A young soccer player with sudden pain after kicking the ball

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Neither hereditary periodic fever nor periodic fever, aphthae, pharingitis, adenitis: Undifferentiated periodic fever in a tertiary pediatric center

AIM: To describe the frequency and clinical characteristics of patients with undifferentiated periodic fever (UPF) and to investigate whether a clinical classification of UPF based on the PRINTO-Eurofever score can help predicting the response to treatment and the outcome at follow-up. METHODS: Clinical and therapeutic information of patients with recurrent fever who presented at a single pediatric rheumatology center from January 2006 through April 2016 were retrospectively collected. Patients with a clinical suspicion of hereditary periodic fever (HPF) syndrome and patients with clinical picture of periodic fever, aphthae, pharingitis, adenitis (PFAPA) who were refractory to tonsillectomy underwent molecular analysis of five HPF-related genes: MEFV (NM_000243.2), MVK (NM_000431.3), TNFRSF1A (NM_001065.3), NLRP3 (NM_001079821.2), NLRP12 (NM_001277126.1). All patients who had a negative genetic result were defined as UPF and further investigated. PRINTO-Eurofever score for clinical diagnosis of HPF was calculated in all cases. RESULTS: Of the 221 patients evaluated for periodic fever, twelve subjects with a clinical picture of PFAPA who were refractory to tonsillectomy and 22 subjects with a clinical suspicion of HPF underwent genetic analysis. Twenty-three patients (10.4%) resulted negative and were classified as UPF. The median age at presentation of patients with UPF was 9.5 mo (IQR 4-24). Patients with UPF had a higher frequency of aphthae (52.2% vs 0%, P = 0.0026) and musculoskeletal pain (65.2% vs 18.2%, P = 0.0255) than patients with genetic confirmed HPF. Also, patients with UPF had a higher frequency of aphthous stomatitis (52.2% vs 10.7%, P < 0.0001), musculoskeletal pain (65.2% vs 8,0%, P < 0.0001), and abdominal pain (52.2% vs 4.8%, P < 0.0001) and a lower frequency of pharyngitis (56.6% vs 81.3%, P = 0.0127) compared with typical PFAPA in the same cohort. Twenty-one of 23 patients with UPF (91.3%) received steroids, being effective in 16; 13 (56.2%) were given colchicine, which was effective in 6. Symptoms resolution occurred in 2 patients with UPF at last follow-up. Classification according to the PRINTO-Eurofever score did not correlate with treatment response and prognosis. CONCLUSION: UPF is not a rare diagnosis among patients with periodic fever. Clinical presentation place UPF half way on a clinical spectrum between PFAPA and HPF. The PRINTO-Eurofever score is not useful to predict clinical outcome and treatment response in these patients

Transcriptomic profiling of white blood cells reveals new insights into the molecular mechanisms of thalidomide in children with inflammatory bowel disease

Thalidomide has emerged as an effective immunomodulator in the treatment of pediatric patients with inflammatory bowel disease (IBD) refractory to standard therapies. Cereblon, a component of E3 protein ligase complex that mediates ubiquitination and proteasomal degradation of target proteins, has been identified as the primary target of thalidomide. Cereblon plays a crucial role in thalidomide teratogenicity, however it is unclear whether it is also involved in the therapeutic effects in IBD patients. This study aimed at identifying the mechanisms underpinning thalidomide action in pediatric IBD. Ten IBD pediatric patients clinically responsive to thalidomide were prospectively enrolled. RNA-sequencing and functional enrichment analysis was carried out on peripheral blood mononuclear cells obtained before and after treatment with thalidomide. RNA-sequencing analysis revealed 378 differentially expressed genes after treatment with thalidomide. The most deregulated pathways were cytosolic calcium ion concentration, cAMP-mediated signaling, eicosanoid signaling and inhibition of matrix metalloproteinases. Neuronal signaling mechanisms such as CREB signaling in neurons and axonal guidance signaling also emerged. Connectivity Map analysis revealed that thalidomide gene expression changes were similar to those induced by MLN4924, an inhibitor of NEDD8 activating enzyme, suggesting that thalidomide exerts its immunomodulatory effects by acting on the ubiquitin-proteasome pathway. In vitro experiments on cell lines confirmed the effect of thalidomide on altered candidate pathways observed in patients. These results represent a unique resource for enhanced understanding of thalidomide mechanism in patients with IBD, providing novel potential targets associated with drug response.Book of abstract: 4th Belgrade Bioinformatics Conference, June 19-23, 202

Summary results of the 2014-2015 DARPA Chikungunya challenge

BACKGROUND: Emerging pathogens such as Zika, chikungunya, Ebola, and dengue viruses are serious threats to national and global health security. Accurate forecasts of emerging epidemics and their severity are critical to minimizing subsequent mortality, morbidity, and economic loss. The recent introduction of chikungunya and Zika virus to the Americas underscores the need for better methods for disease surveillance and forecasting. METHODS: To explore the suitability of current approaches to forecasting emerging diseases, the Defense Advanced Research Projects Agency (DARPA) launched the 2014–2015 DARPA Chikungunya Challenge to forecast the number of cases and spread of chikungunya disease in the Americas. Challenge participants (n=38 during final evaluation) provided predictions of chikungunya epidemics across the Americas for a six-month period, from September 1, 2014 to February 16, 2015, to be evaluated by comparison with incidence data reported to the Pan American Health Organization (PAHO). This manuscript presents an overview of the challenge and a summary of the approaches used by the winners. RESULTS: Participant submissions were evaluated by a team of non-competing government subject matter experts based on numerical accuracy and methodology. Although this manuscript does not include in-depth analyses of the results, cursory analyses suggest that simpler models appear to outperform more complex approaches that included, for example, demographic information and transportation dynamics, due to the reporting biases, which can be implicitly captured in statistical models. Mosquito-dynamics, population specific information, and dengue-specific information correlated best with prediction accuracy. CONCLUSION: We conclude that with careful consideration and understanding of the relative advantages and disadvantages of particular methods, implementation of an effective prediction system is feasible. However, there is a need to improve the quality of the data in order to more accurately predict the course of epidemics

DIAGNOSTIC APPROACH TO MONOGENIC INFLAMMATORY BOWEL DISEASE WITH NEXT-GENERATION SEQUENCING TECHNOLOGIES.

