Skeletal muscle fat quantification by dual-energy computed tomography in comparison with 3T MR imaging.

OBJECTIVES: To quantify the proportion of fat within the skeletal muscle as a measure of muscle quality using dual-energy CT (DECT) and to validate this methodology with MRI. METHODS: Twenty-one patients with abdominal contrast-enhanced DECT scans (100 kV/Sn 150 kV) underwent abdominal 3-T MRI. The fat fraction (DECT-FF), determined by material decomposition, and HU values on virtual non-contrast-enhanced (VNC) DECT images were measured in 126 regions of interest (≥ 6 cm2) within the posterior paraspinal muscle. For validation, the MR-based fat fraction (MR-FF) was assessed by chemical shift relaxometry. Patients were categorized into groups of high or low skeletal muscle mean radiation attenuation (SMRA) and classified as either sarcopenic or non-sarcopenic, according to the skeletal muscle index (SMI) and cut-off values from non-contrast-enhanced single-energy CT. Spearman's and intraclass correlation, Bland-Altman analysis, and mixed linear models were employed. RESULTS: The correlation was excellent between DECT-FF and MR-FF (r = 0.91), DECT VNC HU and MR-FF (r = - 0.90), and DECT-FF and DECT VNC HU (r = - 0.98). Intraclass correlation between DECT-FF and MR-FF was good (r = 0.83 [95% CI 0.71-0.90]), with a mean difference of - 0.15% (SD 3.32 [95% CI 6.35 to - 6.66]). Categorization using the SMRA yielded an eightfold difference in DECT VNC HU values between both groups (5 HU [95% CI 23-11], 42 HU [95% CI 33-56], p = 0.05). No significant relationship between DECT-FF and SMI-based classifications was observed. CONCLUSIONS: Fat quantification within the skeletal muscle using DECT is both feasible and reliable. DECT muscle analysis offers a new approach to determine muscle quality, which is important for the diagnosis and therapeutic monitoring of sarcopenia, as a comorbidity associated with poor clinical outcome. KEY POINTS: • Dual-energy CT (DECT) material decomposition and virtual non-contrast-enhanced DECT HU values assess muscle fat reliably. • Virtual non-contrast-enhanced dual-energy CT HU values allow to differentiate between high and low native skeletal muscle mean radiation attenuation in contrast-enhanced DECT scans. • Measuring muscle fat by dual-energy computed tomography is a new approach for the determination of muscle quality, an important parameter for the diagnostic confirmation of sarcopenia as a comorbidity associated with poor clinical outcome.

Morbidity and mortality of candidaemia in Europe: an epidemiologic meta-analysis.

OBJECTIVES: Candidaemia is a serious hazard to hospitalized patients, but European epidemiological data are restricted to national studies focusing on Northern Europe, population-based surveillance programmes or studies conducted in distinct local areas. The aim was to provide current data on the overall burden and epidemiological development of candidaemia in Europe. METHODS: A Web of Knowledge™ search was carried out from January 2000 to February 2019. Appropriate data were collected on total cases, study duration, incidence, species distribution and/or mortality rates. Meta-analysis was performed to pool individual studies. Heterogeneity was examined using the I2 statistic. Calculations of pooled incidence and mortality rates, subgroup analysis by geographical origin, study period and scenarios were carried out. Daily candidaemia incidence and mortality rates in Europe were extrapolated. Systematic review and meta-analysis were used to determine incidence and mortality of candidaemia in the UN European region. Complete datasets were categorized into population-based and hospital-based epidemiological studies and were analysed separately. Subgroup analyses were performed for geographic distributions and time-dependent developments. RESULTS: In population-based studies, 43 799 cases of candidaemia were diagnosed in 1 885 271 885 person-years, revealing an overall pooled incidence rate of 3.88/100 000. The highest pooled incidence rate was observed in intensive care units (5.5/1000 admissions, Day 30 mortality rate 37%), followed by tertiary care centres (0.96/1000 admissions, pooled Day 30 mortality rate 38%) and the mixed group of teaching and general hospitals (0.52/1000 admissions, pooled Day 30 mortality rate 37%). European incidence of candidaemia was extrapolated to approximately 79 cases per day, of which an estimated 29 patients might have fatal outcome at Day 30. CONCLUSIONS: Pooled incidence rates, species distribution and outcome of candidaemia differ considerably between clinical groups, European regions and over time. We observed an increasing overall pooled incidence rate of candidaemia and a higher proportion of Candida spp. other than C. albicans in the current decade in population-based data.

