Polymorphisms of CSF1 and TM7SF4 genes in a case of mild juvenile Paget's disease found using next-generation sequencing

Juvenile Paget's disease (JPD) is a rare autosomal-recessive condition. It is diagnosed in young children and characterized by a generalized increase in bone turnover, bone pain, and skeletal deformity. Our patient was diagnosed after a pathological fracture when she was 11 years old. When we first examined her at the age of 30 she had bone pain and deformity in both the femur and tibia. Serum alkaline phosphatase (ALP) level, radiology, bone scintigraphy, and densitometry were monitored. Next generation sequencing (NGS) technology, namely semiconductor sequencing, was used to determine the genetic background of JPD. Seven target genes and regions were selected and analyzed after literature review (TM7SF4, SQSTM1, TNFRSF11A, TNFRSF11B, OPTN, CSF1, VCP). No clear pathogenic mutation was found, but we detected missense polymorphisms in CSF1 and TM7SF4 genes. After treatment with zoledronic acid, infusion bone pain and ALP level decreased. We can conclude that intravenous zoledronic acid therapy is effective and safe for suppressing bone turnover and improving symptoms in JPD, but the long-term effects on clinical outcomes are unclear. Our findings also suggest that NGS may help explore the pathogenesis and aid the diagnosis of JPD

The potential use of the Penicillium chrysogenum antifungal protein PAF, the designed variant PAFopt and its γ-core peptide Pγopt in plant protection

The prevention of enormous crop losses caused by pesticide-resistant fungi is a serious challenge in agriculture. Application of alternative fungicides, such as antifungal proteins and peptides, provides a promising basis to overcome this problem; however, their direct use in fields suffers limitations, such as high cost of production, low stability, narrow antifungal spectrum and toxicity on plant or mammalian cells. Recently, we demonstrated that a Penicillium chrysogenum-based expression system provides a feasible tool for economic production of P. chrysogenum antifungal protein (PAF) and a rational designed variant (PAFopt ), in which the evolutionary conserved γ-core motif was modified to increase antifungal activity. In the present study, we report for the first time that γ-core modulation influences the antifungal spectrum and efficacy of PAF against important plant pathogenic ascomycetes, and the synthetic γ-core peptide Pγopt , a derivative of PAFopt , is antifungal active against these pathogens in vitro. Finally, we proved the protective potential of PAF against Botrytis cinerea infection in tomato plant leaves. The lack of any toxic effects on mammalian cells and plant seedlings, as well as the high tolerance to harsh environmental conditions and proteolytic degradation further strengthen our concept for applicability of these proteins and peptide in agriculture

Guidance on noncorticosteroid systemic immunomodulatory therapy in noninfectious uveitis: fundamentals of care for uveitis (focus) initiative

Topic: An international, expert-led consensus initiative to develop systematic, evidence-based recommendations for the treatment of noninfectious uveitis in the era of biologics. Clinical Relevance: The availability of biologic agents for the treatment of human eye disease has altered practice patterns for the management of noninfectious uveitis. Current guidelines are insufficient to assure optimal use of noncorticosteroid systemic immunomodulatory agents. Methods: An international expert steering committee comprising 9 uveitis specialists (including both ophthalmologists and rheumatologists) identified clinical questions and, together with 6 bibliographic fellows trained in uveitis, conducted a Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocol systematic reviewof the literature (English language studies from January 1996 through June 2016; Medline [OVID], the Central Cochrane library, EMBASE,CINAHL,SCOPUS,BIOSIS, andWeb of Science). Publications included randomized controlled trials, prospective and retrospective studies with sufficient follow-up, case series with 15 cases or more, peer-reviewed articles, and hand-searched conference abstracts from key conferences. The proposed statements were circulated among 130 international uveitis experts for review.Atotal of 44 globally representativegroupmembersmet in late 2016 to refine these guidelines using a modified Delphi technique and assigned Oxford levels of evidence. Results: In total, 10 questions were addressed resulting in 21 evidence-based guidance statements covering the following topics: when to start noncorticosteroid immunomodulatory therapy, including both biologic and nonbiologic agents; what data to collect before treatment; when to modify or withdraw treatment; how to select agents based on individual efficacy and safety profiles; and evidence in specific uveitic conditions. Shared decision-making, communication among providers and safety monitoring also were addressed as part of the recommendations. Pharmacoeconomic considerations were not addressed. Conclusions: Consensus guidelines were developed based on published literature, expert opinion, and practical experience to bridge the gap between clinical needs and medical evidence to support the treatment of patients with noninfectious uveitis with noncorticosteroid immunomodulatory agents

High morbid-mortability and reduced level of osteoporosis diagnosis among elderly people who had hip fractures in São Paulo City