Background & aims: Up to 15% inflammatory bowel diseases (IBD) rising before the age of 6 years, defined as Very-Early-Onset IBD (VEO-IBD), may have a monogenic disease. More rarely monogenic defects are found in later onset IBD. Monogenic IBD are associated with high morbidity and mortality and timely genetic diagnosis is essential for adequate treatment. Due to the wide phenotypic and genetic heterogeneity of these conditions, it is often difficult to reach a genetic diagnosis and the best diagnostic approach is still debated. Next generation sequencing (NGS) techniques have been proposed as a screening tool especially in patients with poorly defined phenotypes. In a cohort study that included patients with VEO-IBD and Early-onset IBD with severe/atypical phenotypes (EO-IBD s/a) we aimed to: describe the genetic diagnoses and their therapeutic implications, define the clinical characteristics associated with monogenicity, suggest a diagnostic approach to monogenic IBD. Methods: Clinical information of patients with VEO-IBD and EO-IBD s/a referred to 3 Italian Centers for a genetic work-up over 10 years (2008-2017) were collected. From 2015 newly diagnosed patients and patients without a previous genetic diagnosis were screened using NGS, except patients with disease specific features in whom candidate gene analysis was chosen. Results: 93 patients were collected and 14 (15%) reached a genetic diagnosis. Selective sequencing was performed in 47 patients (50%), NGS in 84 patients (90%). Causative defects were revealed by NGS in 5 patients (NOD2, TTC37, DKC1, XIAP, FERMT3) and candidate sequencing in 8 patients (2WAS, CYBA, CYBB, FOXP3, 2CD40L, XIAP). In 8 of 9 patients diagnosed with candidate sequencing, the analysis was guided by the presence of disease specific features. One patient, with unspecific presentation, underwent sequential sequencing of multiple genes over 15 months before reaching the diagnosis (XIAP). NGS identified a new NOD2 mutation previously missed with single gene approach. One patient with WAS, in whom Sanger sequencing had not revealed mutations, was diagnosed externally through WGS which revealed a large genomic inversion. Genetic diagnosis impacted patient management in 10 patients (71%): 6 underwent bone marrow transplant (2XIAP, 2WAS, 2CD40L, FOXP3), 1 gene therapy, 2 anti-infective prophylaxis and 1 introduced danazole (DKC1). Patients with monogenic IBD more frequently had a history of infections (71%vs30%; p<.001), thrombocytopenia (21% vs 3%; p.003), hemophagocytosis (21% vs 3%; p.02), and disease onset 64 1 month of life (36% vs 1%; p<.001) when compared to the non-monogenic group. Conclusion: We suggest using NGS in all patients presenting with non-specific clinical profiles and selective gene sequencing when clinical characteristics suggestive of specific monogenic conditions are present

Recent Insight into SARS-CoV2 Immunopathology and Rationale for Potential Treatment and Preventive Strategies in COVID-19

As the outbreak of the new coronavirus (SARS-CoV-2) infection is spreading globally, great effort is being made to understand the disease pathogenesis and host factors that predispose to disease progression in an attempt to find a window of opportunity for intervention. In addition to the direct cytopathic effect of the virus, the host hyper-inflammatory response has emerged as a key factor in determining disease severity and mortality. Accumulating clinical observations raised hypotheses to explain why some patients develop more severe disease while others only manifest mild or no symptoms. So far, Covid-19 management remains mainly supportive. However, many researches are underway to clarify the role of antiviral and immunomodulating drugs in changing morbidity and mortality in patients who become severely ill. This review summarizes the current state of knowledge on the interaction between SARS-CoV-2 and the host immune system and discusses recent findings on proposed pharmacologic treatments

L'epistassi nel bambino

Epistaxis is very common in children and usually originates from small anastomotic vessels in the anterior septum as a consequence of local trauma. In most cases bleeding is self-limiting and can be easily managed with direct compression of the nasal ala. Recurrent episodes of epistaxis might be difficult to manage definitively and often raise concern about possible bleeding disorders. The paper discusses the initial assessment and management of epistaxis in children, including when to suspect a systemic cause and when to refer to the ear, nose and throat specialist

What Are the Targets of Inflammatory Bowel Disease Management

With recent evidence suggesting that keeping the inflammatory process under tight control prevents long-term disability, the aim of treatments in inflammatory bowel disease (IBD) has shifted from symptom control toward the resolution of bowel inflammation. Mucosal healing is currently recognized as the principal treatment target to be used in a "treat to target" paradigm, whereas histologic healing and normalization of biomarkers are being evaluated as potential future targets. Although symptom relief is no longer a sufficient target, patient experience with the disease is of unquestionable importance and should be assessed in the form of patient-reported outcomes, to be used as a co-primary target with an objective measure of disease activity. IBD in is a heterogeneous disease; thus besides defining common treatment targets, every effort should be made to deliver a personalized treatment plan based on the risk factors for disease progression and individual drug metabolism to improve treatment success

Acute-onset pretibial swelling

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