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Rheumatology (Oxford, England) Feb 2019Janus kinase (JAK)/signal transducers and activators of transcription (STATs) are a group of molecules associated with one of the major pathways through which many... (Review)
Review
Janus kinase (JAK)/signal transducers and activators of transcription (STATs) are a group of molecules associated with one of the major pathways through which many cytokines exert and integrate their function, and as such they are increasingly recognized as playing critical role in the pathogenesis subserving various immune-mediated diseases, including RA, PsA, SpAs, IBD, skin disorders (e.g. alopecia areata, atopic dermatitis), single-gene disorders like interferonopathies, and others. JAKs are the key initiating players of the JAK/STAT pathway. Upon binding of their respective effector molecules (cytokines, IFNs, growth factors and others) to type I and type II receptors, JAKs are activated, and through phosphorylation of themselves and of other molecules (including STATs), they mediate signal transduction to the nucleus. A class of drugs-called JAK inhibitors or JAKinibs-that block one or more JAKs has been developed in the last decade, and now numbers >20 members. Although, so far, JAK inhibitors have been marketed only for RA and PsA, these drugs have been tested in phase 2 and phase 3 clinical trials for other inflammatory conditions and beyond. In this review, we summarize the clinical data, including efficacy and safety, available for JAK inhibitors used in some immune-mediated conditions other than RA.
Topics: Alopecia Areata; Aortic Diseases; Arthritis, Psoriatic; Arthritis, Rheumatoid; Autoimmune Diseases; Autoimmune Diseases of the Nervous System; Chilblains; Cytokines; Dental Enamel Hypoplasia; Dermatitis, Atopic; Giant Cell Arteritis; Humans; Immunologic Deficiency Syndromes; Inflammatory Bowel Diseases; Janus Kinase Inhibitors; Lupus Erythematosus, Cutaneous; Metacarpus; Muscular Diseases; Nervous System Malformations; Odontodysplasia; Osteoporosis; Psoriasis; Spondylarthropathies; Uveitis; Vascular Calcification
PubMed: 30806709
DOI: 10.1093/rheumatology/key276 -
European Oral Research May 2018The aim of this article was to review the literature and present a case of regional odontodysplasia (ROD) with special emphasis on clinical and radiographic features. A...
The aim of this article was to review the literature and present a case of regional odontodysplasia (ROD) with special emphasis on clinical and radiographic features. A 6-year-old girl was referred to our department with the chief complaint of missing her permanent maxillary left central incisor, lateral incisor, and both of her canines. The gingiva of the involved region was enlarged, fibrous, and tense. Radiographic examination showed abnormal tooth formation and shortened roots. After 3 years of follow up with temporary prosthetic rehabilitation, periodontal surgery was performed. Following forced eruption and levelling, abnormal tooth eruption and root development were observed. ProRoot MTA (Dentsply-Maillefer, Ballaigues, Switzerland) was used for root canal treatment. Intracanal fiber posts selected and access cavities were restored with composite resin. Prosthetic rehabilitation was completed with zirconia ceramic crowns. The time of diagnosis, characteristics of the present/existing symptoms, and functional and esthetic needs of the patient should be considered to determine the optimal treatment modality for ROD.
PubMed: 30775712
DOI: 10.26650/eor.2018.495 -
Journal of Clinical Immunology Jan 2019Singleton-Merten syndrome manifests as dental dysplasia, glaucoma, psoriasis, aortic calcification, and skeletal abnormalities including tendon rupture and arthropathy....
PURPOSE
Singleton-Merten syndrome manifests as dental dysplasia, glaucoma, psoriasis, aortic calcification, and skeletal abnormalities including tendon rupture and arthropathy. Pathogenic variants in IFIH1 have previously been associated with the classic Singleton-Merten syndrome, while variants in DDX58 has been described in association with a milder phenotype, which is suggested to have a better prognosis. We studied a family with severe, "classic" Singleton-Merten syndrome.
METHODS
We undertook clinical phenotyping, next-generation sequencing, and functional studies of type I interferon production in patient whole blood and assessed the type I interferon promoter activity in HEK293 cells transfected with wild-type or mutant DDX58 stimulated with Poly I:C.
