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1.
J Neurotrauma ; 2020 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-32056479

RESUMO

The purpose of this study was to characterize acute changes in inflammatory pathways in the mouse eye following a blast-mediated TBI (bTBI) model, and to determine if modulation of these pathways could protect the structure and function of retinal ganglion cells (RGC). bTBI was induced in C57BL/6J male mice by exposure to three 20 PSI blast waves directed towards the head with the body shielded, with an inter-blast interval of one hour. Acute cytokine expression in retinal tissue was measured through real-time quantitative polymerase chain reaction (RT-qPCR) 4 hours post-blast. Increased retinal expression of IL-1α, IL-1ß, IL-6, and TNFα was observed in bTBI mice exposed to blast when compared to shams, which was associated with activation of microglia and macroglia reactivity, assessed via immunohistochemistry with IBA-1 and GFAP, respectively, 1 week post-blast. Blockade of the IL-1 pathway was accomplished using anakinra, an IL-1RI antagonist, administered intraperitoneally for 1 week prior to injury and continuing for 3 weeks post-injury. Retinal function and RGC layer thickness were evaluated 4 weeks post-injury using pattern electroretinogram (PERG) and optical coherence tomography (OCT), respectively. After bTBI, anakinra treatment resulted in a preservation of RGC function and RGC structure when compared to saline treated bTBI mice. Optic nerve integrity analysis demonstrated a trend of decreased damage suggesting that IL-1 blockade also prevents axonal damage after blast. Blast exposure results in increased retinal inflammation including upregulation of pro-inflammatory cytokines and activation of resident microglia and macroglia. This may partially explain the RGC loss we observed in this model as blockade of the acute inflammatory response after injury with the IL-1R1 antagonist anakinra resulted in preservation of RGC function and structure. Key Words: Blast; IL-1; anakinra; retina; visual function.

2.
Pediatr Radiol ; 50(1): 124-136, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31901992

RESUMO

Chronic recurrent multifocal osteomyelitis (CRMO) is a pediatric autoinflammatory disorder that is characterized by multiple sterile inflammatory bone lesions with a relapsing and remitting course. CRMO belongs to the autoinflammatory family of rheumatologic disorders based on absence of significant titers of autoantibodies and autoreactive T-lymphocytes. In absence of pathognomonic clinical, radiographic or pathological features, diagnosis can be challenging. CRMO shares imaging features with other diseases. It is important for radiologists to be able to differentiate other diseases from CRMO because prognosis varies from completely benign to frankly malignant. In this article we first present the clinical and imaging features of CRMO to help readers gain an understanding of the disease process, then discuss our imaging approach to CRMO and review other disease processes that sometimes share similar imaging findings to CRMO and review differentiating features to help avoid misdiagnoses.

3.
J Rheumatol ; 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31615917

RESUMO

OBJECTIVE: To perform a comparative effectiveness feasibility study in juvenile localized scleroderma (jLS), using standardized treatment regimens (consensus treatment plans, CTPs). METHODS: A prospective, multi-center 1-year pilot observational cohort study was performed by Childhood Arthritis and Rheumatology Research Alliance (CARRA) localized scleroderma workgroup members. Active, moderate to severe jLS patients were treated with one of three CTPs: methotrexate alone, or in combination with intravenous (30 mg/kg/dose for 3 months) or oral corticosteroids (2 mg/kg/day tapered off by 48 weeks). RESULTS: Fifty patients, with demographics typical for jLS, were enrolled, and 44 (88%) completed the study. Most had extracutaneous involvement. Patients improved in all three CTPs, with >75% having a major or moderate level of improvement compared to baseline. Damage accrued in some patients. Major deviations from prescribed regimen resulted from medication intolerance (n = 6, 14%) or treatment failure (n = 11, 25%); failures occurred in all three CTPs. Significant responses to treatment were demonstrated by LS skin scoring measures and overall physician assessments, with differences in response level identified in some patient subsets. Baseline disease activity level, LS subtype, skin disease extent, and extracutaneous involvement were associated with response differences. CONCLUSION: This study demonstrates the feasibility of conducting jLS comparative effectiveness studies. The CTPs were found to be safe, effective, and tolerable. Our assessments performed well. As damage is common and may progress despite effective control of activity, we recommend initial treatment efficacy be evaluated primarily by activity measures. Potential confounders for response were identified that warrant further study.

