Osteopetrosis is a genetic condition of increased bone mass, which is caused by defects in osteoclast formation and function. Both autosomal recessive and autosomal dominant forms exist, but this Review focuses on autosomal recessive osteopetrosis (ARO), also known as malignant infantile osteopetrosis. The genetic basis of this disease is now largely uncovered: mutations in TCIRG1, CLCN7, OSTM1, SNX10 and PLEKHM1 lead to osteoclast-rich ARO (in which osteoclasts are abundant but have severely impaired resorptive function), whereas mutations in TNFSF11 and TNFRSF11A lead to osteoclast-poor ARO. In osteoclast-rich ARO, impaired endosomal and lysosomal vesicle trafficking results in defective osteoclast ruffled-border formation and, hence, the inability to resorb bone and mineralized cartilage. ARO presents soon after birth and can be fatal if left untreated. However, the disease is heterogeneous in clinical presentation and often misdiagnosed. This article describes the genetics of ARO and discusses the diagnostic role of next-generation sequencing methods. The management of affected patients, including guidelines for the indication of haematopoietic stem cell transplantation (which can provide a cure for many types of ARO), are outlined. Finally, novel treatments, including preclinical data on in utero stem cell treatment, RANKL replacement therapy and denosumab therapy for hypercalcaemia are also discussed.

Osteopetrosis: genetics, treatment and new insights into osteoclast function

Detecting outliers is a significant problem that has been studied in various research and application areas. Researchers continue to design robust schemes to provide solutions to detect outliers efficiently. In this survey, we present a comprehensive and organized review of the progress of outlier detection methods from 2000 to 2019. First, we offer the fundamental concepts of outlier detection and then categorize them into different techniques from diverse outlier detection techniques, such as distance-, clustering-, density-, ensemble-, and learning-based methods. In each category, we introduce some state-of-the-art outlier detection methods and further discuss them in detail in terms of their performance. Second, we delineate their pros, cons, and challenges to provide researchers with a concise overview of each technique and recommend solutions and possible research directions. This paper gives current progress of outlier detection techniques and provides a better understanding of the different outlier detection methods. The open research issues and challenges at the end will provide researchers with a clear path for the future of outlier detection methods.

Progress in Outlier Detection Techniques: A Survey

Genetics, pathogenesis and complications of osteopetrosis.

The osteopetroses are caused by reduced activity of osteoclasts which results in defective remodelling of bone and increased bone density. They range from a devastating neurometabolic disease, through severe malignant infantile osteopetrosis (OP) to two more benign conditions principally affecting adults [autosomal dominant OP (ADO I and II)]. In many patients the disease is caused by defects in either the proton pump [the a3 subunit of vacuolar-type H(+)-ATPase, encoded by the gene variously termed ATP6i or TCIRG1] or the ClC-7 chloride channel (ClCN7 gene). These pumps are responsible for acidifying the bone surface beneath the osteoclast. Although generally thought of as bone diseases, the most serious consequences of the osteopetroses are seen in the nervous system. Cranial nerves, blood vessels and the spinal cord are compressed by either gradual occlusion or lack of growth of skull foramina. Most patients with OP have some degree of optic atrophy and many children with severe forms of autosomal recessive OP are rendered blind; optic decompression is frequently attempted to prevent the latter. Auditory, facial and trigeminal nerves may also be affected, and hydrocephalus can develop. Stenosis of both arterial supply (internal carotid and vertebral arteries) and venous drainage may occur. The least understood form of the disease is neuronopathic OP [OP and infantile neuroaxonal dystrophy, MIM (Mendelian inheritance in man) 600329] which causes rapid neurodegeneration and death within the first year. Although characterized by the finding of widespread axonal spheroids and accumulation of ceroid lipofuscin, the biochemical basis of this disease remains unknown. The neurological complications of this disease and other variants are presented in the context of the latest classification of the disease.