RESULTS
We demonstrate a DDX58 autosomal dominant gain-of-function mutation, with constitutive upregulation of type I interferon.
CONCLUSIONS
DDX58 mutations may be associated with the classic features of Singleton-Merten syndrome including dental dysplasia, tendon rupture, and severe cardiac sequela.
Topics: Adult; Aortic Diseases; Cell Line; DEAD Box Protein 58; Dental Enamel Hypoplasia; Female; Gain of Function Mutation; HEK293 Cells; Humans; Interferon Type I; Male; Metacarpus; Middle Aged; Muscular Diseases; Odontodysplasia; Osteoporosis; Phenotype; Promoter Regions, Genetic; Receptors, Immunologic; Vascular Calcification
PubMed: 30574673
DOI: 10.1007/s10875-018-0572-1 -
Transcatheter Aortic Valve Replacement for Severe Aortic Regurgitation in Singleton-Merten Syndrome.JACC. Cardiovascular Interventions Nov 2018
Topics: Aortic Diseases; Aortic Valve Insufficiency; Dental Enamel Hypoplasia; Female; Humans; Metacarpus; Muscular Diseases; Odontodysplasia; Osteoporosis; Recovery of Function; Severity of Illness Index; Transcatheter Aortic Valve Replacement; Treatment Outcome; Vascular Calcification; Young Adult
PubMed: 30343025
DOI: 10.1016/j.jcin.2018.08.024 -
Molecular Cell Oct 2018RIG-I has a remarkable ability to specifically select viral 5'ppp dsRNAs for activation from a pool of cytosolic self-RNAs. The ATPase activity of RIG-I plays a role in...
RIG-I has a remarkable ability to specifically select viral 5'ppp dsRNAs for activation from a pool of cytosolic self-RNAs. The ATPase activity of RIG-I plays a role in RNA discrimination and activation, but the underlying mechanism was unclear. Using transient-state kinetics, we elucidated the ATPase-driven "kinetic proofreading" mechanism of RIG-I activation and RNA discrimination, akin to DNA polymerases, ribosomes, and T cell receptors. Even in the autoinhibited state of RIG-I, the C-terminal domain kinetically discriminates against self-RNAs by fast off rates. ATP binding facilitates dsRNA engagement but, interestingly, makes RIG-I promiscuous, explaining the constitutive signaling by Singleton-Merten syndrome-linked mutants that bind ATP without hydrolysis. ATP hydrolysis dissociates self-RNAs faster than 5'ppp dsRNA but, more importantly, drives RIG-I oligomerization through translocation, which we show to be regulated by helicase motif IVa. RIG-I translocates directionally from the dsRNA end into the stem region, and the 5'ppp end "throttles" translocation to provide a mechanism for threading and building a signaling-active oligomeric complex.
Topics: Adenosine Triphosphatases; Adenosine Triphosphate; Aortic Diseases; Cell Line; DEAD Box Protein 58; DEAD-box RNA Helicases; Dental Enamel Hypoplasia; Female; HEK293 Cells; Humans; Hydrolysis; Kinetics; Metacarpus; Muscular Diseases; Odontodysplasia; Osteoporosis; Protein Binding; RNA; RNA, Double-Stranded; Receptors, Antigen, T-Cell; Receptors, Immunologic; Ribosomes; Signal Transduction; Vascular Calcification
PubMed: 30270105
DOI: 10.1016/j.molcel.2018.08.021 -
ELife Jul 2018The innate immune sensor retinoic acid-inducible gene I (RIG-I) detects cytosolic viral RNA and requires a conformational change caused by both ATP and RNA binding to...