Factors contributing to patient safety incidents in primary care: a descriptive analysis of patient safety incidents in a French study using CADYA (categorization of errors in primary care).

BACKGROUND: Patient safety incidents (PSIs) frequently occur in primary care and are often considered to be preventable. Better knowledge of factors contributing to PSIs is required to build safer care. The aim of this work was to describe the underlying factors, specifically the human factors, that are associated with PSIs in primary care using CADYA ("CAtégorisation des DYsfonctionnements en Ambulatoire" or "Categorization of Errors in Primary Care"). METHODS: We followed a mixed method with content analysis and coding in CADYA of PSIs reported in the ESPRIT study, a French cross-sectional survey of primary care. For each incident, a main contributing factor (MD) and, if applicable, a secondary contributing factor (SD) were identified. Several descriptive keywords from an incremental glossary have been suggested to describe each identified human factor (attitudes or behaviours). A descriptive statistical analysis was then conducted. RESULTS: Among the 482 PSIs reported in the ESPRIT study, from 13,438 acts reported by 127 participating general practitioners (GPs), we identified 590 contributing factors (482 MDs and 178 SDs). Overall, 35% were related to the care process, 30% to human factors, 22% to the healthcare environment and 13% to technical factors. The contributing factors, in decreasing order of frequency, were communication errors (13.7%), human factors related to healthcare providers (12.9%) and human factors related to patients (12.9%). The human factors were mainly related to 'lack of attention', 'stress', 'anger' and 'fatigue'. CONCLUSIONS: Our results tend to prove that human factors are often involved in PSIs in primary care, with GPs and patients being equally responsible. Beyond the identification of communication errors, often found in other international research, we have described the attitudes and behaviours contributing to unsafe care. Further research exploring the links between working conditions and human factors is required.

Developmental validation of the PowerPlex® Y23 System: a single multiplex Y-STR analysis system for casework and database samples.

The PowerPlex® Y23 System combines the seventeen Y-STR loci in current commercially available Y-STR kits (DYS19, DYS385a/b, DYS389I/II, DYS390, DYS391, DYS392, DYS393, DYS437, DYS438, DYS439, DYS448, DYS456, DYS458, DYS635, and Y-GATA-H4) with six new highly discriminating Y-STR loci (DYS481, DYS533, DYS549, DYS570, DYS576, and DYS643). These six new loci have higher gene diversities than most of the loci in other commercial Y-STR analysis kits, allowing for further distinction between unrelated male individuals. In addition, the inclusion of two rapidly mutating Y-STR loci may allow for the discrimination of related individuals. The PowerPlex® Y23 System is designed to amplify DNA from purified extracts as well as direct amplification from substrates used to collect database samples (e.g. swabs and storage cards). Validation of the PowerPlex® Y23 System includes all of the studies required by the FBI and SWGDAM. The results demonstrate that the PowerPlex® Y23 System is a robust and reliable amplification kit capable of overcoming high concentrations of commonly encountered inhibitors such as hematin, humic acid, and tannic acid. Full profiles are consistently detected with 62.5 pg of male DNA, even in the presence of excessive amounts of female DNA, establishing the PowerPlex(®) Y23 System as a sensitive method for Y-STR testing. Complete Y-STR profiles are detected from mixed samples with 62.5 pg of male DNA in a background of 400 ng of female DNA or 125 pg of male DNA mixed with 3000 ng of female DNA.

Readministration of helper-dependent adenovirus to mouse lung.

Adenovirus vectors (Ad) are widely used in gene therapy studies, including those aimed at treating cystic fibrosis lung disease. Various approaches have been investigated to blunt the host immune response to Ad, including development of helper-dependent (HD) Ad. The host cytotoxic T-cell response to HD-Ad is generally lower than to earlier-generation Ad. However, antibodies are formed which could inhibit the efficacy of HD-Ad readministration. In this first study of HD-Ad readministration to the lung, we found that a second administration of HD-Ad to mice was possible with minimal loss of transgene expression. In contrast, when first-generation (FG) Ad was administered initially, followed by HD-Ad or FG-Ad, transgene expression was reduced. Significantly lower concentrations of antibodies against Ad were found in lung lavage fluid and serum from mice that received two doses of HD-Ad (when the initial HD-Ad lacked a transgene), compared to mice that received FG-Ad followed by HD-Ad. These data suggest that readministration of HD-Ad for lung gene therapy may be feasible.