4.
J Neurotrauma ; 2019 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-31621484

RESUMO

Traumatic brain injury (TBI) is a leading cause of death and disability that lacks targeted therapies. Successful translation of promising neuroprotective therapies will likely require more precise identification of target populations through greater study of crucial biological factors like age and sex. A growing body of work supports the impact of these factors on response to and recovery from TBI. However, age and sex are understudied in TBI animal models. The first aim of this study was to demonstrate the feasibility of lateral fluid percussion injury (FPI) in juvenile mice as a model of pediatric TBI. Subsequently, we were interested in examining the impact of young age and sex on TBI outcome. After adapting the lateral FPI model to 21-day-old male and female mice, we characterized the molecular, histological, and functional outcomes. Whereas similar tissue injury was observed in male and female juvenile mice exposed to TBI, we observed differences in neuroinflammation and neurobehavioral function. Overall, our findings revealed less acute inflammatory cytokine expression, greater subacute microglial/macrophage accumulation, and greater neurological recovery in juvenile male mice after TBI. Given that ongoing brain development may affect progression of and recovery from TBI, juvenile models are of critical importance. The sex-dependent differences we discovered after FPI support the necessity of also including this biological variable in future TBI studies. Understanding the mechanisms underlying age- and sex-dependent differences may result in the discovery of novel therapeutic targets for TBI.

5.
J Rheumatol ; 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31575701

RESUMO

OBJECTIVE: Serial magnetic resonance imaging (MRI) examinations are often needed in chronic nonbacterial osteomyelitis (CNO) to determine the objective response to treatment. Our objectives in this study were (1) to develop a consensus-based MRI scoring tool for clinical and research use in CNO; and (2) to evaluate interrater reliability and agreement using whole-body (WB)-MRI from children with CNO. METHODS: Eleven pediatric radiologists discussed definitions and grading of signal intensity, size of signal abnormality within bone marrow, and associated features on MRI through monthly conference calls and a consensus meeting, using a nominal group technique in July 2017. WB-MRI scans from children with CNO were deidentified for training reading and an interrater reliability study. The reading by each radiologist was conducted in a randomized order. Interrater reliability for abnormal signal and severity were assessed using free-marginal κ statistics. RESULTS: Radiologists reached a consensus on grading CNO-specific MRI findings and on describing bone units based on anatomy. A total of 45 sets of WB-MRI scans, including 4 sets of non-CNO MRI examinations, were selected for the final reading. The mean κ of each category of bones was > 0.7 with majority > 0.9 demonstrating substantial/almost perfect interrater reliability of readings among radiologists. The agreement on signal intensity and the size of signal abnormality within the most commonly affected bones (femur and tibia) were lower than those of other bones. CONCLUSION: The chronic nonbacterial osteomyelitis magnetic resonance imaging scoring (CROMRIS) tool is a comprehensive standardized scoring tool for MRI in children with CNO. Our interrater study demonstrated good interrater reliability and agreement of readings.

6.
Pediatr Rheumatol Online J ; 17(1): 43, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31307476

RESUMO

BACKGROUND: We designed and initiated a pilot comparative effectiveness study for juvenile localized scleroderma (jLS), for which there is limited evidence on best therapy. We evaluated the process we used, in relation to the specific protocol and to the general task of identifying strategies for implementing studies in rare pediatric diseases. METHODS: This was a prospective, multi-center, observational cohort study of 50 jLS patients initiating treatment, designed and conducted by the jLS group of the Childhood Arthritis and Rheumatology Research Alliance (CARRA) from 2012 to 2015. A series of virtual and physical meetings were held to design the study, standardize clinical assessments, generate and refine disease activity and damage measures, and monitor the study. Patients were initiated on one of three standardized methotrexate-based treatment regimens (consensus treatment plans, CTPs) and monitored for 1 year. An optional bio-banking sub-study was included. RESULTS: The target enrollment of 50 patients was achieved over 26 months at 10 sites, with patients enrolled into all CTPs. Enrolled patients were typical for jLS. Study eligibility criteria were found to perform well, capturing patients thought appropriate for treatment studies. Minor modifications to the eligibility criteria, primarily to facilitate recruitment for future studies, were discussed with consensus agreement reached on them by the jLS group. There were marked differences in site preferences for specific CTPs, with half the sites treating all their patients with the same CTP. Most patients (88%) completed the study, and 68% participated in the bio-banking substudy. CONCLUSIONS: We demonstrate the feasibility of our approach for conducting comparative effectiveness research in a rare pediatric disease. Multi-center collaboration by dedicated investigators who met regularly was a key factor in the success of this project. Other factors that facilitate these studies include having a sufficient number of investigators to enroll in each regimen, and streamlining study approval and management.


