Keutel Syndrome, a review of 50 years of literature

Keutel syndrome (KS) is a rare autosomal recessive genetic disorder that was first identified in the beginning of the 1970s and nearly 30 years later attributed to loss-of-function mutations in the gene coding for the matrix Gla protein (MGP). Patients with KS are usually diagnosed during childhood (early onset of the disease), and the major traits include abnormal calcification of cartilaginous tissues resulting in or associated with malformations of skeletal tissues (e.g., midface hypoplasia and brachytelephalangism) and cardiovascular defects (e.g., congenital heart defect, peripheral pulmonary artery stenosis, and, in some cases, arterial calcification), and also hearing loss and mild developmental delay. While studies on Mgp-/- mouse, a faithful model of KS, show that pathologic mineral deposition (ectopic calcification) in cartilaginous and vascular tissues is the primary cause underlying many of these abnormalities, the mechanisms explaining how MGP prevents abnormal calcification remain poorly understood. This has negative implication for the development of a cure for KS. Indeed, at present, only symptomatic treatments are available to treat hypertension and respiratory complications occurring in the KS patients. In this review, we summarize the results published in the last 50 years on Keutel syndrome and present the current status of the knowledge on this rare pathology.CA-16115 - EJPRD2019-290 - UIDB/04326/2020info:eu-repo/semantics/publishedVersio

Statistical Learning Methods to Predict Activity Intensity from Body-Worn Accelerometers

 Physical activity, especially when performed at moderate or vigorous intensity, has short- and long-term health benefits, but measurement of free-living physical activity is challenging. Accelerometers are popular tools to assess physical activity, although accuracy of conventional accelerometer analysis methods is suboptimal. This study developed and tested statistical learning models for assessing activity intensity from body-worn accelerometers. Twenty-eight adults performed 10-21 activities of daily living in two visits while wearing four accelerometers (right hip, right ankle, both wrists). Accelerometer placement is of crucial practical concern and this paper addresses this issue. Boosting, bagging, random forest and decision tree models were created for each accelerometer and for two-, three-, and four-accelerometer combinations to predict activity intensity. Research staff observations of activity intensity served as the criterion. Point estimates of error for the ankle accelerometer were 2.2-4.7 percentage points lower than other single-accelerometer placements, and the left wrist-ankle combination had errors 0.8-5.8 percentage points lower than other two-accelerometer combinations. Decision trees had poorer accuracy than the other models. Using an accelerometer worn on the lower limb, by itself or in combination with an upper-limb accelerometer, appears to offer optimal accuracy for activity intensity measurement

Matrix Gla protein deficiency impairs nasal septum growth, causing midface hypoplasia

Genetic and environmental factors may lead to abnormal growth of the orofacial skeleton, affecting the overall structure of the face. In this study, we investigated the craniofacial abnormalities in a mouse model for Keutel syndrome, a rare genetic disease caused by loss-of-function mutations in the matrix Gla protein (MGP) gene. Keutel syndrome patients show diffuse ectopic calcification of cartilaginous tissues and impaired midface development. Our comparative cephalometric analyses of micro-computed tomography images revealed a severe midface hypoplasia in Mgp-/- mice. In vivo reporter studies demonstrated that the Mgp promoter is highly active at the cranial sutures, cranial base synchondroses, and nasal septum. Interestingly, the cranial sutures of the mutant mice showed normal anatomical features. Although we observed a mild increase in mineralization of the spheno-occipital synchondrosis, it did not reduce the relative length of the cranial base in comparison with total skull length. Contrary to this, we found the nasal septum to be abnormally mineralized and shortened in Mgp-/- mice. Transgenic restoration of Mgp expression in chondrocytes fully corrected the craniofacial anomalies caused by MGP deficiency, suggesting a local role for MGP in the developing nasal septum. Although there was no up-regulation of markers for hypertrophic chondrocytes, a TUNEL assay showed a marked increase in apoptotic chondrocytes in the calcified nasal septum. Transmission electron microscopy confirmed unusual mineral deposits in the septal extracellular matrix of the mutant mice. Of note, the systemic reduction of the inorganic phosphate level was sufficient to prevent abnormal mineralization of the nasal septum in Mgp-/-;Hyp compound mutants. Our work provides evidence that modulation of local and systemic factors regulating extracellular matrix mineralization can be possible therapeutic strategies to prevent ectopic cartilage calcification and some forms of congenital craniofacial anomalies in humans

A cell-autonomous requirement for neutral sphingomyelinase 2 in bone mineralization

nSMase2, which cleaves sphingomyelin to generate bioactive lipids, is required for chondrocyte apoptosis and, cell autonomously, for bone mineralization

Time to discover and fix software vulnerabilities in open source software projects: Notes on measurement and data availability

Reducing the time taken to discover and fix vulnerabilities in open source software projects is increasingly relevant to technology entrepreneurs and technology managers at all levels of industry. Rigorous research requires access to valid and reliable data on when vulnerabilities were introduced, discovered, and closed. This article offers three contributions about measurement and data availability: (1) an approach to measuring the time to discover and time to fix vulnerabilities in open source software projects, (2) evidence that combining project release histories and metrics from two online databases can provide reliable proxy dates for vulnerability introduction and fix, but not discovery, and (3) possible technical and open collaboration solutions to the data availability limitations of current databases. These results were part of a larger mixed-method study on the relationship between open source project and community attributes and software vulnerabilities with a data set of 1268 vulnerabilities affecting the software produced by 60 open source projects