OBJECTIVE: To know the morbid-mortality following an osteoporotic hip fracture in elderly patients living in São Paulo. PATIENTS AND METHODS: This study evaluated prospectively all patient over 60 years admitted in 2 school-hospitals in the city of São Paulo in a following 6-month period due to a osteoporotic proximal femur fracture. All of them filled up the Health Assessment Questionnaire (HAQ) and had their chart reviewed. After 6 months they were re-interviewed. Linear regression analysis was utilized to determine the factors related to functional ability. RESULTS: 56 patients were included (mean age 80.7 ± 7.9 years old, 80.4% females). After the 6-month follow up the mortality rate was 23.2%. Only 30% of the patients returned to their previous activities, and 11.6% became totally dependent. Factors related to worse functional ability after fracture were HAQ before fracture, institutionalization after fracture and age (r² 0.482). The diagnosis of osteoporosis was informed only by 13.9% of them, and just 11.6% received any treatment for that. CONCLUSION: Our results showed the great impact of these fractures on mortality and in the functional ability of these patients. Nevertheless, many of our physicians do not inform the patients about the diagnosis of osteoporosis and, consequently, the treatment of this condition is jeopardized.As fraturas osteoporóticas de fêmur proximal trazem graves conseqüências quanto à morbimortalidade e à qualidade de vida, mas desconhece-se este impacto no Brasil. OBJETIVO: Conhecer a morbimortalidade decorrente deste tipo de fraturas em idosos na cidade de São Paulo. MÉTODOS: Foram incluídos todos os pacientes com mais de 60 anos internados por fraturas de fêmur proximal durante seis meses, em dois hospitais de São Paulo. Os pacientes preencheram o questionário de capacidade funcional (HAQ), tiveram seu prontuário examinado e foram reavaliados após seis meses. Utilizou-se a análise de regressão linear para determinar os fatores relacionados à capacidade funcional. RESULTADOS: Cinqüenta e seis pacientes foram incluídos no estudo (80,7 ± 7,9 anos; 80,4% mulheres). A mortalidade em seis meses foi de 23,2%. Apenas 30% retornaram plenamente às suas atividades prévias e 11,6% tornaram-se completamente dependentes. Os fatores que mais bem conseguiram prever pior capacidade funcional após a fratura foram HAQ pré-fratura, institucionalização pós-fratura e idade (r² 0,482). Somente 13,9% receberam o diagnóstico de osteoporose e 11,6% iniciaram algum tratamento. CONCLUSÕES: Os resultados do presente estudo demonstram o impacto deste tipo de fraturas sobre a mortalidade e a capacidade funcional. Entretanto, a falha médica no diagnóstico e na orientação de tratamento da osteoporose permanece elevada.Universidade Federal de São Paulo (UNIFESP) Escola Paulista de MedicinaSanta Casa de Misericórdia de São Paulo Departamento de OrtopediaUNIFESP-EPM EPMUNIFESP, EPM, EPMSciEL

EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update

Objectives: To provide an update of the European League Against Rheumatism (EULAR) rheumatoid arthritis (RA) management recommendations to account for the most recent developments in the field. Methods: An international task force considered new evidence supporting or contradicting previous recommendations and novel therapies and strategic insights based on two systematic literature searches on efficacy and safety of disease-modifying antirheumatic drugs (DMARDs) since the last update (2016) until 2019. A predefined voting process was applied, current levels of evidence and strengths of recommendation were assigned and participants ultimately voted independently on their level of agreement with each of the items. Results: The task force agreed on 5 overarching principles and 12 recommendations concerning use of conventional synthetic (cs) DMARDs (methotrexate (MTX), leflunomide, sulfasalazine); glucocorticoids (GCs); biological (b) DMARDs (tumour necrosis factor inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab), abatacept, rituximab, tocilizumab, sarilumab and biosimilar (bs) DMARDs) and targeted synthetic (ts) DMARDs (the Janus kinase (JAK) inhibitors tofacitinib, baricitinib, filgotinib, upadacitinib). Guidance on monotherapy, combination therapy, treatment strategies (treat-to-target) and tapering on sustained clinical remission is provided. Cost and sequencing of b/tsDMARDs are addressed. Initially, MTX plus GCs and upon insufficient response to this therapy within 3 to 6 months, stratification according to risk factors is recommended. With poor prognostic factors (presence of autoantibodies, high disease activity, early erosions or failure of two csDMARDs), any bDMARD or JAK inhibitor should be added to the csDMARD. If this fails, any other bDMARD (from another or the same class) or tsDMARD is recommended. On sustained remission, DMARDs may be tapered, but not be stopped. Levels of evidence and levels of agreement were mostly high. Conclusions: These updated EULAR recommendations provide consensus on the management of RA with respect to benefit, safety, preferences and cost