Assuntos
Antirreumáticos/uso terapêutico , Pesquisa Comparativa da Efetividade/métodos , Glucocorticoides/uso terapêutico , Metotrexato/uso terapêutico , Esclerodermia Localizada/tratamento farmacológico , Escleroderma Sistêmico/tratamento farmacológico , Administração Intravenosa , Administração Oral , Adolescente , Criança , Quimioterapia Combinada , Estudos de Viabilidade , Feminino , Humanos , Masculino , Metilprednisolona/uso terapêutico , Projetos Piloto , Prednisona/uso terapêutico , Estudos Prospectivos , Doenças Raras , Adulto Jovem
7.
Genet Res (Camb) ; 101: e8, 2019 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-31190668

RESUMO

Compound heterozygotes occur when different variants at the same locus on both maternal and paternal chromosomes produce a recessive trait. Here we present the tool VarCount for the quantification of variants at the individual level. We used VarCount to characterize compound heterozygous coding variants in patients with epileptic encephalopathy and in the 1000 Genomes Project participants. The Epi4k data contains variants identified by whole exome sequencing in patients with either Lennox-Gastaut Syndrome (LGS) or infantile spasms (IS), as well as their parents. We queried the Epi4k dataset (264 trios) and the phased 1000 Genomes Project data (2504 participants) for recessive variants. To assess enrichment, transcript counts were compared between the Epi4k and 1000 Genomes Project participants using minor allele frequency (MAF) cutoffs of 0.5 and 1.0%, and including all ancestries or only probands of European ancestry. In the Epi4k participants, we found enrichment for rare, compound heterozygous variants in six genes, including three involved in neuronal growth and development - PRTG (p = 0.00086, 1% MAF, combined ancestries), TNC (p = 0.022, 1% MAF, combined ancestries) and MACF1 (p = 0.0245, 0.5% MAF, EU ancestry). Due to the total number of transcripts considered in these analyses, the enrichment detected was not significant after correction for multiple testing and higher powered or prospective studies are necessary to validate the candidacy of these genes. However, PRTG, TNC and MACF1 are potential novel recessive epilepsy genes and our results highlight that compound heterozygous variants should be considered in sporadic epilepsy.

8.
Proc Natl Acad Sci U S A ; 116(24): 11872-11877, 2019 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-31138708

RESUMO

Autoinflammatory syndromes are characterized by dysregulation of the innate immune response with subsequent episodes of acute spontaneous inflammation. Chronic recurrent multifocal osteomyelitis (CRMO) is an autoinflammatory bone disorder that presents with bone pain and localized swelling. Ali18 mice, isolated from a mutagenesis screen, exhibit a spontaneous inflammatory paw phenotype that includes sterile osteomyelitis and systemic reduced bone mineral density. To elucidate the molecular basis of the disease, positional cloning of the causative gene for Ali18 was attempted. Using a candidate gene approach, a missense mutation in the C-terminal region of Fgr, a member of Src family tyrosine kinases (SFKs), was identified. For functional confirmation, additional mutations at the N terminus of Fgr were introduced in Ali18 mice by CRISPR/Cas9-mediated genome editing. N-terminal deleterious mutations of Fgr abolished the inflammatory phenotype in Ali18 mice, but in-frame and missense mutations in the same region continue to exhibit the phenotype. The fact that Fgr null mutant mice are morphologically normal suggests that the inflammation in this model depends on Fgr products. Furthermore, the levels of C-terminal negative regulatory phosphorylation of Fgr Ali18 are distinctly reduced compared with that of wild-type Fgr. In addition, whole-exome sequencing of 99 CRMO patients including 88 trios (proband and parents) identified 13 patients with heterozygous coding sequence variants in FGR, including two missense mutant proteins that affect kinase activity. Our results strongly indicate that gain-of-function mutations in Fgr are involved in sterile osteomyelitis, and thus targeting SFKs using specific inhibitors may allow for efficient treatment of the disease.

