Background: Severe acute malnutrition (SAM) is currently defined by the WHO as either a low mid-upper arm circumference (i.e. MUAC <115 mm), a low weight-for-height z-score (i.e. WHZ <− 3), or bilateral pitting oedema. MUAC and WHZ do not always identify the same children as having SAM. This has generated broad debate, as illustrated by the recent article by Grellety & Golden (BMC Nutr. 2016;2:10). Discussion: Regional variations in the proportion of children selected by each index seem mostly related to differences in body shape, including stuntedness. However, the practical implications of these variations in relation to nutritional status and also to outcome are not clear. All studies that have examined the relationship between anthropometry and mortality in representative population samples in Africa and in Asia have consistently showed that MUAC is more sensitive at high specificity levels than WHZ for identifying children at high risk of death. Children identified as SAM cases by low MUAC gain both weight and MUAC in response to treatment. The widespread use of MUAC has brought enormous benefits in terms of the coverage and efficiency of programs. As a large high-risk group responding to treatment, children with low MUAC should be regarded as a public health priority independently of their WHZ. Conclusion: While a better understanding of the mechanism behind the discrepancy between MUAC and WHZ is desirable, research in this area should not delay the implementation of programs aiming at effectively reducing malnutrition-related deaths by prioritising the detection and treatment of children with low MUAC.

Plasminogen activator inhibitor-1 (PAI-1)-deficient transgenic mice have improved survival and less fibrosis after intratracheal bleomycin instillation. We hypothesize that PAI-1 deficiency limits scarring through unopposed plasminogen activation. If this is indeed true, then we would expect increased urokinase-type plasminogen activator (uPA) expression to result in a similar reduction in scarring and improvement in mortality. To test our hypothesis, using the tetracycline gene regulatory system, we have generated a transgenic mouse model with the features of inducible, lung-specific uPA production. After doxycycline administration, these transgenic animals expressed increased levels of uPA in their bronchoalveolar lavage (BAL) fluid that accelerated intrapulmonary fibrin clearance. Importantly, this increased plasminogen activator production led to a reduction in both lung collagen accumulation and mortality after bleomycin-induced injury. These results suggest that PAI-1 deficiency does protect against the effects of bleomycin-induced lung injury through unopposed plasmin generation. By allowing the manipulation of plasminogen activation at different phases of the fibrotic process, this model will serve as a powerful tool in further investigations into the pathogenesis of pulmonary fibrosis.

The doxycycline-inducible, gene regulatory system allows tight control of transgene expression for the study of organ development and disease pathogenesis. Multiple recent reports have employed this model to investigate various lung diseases including emphysema. For our study, we used this transgenic system to test whether prolonged, lung-specific, overexpression of the serine protease urokinase plasminogen activator (uPA) would result in alveolar wall destruction. Double transgenic mice were generated that possessed: (1) the rat Clara cell secretory protein promoter controlling the reverse tetracycline transactivator gene (CCSP:rtTA) and (2) the tetracycline operator controlling the murine uPA cDNA (tet[O]:muPA). Mice were treated with doxycycline beginning at age 6 wk to initiate uPA overexpression. Single transgenic and wild-type animals served as controls. A second group of double transgenic and control animals were maintained off of doxycycline. At ages 10, 18, and 30 wk, the mice underwent measurements of alveolar size, lung compliance, and total lung capacity. We found that, although the uPA overexpressing mice demonstrated an emphysema phenotype, similar abnormalities occurred in the CCSP-rtTA control animals. These CCSP-rtTA-related alterations occurred even without doxycycline exposure. Evaluation of a second transgenic line possessing the human surfactant protein C promoter controlling rtTA expression also exhibited lung abnormalities consistent with emphysema. These findings indicate that pulmonary epithelial expression of rtTA alone causes an emphysema phenotype in mice. Therefore, when using this system to study emphysema pathogenesis, the inclusion of proper controls is essential for accurate data interpretation.

The pathogenesis of pulmonary fibrosis is thought to involve alveolar epithelial injury that, when successfully repaired, can limit subsequent scarring. The plasminogen system participates in this process with the balance between urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor-1 (PAI-1) being a critical determinant of the extent of collagen accumulation that follows lung injury. Because the plasminogen system is known to influence the rate of migration of epithelial cells, including keratinocytes and bronchial epithelial cells, we hypothesized that the balance of uPA and PAI-1 would affect the efficiency of alveolar epithelial cell (AEC) wound repair. Using an in vitro model of AEC wounding, we show that the efficiency of repair is adversely affected by a deficiency in uPA or by the exogenous administration of PAI-1. By using PAI-1 variants and AEC from mice transgenically deficient in vitronectin (Vn), we demonstrate that the PAI-1 effect requires its Vn-binding activity. Furthermore, we have found that cell motility is enhanced by the availability of Vn in the matrix and that the AEC-Vn interaction is mediated, in part, by the alpha(v)beta(1) integrin. The significant effect of uPA and PAI-1 on epithelial repair suggests a mechanism by which the plasminogen system may modulate pulmonary fibrosis.