Neurological aspects of osteopetrosis

The osteopetroses are a heterogeneous group of bone remodeling disorders characterized by an increase in bone density due to a defect in osteoclastic bone resorption. In humans, several types can be distinguished and a classification has been made based on their mode of inheritance, age of onset, severity, and associated clinical symptoms. The best-known forms of osteopetrosis are the malignant and intermediate autosomal recessive forms and the milder autosomal dominant subtypes. In addition to these forms, a restricted number of cases have been reported in which additional clinical features unrelated to the increased bone mass occur. During the last years, molecular genetic studies have resulted in the identification of several disease-causing gene mutations. Thus far, all genes associated with a human osteopetrosis encode proteins that participate in the functioning of the differentiated osteoclast. This contributed substantially to the understanding of osteoclast functioning and the pathogenesis of the human osteopetroses and will provide deeper insights into the molecular pathways involved in other bone pathologies, including osteoporosis.

A clinical and molecular overview of the human osteopetroses.

Outlier detection approaches for wireless sensor networks

A severe form of autosomal recessive osteopetrosis associated with Dandy-Walker syndrome and agenesis of the corpus callosum is reported in a full-term boy born to consanguineous parents. The diagnosis was made shortly after birth. Clinical features were cranio-facial dysmorphy, macrocephaly, hepatosplenomegaly, severe anemia and thrombocytopenia. Skeletal radiographs revealed generalized increase in bone density and abnormal metaphyseal remodeling. Cranial ultrasonogram and computed tomography scan showed Dandy-Walker syndrome, agenesis of corpus callosum and hydrocephalus. The patient rapidly developed severe medullary deficiency and a severe pulmonary infection. He died at the age of 2 months. This association seems extremely rare and was not previously reported in the literature.

Association of severe autosomal recessive osteopetrosis and Dandy-Walker syndrome with agenesis of the corpus callosum.

Resume Objectifs Etudier les aspects epidemiologiques, cliniques, bacteriologiques et evolutifs des meningites bacteriennes neonatales et analyser les facteurs de mauvais pronostic de cette affection. Patients et methodes Analyse retrospective de 44 cas de meningite bacterienne neonatale observes dans un service de pediatrie entre janvier 1996 et decembre 2010. Ont ete inclus les nouveau-nes d’âge inferieur a 29 j, hospitalises pour une meningite bacterienne retenue sur la presence d’une bacterie dans le liquide cephalorachidien (LCR) ou une pleiocytose superieure a 50 elements blancs/mm3 avec une predominance des polynucleaires neutrophiles et une proteinorachie superieure a 1,2 g/L. Resultats La prevalence des meningites bacteriennes neonatales a ete de 0,49 pour 1000 naissances vivantes. Les enfants etaient des prematures dans 20,4 % des cas et de faible poids de naissance dans 13,6 % des cas. Les principaux signes a l’admission avaient ete la fievre (43,2 %), le refus de teter (20,4 %), des convulsions (18,2 %) et une detresse respiratoire (13,6 %). La culture du LCR avait ete positive dans 36,4 % des cas et le streptocoque du groupe B avait ete le plus frequemment isole (62,5 %) suivi par Escherichia coli (12,5 %). L’association cefotaxime-ampicilline-gentamicine avait ete utilisee en premiere intention dans tous les cas. L’ofloxacine avait ete associee a l’antibiotherapie initiale pendant les 5 premiers jours dans 20,4 % des cas. Le taux de mortalite avait ete de 15,9 % et le taux des sequelles neurosensorielles chez les survivants etait de 21,6 %. La prematurite, le faible poids de naissance, l’etat de choc, la detresse respiratoire et une pleiocytose inferieure a 500 elements blancs/mm3 etaient les principaux facteurs de mauvais pronostic. L’adjonction de l’ofloxacine a l’antibiotherapie initiale etait associee a une diminution du taux de sequelles neurosensorielles chez les survivants (11 % vs 25 %, p = 0,042). Conclusion Cette etude souligne la gravite des meningites bacteriennes neonatales avec des taux de mortalite et de sequelles neurosensorielles eleves surtout chez les prematures et les faibles poids de naissance. Un diagnostic precoce et une antibiotherapie efficace sont necessaires pour ameliorer le pronostic.

A. Ayadi

Papers

Outlier detection approaches for wireless sensor networks

Association of severe autosomal recessive osteopetrosis and Dandy-Walker syndrome with agenesis of the corpus callosum.

Aspects cliniques et évolutifs des méningites bactériennes néonatales

Spatio-temporal correlations for damages identification and localization in water pipeline systems based on WSNs

A framework of monitoring water pipeline techniques based on sensors technologies