9.
Arthritis Rheumatol ; 71(6): 864-877, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31021511

RESUMO

OBJECTIVE: To develop recommendations for the screening, monitoring, and treatment of uveitis in children with juvenile idiopathic arthritis (JIA). METHODS: Pediatric rheumatologists, ophthalmologists with expertise in uveitis, patient representatives, and methodologists generated key clinical questions to be addressed by this guideline. This was followed by a systematic literature review and rating of the available evidence according to the GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology. A group consensus process was used to compose the final recommendations and grade their strength as conditional or strong. RESULTS: Due to a lack of literature with good quality of evidence, recommendations were formulated on the basis of available evidence and a consensus expert opinion. Regular ophthalmic screening of children with JIA is recommended because of the risk of uveitis, and the frequency of screening should be based on individual risk factors. Regular ophthalmic monitoring of children with uveitis is recommended, and intervals should be based on ocular examination findings and treatment regimen. Ophthalmic monitoring recommendations were strong primarily because of concerns of vision-threatening complications of uveitis with infrequent monitoring. Topical glucocorticoids should be used as initial treatment to achieve control of inflammation. Methotrexate and the monoclonal antibody tumor necrosis factor inhibitors adalimumab and infliximab are recommended when systemic treatment is needed for the management of uveitis. The timely addition of nonbiologic and biologic drugs is recommended to maintain uveitis control in children who are at continued risk of vision loss. CONCLUSION: This guideline provides direction for clinicians and patients/parents making decisions on the screening, monitoring, and management of children with JIA and uveitis, using GRADE methodology and informed by a consensus process with input from rheumatology and ophthalmology experts, current literature, and patient/parent preferences and values.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Juvenil/terapia , Glucocorticoides/uso terapêutico , Metotrexato/uso terapêutico , Uveíte/tratamento farmacológico , Adalimumab/uso terapêutico , Administração Oftálmica , Artrite Juvenil/complicações , Humanos , Infliximab/uso terapêutico , Programas de Rastreamento , Uveíte/diagnóstico , Uveíte/etiologia
10.
Arthritis Care Res (Hoboken) ; 71(6): 717-734, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31021516

RESUMO

OBJECTIVE: To develop treatment recommendations for children with juvenile idiopathic arthritis manifesting as non-systemic polyarthritis, sacroiliitis, or enthesitis. METHODS: The Patient/Population, Intervention, Comparison, and Outcomes (PICO) questions were developed and refined by members of the guideline development teams. A systematic review was conducted to compile evidence for the benefits and harms associated with treatments for these conditions. GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology was used to rate the quality of evidence. A group consensus process was conducted among the Voting Panel to generate the final recommendations and grade their strength. A Parent and Patient Panel used a similar consensus approach to provide patient/caregiver preferences for key questions. RESULTS: Thirty-nine recommendations were developed (8 strong and 31 conditional). The quality of supporting evidence was very low or low for 90% of the recommendations. Recommendations are provided for the use of nonsteroidal antiinflammatory drugs, disease-modifying antirheumatic drugs, biologics, and intraarticular and oral glucocorticoids. Recommendations for the use of physical and occupational therapy are also provided. Specific recommendations for polyarthritis address general medication use, initial and subsequent treatment, and adjunctive therapies. Good disease control, with therapeutic escalation to achieve low disease activity, was recommended. The sacroiliitis and enthesitis recommendations primarily address initial therapy and adjunctive therapies. CONCLUSION: This guideline provides direction for clinicians, caregivers, and patients making treatment decisions. Clinicians, caregivers, and patients should use a shared decision-making process that accounts for patients' values, preferences, and comorbidities. These recommendations should not be used to limit or deny access to therapies.