Gene delivery to human sweat glands: a model for cystic fibrosis gene therapy.

Gene therapy vectors are mostly studied in cultured cells, rodents, and sometimes in non-human primates, but it is useful to test them in human tissue prior to clinical trials. In this study, we investigated the possibility of using human sweat glands as a model for testing cystic fibrosis (CF) gene therapy vectors. Human sweat glands are relatively easy to obtain from skin biopsy, and can be tested for CFTR function. Using patients' sweat glands could provide a safe model to study the efficacy of CF gene therapy. As the first step to explore using sweat glands as a model for CF gene therapy, we examined various ex vivo gene delivery methods for a helper-dependent adenovirus (HD-Ad) vector. Gene delivery to sweat glands in skin organ culture was studied by topical application, intradermal injection or submerged culture. We found that transduction efficiency can be enhanced by pretreating isolated sweat glands with dispase, which suggests that the basement membrane is a critical barrier to gene delivery by adenoviral vectors. Using this approach, we showed that Cftr could be efficiently delivered to and expressed by the epithelial cells of sweat glands with our helper-dependent adenoviral vector containing cytokeratin 18 regulatory elements. Based on this study we propose that sweat glands might be used as an alternative model to study CF gene therapy in humans.

Low incidence of paradoxical bronchoconstriction with bronchodilator drugs administered by Respimat Soft Mist inhaler: results of phase II single-dose crossover studies.

BACKGROUND AND OBJECTIVES: Respimat Soft Mist Inhaler (SMI) is an innovative device that offers improved lung deposition and is an environmentally friendly alternative to conventional, chlorofluorocarbon-containing metered-dose inhalers (CFC-MDIs). The aqueous formulations of bronchodilator drugs administered from Respimat SMI contain low concentrations of ethylene diamine tetra-acetic acid (EDTA), a stabilising agent, and benzalkonium chloride (BAC), an antibacterial agent, both of which have been associated with bronchoconstriction when administered via nebulisers. The aim of this retrospective analysis was to compare the incidence of paradoxical bronchoconstriction with bronchodilator drugs administered via Respimat SMI or a CFC-MDI in patients with asthma or chronic obstructive pulmonary disease (COPD). METHODS: Nine randomised, active- and/or placebo-controlled, double-blind, crossover studies, in which asthmatic and COPD patients (n = 444 and n = 216, respectively) received a beta(2)-agonist and/or anticholinergic or placebo via Respimat SMI or CFC-MDI, were included in the analysis. The incidence of conditions indicative of paradoxical bronchoconstriction were collated and divided into four categories: (1) 'bronchospasm'; (2) two or more of the following events: 'other respiratory adverse events', 'rescue medication use' or 'asymptomatic drop in forced expiratory volume in one second' (FEV(1)); (3) either 'rescue medication use' or 'other respiratory adverse event'; (4) 'asymptomatic drop in FEV(1)'. RESULTS: The incidence of adverse events indicative of paradoxical bronchoconstriction was low in those patients using the Respimat SMI device, and similar to that seen in the CFC-MDI group. In addition, the incidence of adverse events indicative of paradoxical bronchoconstriction observed in the Respimat SMI group was similar for BAC + EDTA and BAC-only drug formulations. CONCLUSIONS: These studies demonstrate that, due to the extremely low absolute amounts of BAC and EDTA delivered to the lungs by the device, Respimat SMI is safe with regard to paradoxical bronchoconstriction in patients with asthma or COPD.

Impact of energy intake and pregnancy status on rate and efficiency of gain and backfat changes of sows postweaning.