The innate immune sensor retinoic acid-inducible gene I (RIG-I) detects cytosolic viral RNA and requires a conformational change caused by both ATP and RNA binding to induce an active signaling state and to trigger an immune response. Previously, we showed that ATP hydrolysis removes RIG-I from lower-affinity self-RNAs (
Lässig et al., 2015 ), revealing how ATP turnover helps RIG-I distinguish viral from self-RNA and explaining why a mutation in a motif that slows down ATP hydrolysis causes the autoimmune disease Singleton-Merten syndrome (SMS). Here we show that a different, mechanistically unexplained SMS variant, C268F, which is localized in the ATP-binding P-loop, can signal independently of ATP but is still dependent on RNA. The structure of RIG-I C268F in complex with double-stranded RNA reveals that C268F helps induce a structural conformation in RIG-I that is similar to that induced by ATP. Our results uncover an unexpected mechanism to explain how a mutation in a P-loop ATPase can induce a gain-of-function ATP state in the absence of ATP.Topics: AAA Proteins; Adenosine Triphosphatases; Adenosine Triphosphate; Aortic Diseases; Cytosol; DEAD Box Protein 58; Dental Enamel Hypoplasia; Humans; Hydrolysis; Immunity, Innate; Metacarpus; Muscular Diseases; Mutation; Odontodysplasia; Osteoporosis; Protein Binding; Protein Conformation; RNA, Double-Stranded; RNA, Viral; Receptors, Immunologic; Vascular Calcification
PubMed: 30047865
DOI: 10.7554/eLife.38958 -
Acta Stomatologica Croatica Mar 2018Molar-incisor-hypomineralisation (MIH) is a disturbance in dental development that commonly involves first permanent molars but permanent incisors may also be...
BACKGROUND
Molar-incisor-hypomineralisation (MIH) is a disturbance in dental development that commonly involves first permanent molars but permanent incisors may also be compromised. The prevalence of MIH in the literature varies between 2.5% and 40% of the world child population. Little information is gained on the prevalence of MIH among children in Spain.
AIM
The aim of this study was to investigate the prevalence of MIH among school children from Barcelona, Spain.
MATERIAL AND METHODS
A cross-sectional study which included 705 children, aged 6 -14 years and 11 months was carried out. Full mouth examinations were performed using the European Academy of Paediatric Dentistry (EAPD) criteria for the diagnosis of MIH.
RESULTS
A total of 56 cases of MIH were found, 22 (39.3%) boys and 34 (60.7%) girls. The prevalence was 7.94% (6.39% for boys and 9.41% for girls). MIH lesions were seen more often in girls than boys (χ = 4.9, p= 0.023) the male/female ratio being 1:1.54. Upper teeth were more prevalent than lower teeth in both genders with an upper/lower ratio of 1.86/1 for boys and 1.68/1 for girls.
CONCLUSION
Considered either by gender or by teeth, upper teeth and girls were ahead in our sample.
PubMed: 30033998
DOI: 10.15644/asc52/1/1 -
International Journal of Clinical... 2018Regional odontodysplasia (RO) is a rare nonhereditary developmental condition usually affecting maxilla and female patients. A few number of articles have used the cone...
UNLABELLED
Regional odontodysplasia (RO) is a rare nonhereditary developmental condition usually affecting maxilla and female patients. A few number of articles have used the cone beam computed tomography (CBCT) to describe imaging findings in RO. Thus, this article aims to report unusual imaging findings in a Brazilian child who presented with mandibular RO. A healthy 8-year-old boy was referred for evaluation of an anterior mandibular gingival enlargement. Radiographically, all right mandibular teeth showed wide pulp chambers and shortened roots with thin dentinal walls and open apices, featuring a "ghost teeth" appearance, which indicated a diagnosis of RO. Missing teeth and altered radiopacity were observed. Cone beam computed tomography provided great insight into RO, allowing to identify gubernaculum tracts (GTs) associated with RO teeth. Fractal analysis of the bone surrounding RO teeth revealed an altered trabecular pattern.