11.
Arthritis Rheumatol ; 71(6): 846-863, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31021537

RESUMO

OBJECTIVE: To develop treatment recommendations for children with juvenile idiopathic arthritis manifesting as non-systemic polyarthritis, sacroiliitis, or enthesitis. METHODS: The Patient/Population, Intervention, Comparison, and Outcomes (PICO) questions were developed and refined by members of the guideline development teams. A systematic review was conducted to compile evidence for the benefits and harms associated with treatments for these conditions. GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology was used to rate the quality of evidence. A group consensus process was conducted among the Voting Panel to generate the final recommendations and grade their strength. A Parent and Patient Panel used a similar consensus approach to provide patient/caregiver preferences for key questions. RESULTS: Thirty-nine recommendations were developed (8 strong and 31 conditional). The quality of supporting evidence was very low or low for 90% of the recommendations. Recommendations are provided for the use of nonsteroidal antiinflammatory drugs, disease-modifying antirheumatic drugs, biologics, and intraarticular and oral glucocorticoids. Recommendations for the use of physical and occupational therapy are also provided. Specific recommendations for polyarthritis address general medication use, initial and subsequent treatment, and adjunctive therapies. Good disease control, with therapeutic escalation to achieve low disease activity, was recommended. The sacroiliitis and enthesitis recommendations primarily address initial therapy and adjunctive therapies. CONCLUSION: This guideline provides direction for clinicians, caregivers, and patients making treatment decisions. Clinicians, caregivers, and patients should use a shared decision-making process that accounts for patients' values, preferences, and comorbidities. These recommendations should not be used to limit or deny access to therapies.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Juvenil/terapia , Entesopatia/terapia , Glucocorticoides/uso terapêutico , Sacroileíte/terapia , /uso terapêutico , Artrite/terapia , Humanos , Injeções Intra-Articulares , Terapia Ocupacional , Modalidades de Fisioterapia
12.
Arthritis Care Res (Hoboken) ; 71(6): 703-716, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31021540

RESUMO

OBJECTIVE: To develop recommendations for the screening, monitoring, and treatment of uveitis in children with juvenile idiopathic arthritis (JIA). METHODS: Pediatric rheumatologists, ophthalmologists with expertise in uveitis, patient representatives, and methodologists generated key clinical questions to be addressed by this guideline. This was followed by a systematic literature review and rating of the available evidence according to the GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology. A group consensus process was used to compose the final recommendations and grade their strength as conditional or strong. RESULTS: Due to a lack of literature with good quality of evidence, recommendations were formulated on the basis of available evidence and a consensus expert opinion. Regular ophthalmic screening of children with JIA is recommended because of the risk of uveitis, and the frequency of screening should be based on individual risk factors. Regular ophthalmic monitoring of children with uveitis is recommended, and intervals should be based on ocular examination findings and treatment regimen. Ophthalmic monitoring recommendations were strong primarily because of concerns of vision-threatening complications of uveitis with infrequent monitoring. Topical glucocorticoids should be used as initial treatment to achieve control of inflammation. Methotrexate and the monoclonal antibody tumor necrosis factor inhibitors adalimumab and infliximab are recommended when systemic treatment is needed for the management of uveitis. The timely addition of nonbiologic and biologic drugs is recommended to maintain uveitis control in children who are at continued risk of vision loss. CONCLUSION: This guideline provides direction for clinicians and patients/parents making decisions on the screening, monitoring, and management of children with JIA and uveitis, using GRADE methodology and informed by a consensus process with input from rheumatology and ophthalmology experts, current literature, and patient/parent preferences and values.

13.
J Allergy Clin Immunol Pract ; 7(6): 1970-1985.e4, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30877075

RESUMO

BACKGROUND: Although autoimmunity and hyperinflammation secondary to recombination activating gene (RAG) deficiency have been associated with delayed diagnosis and even death, our current understanding is limited primarily to small case series. OBJECTIVE: Understand the frequency, severity, and treatment responsiveness of autoimmunity and hyperinflammation in RAG deficiency. METHODS: In reviewing the literature and our own database, we identified 85 patients with RAG deficiency, reported between 2001 and 2016, and compiled the largest case series to date of 63 patients with prominent autoimmune and/or hyperinflammatory pathology. RESULTS: Diagnosis of RAG deficiency was delayed a median of 5 years from the first clinical signs of immune dysregulation. Most patients (55.6%) presented with more than 1 autoimmune or hyperinflammatory complication, with the most common etiologies being cytopenias (84.1%), granulomas (23.8%), and inflammatory skin disorders (19.0%). Infections, including live viral vaccinations, closely preceded the onset of autoimmunity in 28.6% of cases. Autoimmune cytopenias had early onset (median, 1.9, 2.1, and 2.6 years for autoimmune hemolytic anemia, immune thrombocytopenia, and autoimmune neutropenia, respectively) and were refractory to intravenous immunoglobulin, steroids, and rituximab in most cases (64.7%, 73.7%, and 71.4% for autoimmune hemolytic anemia, immune thrombocytopenia, and autoimmune neutropenia, respectively). Evans syndrome specifically was associated with lack of response to first-line therapy. Treatment-refractory autoimmunity/hyperinflammation prompted hematopoietic stem cell transplantation in 20 patients. CONCLUSIONS: Autoimmunity/hyperinflammation can be a presenting sign of RAG deficiency and should prompt further evaluation. Multilineage cytopenias are often refractory to immunosuppressive treatment and may require hematopoietic cell transplantation for definitive management.