A collaborative study was conducted to evaluate factors related to determining optimal feeding and management programs for increasing net returns from marketing cull sows. A total of 269 multiparous sows averaging 192 kg of body weight were weaned, moved to individual gestation crates, and assigned to one of eight treatment combinations in a 2 x 2 x 2 factorial arrangement for a 42-d postweaning feeding experiment. Factors included limited (L) (1.8 kg/sow/d) or ad libitum (AL) access to feed during wk 1 postweaning, a corn-soybean meal (corn) or barley-sunflower meal (barley) diet, and pregnant or nonpregnant status. All sows were provided ad libitum access to feed from wk 2 to 6 postweaning. Gain and feed intake (FI) data were collected weekly for each sow and used to calculate gain:feed (G/F). Ultrasonic backfat (BF) data were collected on d 0, 21, and 42 postweaning. Sows on the AL treatment had greater FI (P < 0.05) but similar gain (P = 0.80) for the 42-d postweaning period compared to sows on the L treatment. Most of this response was due to lower sow body weight loss during wk 1 postweaning (P < 0.01) when sows were provided AL (-7.2 kg) vs L (-13.2 kg) access to feed. Sows fed the corn diet had higher gain (P < 0.01), improved G/F (P < 0.01), and increased BF (P < 0.01) over the 42-d feeding period than sows fed barley. The corn diet resulted in less sow BW loss (P < 0.01) during wk 1 (-8.8 kg) than the barley diet (-11.6 kg). Pregnant sows had higher gain, FI, G/ F, and BF (P < 0.01) than nonpregnant sows over the 42-d feeding period. Most of this advantage occurred during wk 4 postweaning when FI and gain of nonpregnant sows was lower (P < 0.01) than for pregnant sows. An economic analysis indicated that, when cull sow prices are relatively high and feed prices are moderate to low, maintaining and managing cull sows for an additional 6 wk postweaning may be economically advantageous compared to 0 or 3 wk. Pregnant sows fed the corn diet produced the greatest economic return. These results suggest that mating sows as they return to estrus postweaning and providing ad libitum access to a corn-soybean meal diet improves growth performance and feed efficiency, and may thereby provide increased returns when marketing cull sows.

[Validity of nonspecific bronchial provocation tests for the diagnosis of airway hyperresponsiveness--a comparison of different methods]. / Validität inhalativer Provokationstests zur Bestimmung der unspezifischen bronchialen Reaktivität - Vergleich verschiedener Methoden.

OBJECTIVE: To compare the validity of different methods for the assessment of bronchial hyperresponsiveness used by different centers. METHODS: Case series of 648 subjects referred to six pulmonary centers, all with a history of shortness of breath without airway obstruction, without use of medication that might influence the tests and without viral infections during the previous two weeks. All subjects answered a questionnaire of recent symptoms and underwent bronchial challenge with a chemical stimulus according to each center's protocol. Analysis was performed by receiver operating characteristic (ROC) plots using the questionnaire's answers as the gold standard. Diagnostic test sensitivities at the cut-offs for bronchial hyperresponsiveness indicated by each center were compared. RESULTS: ROC plots showed poor validity of all tests, i.e. both acceptable sensitivity and specificity were not observed with any test. There was no obvious difference of the slope of the ROC plots between the different centers. However, maximal sensitivity differed considerably: for "wheeze during the previous 12 months", sensitivity at each center's cut-off for the definition of bronchial hyperresponsiveness varied between 0.35 and 0.73. The choice of the question used as the standard had little influence on test validity. CONCLUSION: Although some of the differences between centers may be explained by subject characteristics, the large differences of the test sensitivities are unacceptable and underscore the need for standardization of these tests, primarily with respect to sufficient sensitivity.

Challenges and strategies for cystic fibrosis lung gene therapy.

Gene replacement therapy represents an interesting new approach for the treatment of cystic fibrosis (CF) lung disease. Basic research suggests that CF gene therapy is feasible, but major technological challenges must be addressed before clinical applications are likely to succeed. Therapeutic genes can be delivered to and expressed in human airways, but the number of cells expressing the transgene is relatively low. The inefficiency of gene delivery is largely attributable to the remarkable defenses of human airways. Maintaining long-term transgene expression in airway cells is also a significant obstacle. Recent advances have been made in the development of vectors, expression cassettes, and delivery techniques for enhancing airway gene transfer and expression. These advances have the potential to improve the efficiency of lung gene therapy and to achieve clinical benefits for CF patients in the future.

Targeting transgene expression for cystic fibrosis gene therapy.