CLINICAL SIGNIFICANCE
This case describes a rare developmental teeth-related pathology in a boy who showed unusual features on imaging exams. The CBCT provided the observation of RO tooth-related GTs, probably a new finding added to the international literature regarding RO, as well as the pulp chamber volume characterization of an affected tooth not published yet. In addition, it was observed an altered fractal pattern of the mandibular bone adjacent to RO teeth, which has not been described to date. de Sa Cavalcante D, Fonteles CSR, Ribeiro TR, Kurita LM, Pimenta AVM, Carvalho FSR, Costa FWG. Mandibular Regional Odontodysplasia in an 8-year-old Boy showing Teeth Disorders, Gubernaculum Tracts, and Altered Bone Fractal Pattern. Int J Clin Pediatr Dent 2018;11(2):128-134.
PubMed: 29991866
DOI: 10.5005/jp-journals-10005-1498 -
Journal of Oral and Maxillofacial... Jan 2018Regional odontodysplasia (RO) also known as ghost teeth is a rare developmental anomaly affecting the mesodermal and ectodermal components of teeth with characteristic...
Regional odontodysplasia (RO) also known as ghost teeth is a rare developmental anomaly affecting the mesodermal and ectodermal components of teeth with characteristic clinical and radiographic findings. The enamel and dentin are hypomineralized and hypocalcified with short roots and open apices. The affected teeth have an abnormal morphology, meaning they are fragile and thin and liable to fracture and decay. Radiographically, there is a marked reduction in radiodensity with little distinction between the enamel and dentin, hence the term "ghost teeth." RO generally affects one particular segment in one or both arches of the maxilla or mandible and can affect both the primary and permanent dentition. We report a unique case of a 3-year-old female who presented to Alder Hey Children's Hospital acutely unwell with a left-sided cervicofacial swelling from RO affecting the entire portion of the left maxilla.
PubMed: 29491620
DOI: 10.4103/jomfp.JOMFP_146_17 -
Arthritis & Rheumatology (Hoboken, N.J.) Oct 2017To define the molecular basis of a multisystem phenotype with progressive musculoskeletal disease of the hands and feet, including camptodactyly, subluxation, and tendon...
OBJECTIVE
To define the molecular basis of a multisystem phenotype with progressive musculoskeletal disease of the hands and feet, including camptodactyly, subluxation, and tendon rupture, reminiscent of Jaccoud's arthropathy.
METHODS
We identified 2 families segregating an autosomal-dominant phenotype encompassing musculoskeletal disease and variable additional features, including psoriasis, dental abnormalities, cardiac valve involvement, glaucoma, and basal ganglia calcification. We measured the expression of interferon (IFN)-stimulated genes in the peripheral blood and skin, and undertook targeted Sanger sequencing of the IFIH1 gene encoding the cytosolic double-stranded RNA (dsRNA) sensor melanoma differentiation-associated protein 5 (MDA-5). We also assessed the functional consequences of IFIH1 gene variants using an in vitro IFNβ reporter assay in HEK 293T cells.
RESULTS
We recorded an up-regulation of type I IFN-induced gene transcripts in all 5 patients tested and identified a heterozygous gain-of-function mutation in IFIH1 in each family, resulting in different substitutions of the threonine residue at position 331 of MDA-5. Both of these variants were associated with increased IFNβ expression in the absence of exogenous dsRNA ligand, consistent with constitutive activation of MDA-5.
CONCLUSION
These cases highlight the significant musculoskeletal involvement that can be associated with mutations in MDA-5, and emphasize the value of testing for up-regulation of IFN signaling as a marker of the underlying molecular lesion. Our data indicate that both Singleton-Merten syndrome and neuroinflammation described in the context of MDA-5 gain-of-function constitute part of the same type I interferonopathy disease spectrum, and provide possible novel insight into the pathology of Jaccoud's arthropathy.
Topics: Adolescent; Adult; Aortic Diseases; Basal Ganglia Diseases; Calcinosis; Child; Dental Enamel Hypoplasia; Glaucoma; HEK293 Cells; Heart Valve Diseases; Heterozygote; Humans; Interferon-Induced Helicase, IFIH1; Metacarpus; Middle Aged; Muscular Diseases; Musculoskeletal Diseases; Mutation; Odontodysplasia; Osteoporosis; Psoriasis; Syndrome; Vascular Calcification
PubMed: 28605144
DOI: 10.1002/art.40179