14.
Pediatr Clin North Am ; 65(4): 783-800, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30031498

RESUMO

Chronic nonbacterial osteomyelitis (CNO) is an innate immune system disorder that predominantly affects children. It can present as part of a syndrome or in isolation. It presents as bone pain with or without fever or objective swelling at the site. It is difficult to diagnose. Laboratory studies can be normal, whereas a biopsy reveals sterile osteomyelitis. Osteolytic or sclerotic bone changes may be seen on radiographs. However, MRI is more sensitive for detecting CNO and is considered the gold standard for monitoring the disease. Treatment depends on disease severity and includes nonsteroidal antiinflammatory drugs, bisphosphonates, and cytokine inhibitors.


Assuntos
Osteomielite/diagnóstico , Idade de Início , Anti-Inflamatórios não Esteroides/uso terapêutico , Criança , Pré-Escolar , Doença Crônica , Diagnóstico Diferencial , Quimioterapia Combinada , Feminino , Humanos , Imunossupressores/uso terapêutico , Incidência , Imagem por Ressonância Magnética , Masculino , Osteomielite/complicações , Osteomielite/tratamento farmacológico , Radiografia , Cintilografia
15.
Curr Opin Rheumatol ; 30(5): 521-525, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29912021

RESUMO

PURPOSE OF REVIEW: To summarize the current advances in our understanding or the genetic basis of nonbacterial osteomyelitis. RECENT FINDINGS: Chronic recurrent multifocal osteomyelitis (CRMO) is a complex genetic disorder. Past discoveries identified several single gene defects (LPIN2, Pstpip2 and IL1RN) that cause IL-1-mediated sterile multifocal osteomyelitis. Recently Lorden et al.'s studies show that LIPIN2 deficiency can activate the NLRP3 inflammasome through alterations in the function of P2X7 receptor providing evidence that Majeed syndrome is an NLRP3 inflammasomopathy. New gene discoveries include the identification of FBLIM1 as a CRMO susceptibility gene. Mutations in FBLIM1 were found in a consanguineous family with CRMO. Fblim1 is one of the most significantly differentially expressed gene in bone from chronic multifocal osteomyelitis (cmo) mice, plays a role in IL-10-driven anti-inflammatory responses, and is involved in the physiology of bone remodeling. Lastly, new data on the putative CRMO susceptibility locus on chromosome 18 is presented here. Using Sanger sequencing, rather than microsatellite analysis, the DS18S60 susceptibility region could not be replicated in a larger cohort. SUMMARY: CRMO occurs in humans, nonhuman primates, dogs and mice. There is a genetic component to disease but the genetic basis has only been identified for a small percentage of all cases.


Assuntos
Osteomielite/genética , Animais , Moléculas de Adesão Celular/genética , Cromossomos Humanos Par 18/genética , Doença Crônica , Proteínas do Citoesqueleto/genética , Predisposição Genética para Doença , Humanos , Inflamassomos/genética , Camundongos , Mutação
16.
eNeuro ; 5(2)2018.
Artigo em Inglês | MEDLINE | ID: mdl-29662944

RESUMO

Diffuse activation of interleukin-1 inflammatory cytokine signaling after traumatic brain injury (TBI) elicits progressive neurodegeneration and neuropsychiatric dysfunction, and thus represents a potential opportunity for therapeutic intervention. Although interleukin (IL)-1α and IL-1ß both activate the common type 1 IL-1 receptor (IL-1RI), they manifest distinct injury-specific roles in some models of neurodegeneration. Despite its potential relevance to treating patients with TBI, however, the individual contributions of IL-1α and IL-1ß to TBI-pathology have not been previously investigated. To address this need, we applied genetic and pharmacologic approaches in mice to dissect the individual contributions of IL-1α, IL-ß, and IL-1RI signaling to the pathophysiology of fluid percussion-mediated TBI, a model of mixed focal and diffuse TBI. IL-1RI ablation conferred a greater protective effect on brain cytokine expression and cognitive function after TBI than did individual IL-1α or IL-1ß ablation. This protective effect was recapitulated by treatment with the drug anakinra, a recombinant naturally occurring IL-1RI antagonist. Our data thus suggest that broad targeting of IL-1RI signaling is more likely to reduce neuroinflammation and preserve cognitive function after TBI than are approaches that individually target IL-1α or IL-1ß signaling.