We have developed an expression cassette for cystic fibrosis (CF) gene therapy using control elements from the human cytokeratin 18 gene (KRT18, also known as K18). KRT18 is naturally expressed in a spatial pattern similar to that of CFTR, the gene mutated in CF. We delivered a KRT18-driven lacZ plasmid complexed with cationic liposomes intravenously to mice and examined expression in various tissues. We found expression in nasal and bronchial epithelium, airway submucosal glands, gall bladder, and kidneys. Expression was low in pancreas and gut, and absent from liver and alveolar lung. This is consistent with the expression pattern reported for a K18lacZ transgenic mouse. Following delivery of a cytomegalovirus (CMV) major immediate-early promoter/enhancer-driven lacZ plasmid, we found expression in bronchi, submucosal glands, alveolar cells, liver, and kidney. We did not detect expression in nose, pancreas, gall bladder, or gut. Using fluorescently labeled plasmid delivered by means of liposomes, we identified the liver, alveolar lung, and kidneys as the major plasmid deposition sites. Our data demonstrate that a KRT18-driven expression vector delivered systemically can target gene expression to CF-affected tissues, despite an uneven distribution of plasmid DNA. A KRT18-based vector may be a useful alternative to viral promoter-based vectors in clinical gene therapy trials to treat CF.

People focus on optimistic scenarios and disregard pessimistic scenarios while predicting task completion times.

Task completion plans normally resemble best-case scenarios and yield overly optimistic predictions of completion times. The authors induced participants to generate more pessimistic scenarios and examined completion predictions. Participants described a pessimistic scenario of task completion either alone or with an optimistic scenario. Pessimistic scenarios did not affect predictions or accuracy and were consistently rated less plausible than optimistic scenarios (Experiments 1-3). Experiment 4 independently manipulated scenario plausibility and optimism. Plausibility moderated the impact of optimistic, but not pessimistic, scenarios. Experiment 5 supported a motivational explanation of the tendency to disregard pessimistic scenarios regardless of their plausibility. People took pessimistic scenarios into account when predicting someone else's completion times. The authors conclude that pessimistic-scenario generation may not be an effective debiasing technique for personal predictions.

A human epithelium-specific vector optimized in rat pneumocytes for lung gene therapy.

Gene therapy vectors based on mammalian promoters offer the potential for increased cell specificity and may be less susceptible than viral promoters to transcription attenuation by host cytokines. The human cytokeratin 18 (K18) gene is naturally expressed in the lung epithelia, a target site for gene therapies to treat certain genetic pediatric lung diseases. Our original vector based on the promoter and 5' control elements of K18 offered excellent epithelial cell specificity but relatively low expression levels compared with viral promoters. In the present study, we found that adding a stronger SV40 poly(A) signal boosted primary rat lung epithelial cell expression but greatly reduced cell specificity. Addition of a 3' portion of the K18 gene to our vector as a 3' untranslated region (UTR) improved epithelial cell-specific expression by reducing expression in lung fibroblasts. The effect of the 3' UTR was not related to gross differences in cell-specific splicing. A deletion variant of this UTR further increased lung epithelial cell expression while retaining some cell specificity. These data illustrate the possibilities for using 3' UTR to regulate cell-specific transgene expression. Our improved K18 vector should prove useful for pediatric lung gene therapy applications.

Superior single dimension relative to "exclusive or" categorization performance by a patient with category-specific visual agnosia: empirical data and an ALCOVE simulation.

ELM, a patient with category-specific visual agnosia, was tested on a single-dimension categorization problem, and the "exclusive or" (XOR) categorization problem. Stimuli were computer-generated shapes in which exemplars within a shape set shared values across two visual dimensions (curvature and thickness). In single-dimension categorization only curvature was relevant, and ELM performed as well as normal participants. In the XOR problem, categorization depended on being able to extract from memory values on curvature AND thickness for each exemplar, and ELM was significantly impaired on this task. A computer simulation using ALCOVE (Kruschke, 1992) reproduced ELM's behavior by changing a single (specificity) parameter related to how easily proximate objects within a multidimensional shape space could be disambiguated.

A novel karyopherin-beta homolog is developmentally and hormonally regulated in fetal lung.

