the upper limit of normal. In contrast, it was above the upper limit of normal in 29 of 31 subjects with reversible airway obstruction (sensitivity 94%, 95% CI 79-99%; specificity 92%, 95% CI 74-99%) and in 59 of 62 of subjects with obstruction, hyperinflation, and air trapping (sensitivity 92%, 95% CI 74-99%; specificity 95%, 95% CI 86-99%). CONCLUSIONS: Flow decay distinguished subjects with obstructive lung defects from healthy subjects. It is a straightforward representation of spirometry data that provides a reproducible index to quantify dynamic airway obstruction.

Need for injury-prevention education in medical school curriculum.

Injury is the leading cause of death and disability among the U.S. population aged 1 to 44 years. In 2006 more than 179,000 fatalities were attributed to injury. Despite increasing awareness of the global epidemic of injury and violence, a considerable gap remains between advances in injury-prevention research and prevention knowledge that is taught to medical students. This article discusses the growing need for U.S medical schools to train future physicians in the fundamentals of injury prevention and control. Teaching medical students to implement injury prevention in their future practice should help reduce injury morbidity and mortality. Deliberate efforts should be made to integrate injury-prevention education into existing curriculum. Key resources are available to do this. Emergency physicians can be essential advocates in establishing injury prevention training because of their clinical expertise in treating injury. Increasing the number of physicians with injury- and violence- prevention knowledge and skills is ultimately an important strategy to reduce the national and global burden of injury.

BMPs regulate multiple aspects of growth-plate chondrogenesis through opposing actions on FGF pathways.

Bone morphogenetic protein (BMP) signaling pathways are essential regulators of chondrogenesis. However, the roles of these pathways in vivo are not well understood. Limb-culture studies have provided a number of essential insights, including the demonstration that BMP pathways are required for chondrocyte proliferation and differentiation. However, limb-culture studies have yielded contradictory results; some studies indicate that BMPs exert stimulatory effects on differentiation, whereas others support inhibitory effects. Therefore, we characterized the skeletal phenotypes of mice lacking Bmpr1a in chondrocytes (Bmpr1a(CKO)) and Bmpr1a(CKO);Bmpr1b+/- (Bmpr1a(CKO);1b+/-) in order to test the roles of BMP pathways in the growth plate in vivo. These mice reveal requirements for BMP signaling in multiple aspects of chondrogenesis. They also demonstrate that the balance between signaling outputs from BMP and fibroblast growth factor (FGF) pathways plays a crucial role in the growth plate. These studies indicate that BMP signaling is required to promote Ihh expression, and to inhibit activation of STAT and ERK1/2 MAPK, key effectors of FGF signaling. BMP pathways inhibit FGF signaling, at least in part, by inhibiting the expression of FGFR1. These results provide a genetic in vivo demonstration that the progression of chondrocytes through the growth plate is controlled by antagonistic BMP and FGF signaling pathways.

Bmpr1a and Bmpr1b have overlapping functions and are essential for chondrogenesis in vivo.

Previous studies have demonstrated the ability of bone morphogenetic proteins (BMPs) to promote chondrogenic differentiation in vitro. However, the in vivo role of BMP signaling during chondrogenesis has been unclear. We report here that BMP signaling is essential for multiple aspects of early chondrogenesis. Whereas mice deficient in type 1 receptors Bmpr1a or Bmpr1b in cartilage are able to form intact cartilaginous elements, double mutants develop a severe generalized chondrodysplasia. The majority of skeletal elements that form through endochondral ossification are absent, and the ones that form are rudimentary. The few cartilage condensations that form in double mutants are delayed in the prechondrocytic state and never form an organized growth plate. The reduced size of mutant condensations results from increased apoptosis and decreased proliferation. Moreover, the expression of cartilage-specific extracellular matrix proteins is severely reduced in mutant elements. We demonstrate that this defect in chondrocytic differentiation can be attributed to lack of Sox9, L-Sox5, and Sox6 expression in precartilaginous condensations in double mutants. In summary, our study demonstrates that BMPR1A and BMPR1B are functionally redundant during early chondrogenesis and that BMP signaling is required for chondrocyte proliferation, survival, and differentiation in vivo.