Assuntos
Lesões Encefálicas Traumáticas , Disfunção Cognitiva/prevenção & controle , Inflamação/prevenção & controle , Interleucina-1alfa/metabolismo , Interleucina-1beta/metabolismo , Transdução de Sinais , Animais , Comportamento Animal/efeitos dos fármacos , Lesões Encefálicas Traumáticas/complicações , Lesões Encefálicas Traumáticas/imunologia , Lesões Encefálicas Traumáticas/metabolismo , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/imunologia , Disfunção Cognitiva/metabolismo , Modelos Animais de Doenças , Inflamação/etiologia , Inflamação/imunologia , Inflamação/metabolismo , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Interleucina-1alfa/antagonistas & inibidores , Interleucina-1alfa/deficiência , Interleucina-1beta/antagonistas & inibidores , Interleucina-1beta/deficiência , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia
17.
Ann Clin Transl Neurol ; 5(3): 240-251, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29560370

RESUMO

Objective: Limited attention has been given to ocular injuries associated with traumatic brain injury (TBI). The retina is an extension of the central nervous system and evaluation of ocular damage may offer a less-invasive approach to gauge TBI severity and response to treatment. We aim to characterize acute changes in the mouse eye after exposure to two different models of TBI to assess the utility of eye damage as a surrogate to brain injury. Methods: A model of blast TBI (bTBI) using a shock tube was compared to a lateral fluid percussion injury model (LFPI) using fluid pressure applied directly to the brain. Whole eyes were collected from mice 3 days post LFPI and 24 days post bTBI and were evaluated histologically using a hematoxylin and eosin stain. Results: bTBI mice showed evidence of vitreous detachment in the posterior chamber in addition to vitreous hemorrhage with inflammatory cells. Subretinal hemorrhage, photoreceptor degeneration, and decreased cellularity in the retinal ganglion cell layer was also seen in bTBI mice. In contrast, eyes of LFPI mice showed evidence of anterior uveitis and subcapsular cataracts. Interpretation: We demonstrated that variations in the type of TBI can result in drastically different phenotypic changes within the eye. As such, molecular and phenotypic changes in the eye following TBI may provide valuable information regarding the mechanism, severity, and ongoing pathophysiology of brain injury. Because vitreous samples are easily obtained, molecular changes within the eye could be utilized as biomarkers of TBI in human patients.

18.
Artigo em Inglês | MEDLINE | ID: mdl-29472286

RESUMO

Mutations that activate the protease calpain-5 (CAPN5) cause a nonsyndromic adult-onset autoinflammatory eye disease characterized by uveitis, altered synaptic signaling, retinal degeneration, neovascularization, and intraocular fibrosis. We describe a pediatric patient with severe inflammatory vitreoretinopathy accompanied by hearing loss and developmental delay associated with a novel, de novo CAPN5 missense mutation (c.865C>T, p.Arg289Trp) that shows greater hyperactivation of the calpain protease, indicating a genotype-phenotype correlation that links mutation severity to proteolytic activity and the possibility of earlier onset syndromic disease with auditory and neurological abnormalities.


Assuntos
Calpaína/genética , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/genética , Perda Auditiva/diagnóstico , Perda Auditiva/genética , Mutação , Vitreorretinopatia Proliferativa/diagnóstico , Vitreorretinopatia Proliferativa/genética , Alelos , Sequência de Aminoácidos , Calpaína/química , Pré-Escolar , Eletroencefalografia , Estudos de Associação Genética , Genótipo , Humanos , Masculino , Modelos Moleculares , Linhagem , Fenótipo , Conformação Proteica , Sequenciamento Completo do Exoma
19.
Arthritis Care Res (Hoboken) ; 70(8): 1228-1237, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29112802