To investigate molecular mechanisms of lung organogenesis, we used representational difference analysis to search for glucocorticoid-inducible genes in developing lung in a fetal rat model. Messenger RNA prepared from fetal and adult rat lung was used to prepare "representative amplicons." Adult-lung complementary DNA (cDNA) amplicons were used as "driver" in successive rounds of subtractive hybridization/amplification to isolate target fetal lung-specific cDNAs. A single clone, which was conserved and had near-perfect homology to eight human/rodent expressed sequence tags, was used as template for 5' and 3' rapid amplification of cDNA ends and SPICE (system for polymerase chain reaction amplification of cDNA ends) reactions to obtain the 3.6-kb cDNA, LGL2 (Genbank, AF 110195) encoding a deduced polypeptide (lgl2) of 963 amino acids. Northern analysis confirmed that LGL2 is differentially expressed in fetal lung (maximal during the pseudoglandular stage, gestational Days 14 to 16), induced by glucocorticoid, and enriched in epithelium relative to the mesenchyme. LGL2 was also detected in human fetal lung at gestational Week 16 as well as in human and rat fetal brain, heart, intestine, and kidney. We mapped LGL2 to chromosome 1p33-34.2. Comparison with sequences in the genome database identified lgl2 as a member of the karyopherin-beta family of nuclear import proteins, with greatest homology to transportin SR. Maximal expression of LGL2 in the pseudoglandular stage of development is coordinate with that of key transcription factors that regulate prominent signal transduction pathways in fetal lung organogenesis. We propose a role for lgl2 in nuclear import of transcription factors that regulate signal transduction during fetal lung development.

Probability judgment in three-category classification learning.

People give subadditive probability judgments--in violation of probability theory--when asked to assess each in a set of 3 or more mutually exclusive hypotheses, as indicated by their sum exceeding 1. Three potential evidential influences on subadditivity--cue conflict, cue frequency, and cue redundancy--are distinguished and tested in 5 experiments using a classification-learning task. Results indicate that (a) judgments of probability and of frequency are systematically subadditive even when the judgments are based on cues learned within the experimental context, (b) cue conflict has a reliable influence on the degree of subadditivity, and (c) judgments in this context are well described by a linear-discounting model within the framework of support theory.

Illusory correlations in graphological inference.

The authors investigate the illusory correlation phenomenon as a possible contributor to the persistence of graphology's use to predict personality. Participants unfamiliar with graphology inspected handwriting samples paired with fabricated personality profiles. In Experiment 1, handwriting samples and personality profiles were randomly paired. In Experiment 2, discernible correlations near unity were set between targeted handwriting-feature-personality-trait pairs in a congruent or incongruent direction with graphologists' claims. In both experiments, participants' judgments of the correlation between designated handwriting-feature-personality-trait pairs agreed with graphologists' claims, even after controlling for their actual statistical association. Semantic association between words used to describe handwriting features and personality traits was the source of biases in perceived correlation. Results may partially account for continued use of graphology despite overwhelming evidence against its predictive validity.

A novel developmentally regulated gene in lung mesenchyme: homology to a tumor-derived trypsin inhibitor.

We used differential display-PCR (DD-PCR) to identify glucocorticoid-inducible genes that regulate lung development in late gestation. DD-PCR, a method to screen for differentially expressed genes, is based on a comparison of mRNAs isolated from a subset of two or more cell populations by analysis of RT-PCR products on DNA-sequencing gels. We isolated cDNA probes representing mRNAs expressed in primary cultures of rat lung fibroblasts, but not in epithelial cells, on fetal day 20. A day 20 glucocorticoid-treated fibroblast cDNA library was screened with a single probe to isolate the 3.1-kb cDNA late-gestation lung 1 (LGL1; GenBank accession no. AF109674) encoding a deduced polypeptide of 188 amino acids. Northern analysis confirmed that LGL1 is expressed in human, rat, and mouse fetal lungs, induced by glucocorticoid, developmentally regulated in fibroblasts but not detectable in epithelium. In situ hybridization confirmed LGL1 expression in the mesenchyme, but not in the epithelium, of fetal rat lung, kidney, and gut. The predicted LGL1 gene product (lgl1) showed 81% homology to P25TI, a polypeptide trypsin inhibitor recently identified in human glioblastoma and neuroblastoma cells but not detected in normal human tissues. Both lgl1 and P25TI belong to the CRISP family of cysteine-rich extracellular proteins. Trypsin is produced by both normal bronchial epithelial and lung adenocarcinoma cells. Although additional studies will be necessary to clearly establish a functional role for lgl1, we propose that lgl1 has a role in normal lung development that is likely to be via regulation of extracellular matrix degradation.