RESUMO

OBJECTIVE: To develop standardized treatment regimens for chronic nonbacterial osteomyelitis (CNO), also known as chronic recurrent multifocal osteomyelitis (CRMO), to enable comparative effectiveness treatment studies. METHODS: Virtual and face-to-face discussions and meetings were held within the CNO/CRMO subgroup of the Childhood Arthritis and Rheumatology Research Alliance (CARRA). A literature search was conducted, and CARRA membership was surveyed to evaluate available treatment data and identify current treatment practices. Nominal group technique was used to achieve consensus on treatment plans for CNO refractory to nonsteroidal antiinflammatory drug (NSAID) monotherapy and/or with active spinal lesions. RESULTS: Three consensus treatment plans (CTPs) were developed for the first 12 months of therapy for CNO patients refractory to NSAID monotherapy and/or with active spinal lesions. The 3 CTPs are methotrexate or sulfasalazine, tumor necrosis factor inhibitors with optional methotrexate, and bisphosphonates. Short courses of glucocorticoids and continuation of NSAIDs are permitted for all regimens. Consensus was achieved on these CTPs among CARRA members. Consensus was also reached on subject eligibility criteria, initial evaluations that should be conducted prior to the initiation of CTPs, and data items to collect to assess treatment response. CONCLUSION: Three consensus treatment plans were developed for pediatric patients with CNO refractory to NSAIDs and/or with active spinal lesions. Use of these CTPs will provide additional information on efficacy and will generate meaningful data for comparative effectiveness research in CNO.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Antirreumáticos/uso terapêutico , Produtos Biológicos/uso terapêutico , Osteomielite/tratamento farmacológico , Planejamento de Assistência ao Paciente/normas , Doenças da Coluna Vertebral/tratamento farmacológico , Adolescente , Criança , Consenso , Feminino , Humanos , Masculino , Osteomielite/diagnóstico , Prognóstico , Retratamento/métodos , Medição de Risco , Índice de Gravidade de Doença , Doenças da Coluna Vertebral/diagnóstico , Falha de Tratamento
20.
Curr Osteoporos Rep ; 15(6): 542-554, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29080202

RESUMO

PURPOSE OF REVIEW: Chronic non-bacterial osteomyelitis (CNO) with its most severe form chronic recurrent multifocal osteomyelitis (CRMO) is an autoinflammatory bone disorder. We summarize the clinical presentation, diagnostic approaches, most recent advances in understanding the pathophysiology, and available treatment options and outcomes in CNO/CRMO. RECENT FINDINGS: Though the exact molecular pathophysiology of CNO/CRMO remains somewhat elusive, it appears likely that variable defects in the TLR4/MAPK/inflammasome signaling cascade result in an imbalance between pro- and anti-inflammatory cytokine expressions in monocytes from CNO/CRMO patients. In this context, we present previously unpublished data on cytokine and chemokine expression in monocytes and tissues. CNO/CRMO is an autoinflammatory bone disorder resulting from imbalanced cytokine expression from innate immune cells. Though the exact molecular pathophysiology remains unclear, variable molecular defects appear to result in inflammasome activation and pro-inflammatory cytokine expression in monocytes from CNO/CRMO patients. Recent advances suggest signaling pathways and single molecules as biomarkers for CNO/CRMO as well as future treatment targets.


Assuntos
Citocinas/imunologia , Inflamassomos/imunologia , Proteínas Quinases Ativadas por Mitógeno/imunologia , Monócitos/imunologia , Osteomielite/imunologia , Receptor 4 Toll-Like/imunologia , Corticosteroides/uso terapêutico , Animais , Anti-Inflamatórios não Esteroides/uso terapêutico , Conservadores da Densidade Óssea/uso terapêutico , Quimiocina CCL2/imunologia , Quimiocina CCL4/imunologia , Quimiocina CCL5/imunologia , Quimiocinas/imunologia , Difosfonatos/uso terapêutico , Modelos Animais de Doenças , Humanos , Imunossupressores/uso terapêutico , Interleucina-12/imunologia , Interleucina-6/imunologia , Metotrexato/uso terapêutico , Camundongos , Osteomielite/diagnóstico , Osteomielite/terapia , Receptores de Interleucina-2/imunologia , Transdução de Sinais , Sulfassalazina/uso terapêutico , Fator de Necrose Tumoral alfa/antagonistas & inibidores
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