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Genome-wide whole blood transcriptome profiling in a large European cohort of systemic sclerosis patients
Get PDFObjectives: The analysis of annotated transcripts from genome-wide expression studies may help to understand the pathogenesis of complex diseases, such as systemic sclerosis (SSc). We performed a whole blood (WB) transcriptome analysis on RNA collected in the context of the European PRECISESADS project, aiming at characterising the pathways that differentiate SSc from controls and that are reproducible in geographically diverse populations.
Methods: Samples from 162 patients and 252 controls were collected in RNA stabilisers. Cases and controls were divided into a discovery (n=79+163; Southern Europe) and validation cohort (n=83+89; Central-Western Europe). RNA sequencing was performed by an Illumina assay. Functional annotations of Reactome pathways were performed with the Functional Analysis of Individual Microarray Expression (FAIME) algorithm. In parallel, immunophenotyping of 28 circulating cell populations was performed. We tested the presence of differentially expressed genes/pathways and the correlation between absolute cell counts and RNA transcripts/FAIME scores in regression models. Results significant in both populations were considered as replicated.
Results: Overall, 15 224 genes and 1277 functional pathways were available; of these, 99 and 225 were significant in both sets. Among replicated pathways, we found a deregulation in type-I interferon, Toll-like receptor cascade, tumour suppressor p53 protein function, platelet degranulation and activation. RNA transcripts or FAIME scores were jointly correlated with cell subtypes with strong geographical differences; neutrophils were the major determinant of gene expression in SSc-WB samples.
Conclusions: We discovered a set of differentially expressed genes/pathways validated in two independent sets of patients with SSc, highlighting a number of deregulated processes that have relevance for the pathogenesis of autoimmunity and SSc.This work was supported by eU/eFPia/innovative Medicines initiative Joint Undertaking PRECISESADs Grant no. 115 565info:eu-repo/semantics/publishedVersio
Malformação congénita bilateral dos canais semicirculares e perda auditiva – Descrição de casos
Get PDFThe main aims of this observational study were to describe a poorly characterized malformation of the inner ear termed bilateral congenital semicircular canal malformation; determine if the degree and pattern of semicircular canal dysmorphology and the presence or absence of a well-formed cochlea predict audiological outcomes, type, and severity of congenital hearing loss; and investigate its relationship with known syndromic forms of hearing loss. Review of eight cases of hearing loss with radiographic evidence of congenital semicircular canal malformation was performed. Information was collected on clinical history, physical examination, computed tomography study and serial audiograms for all patients. Analyzed features included other syndrome-characteristic phenotypic dysmorphologies, audiometric configuration, severity and type of hearing loss, type of audiological rehabilitation, and presence of associated inner ear abnormalities besides those in the vestibular system.
Among the eight cases included in the study, six patients had recognized syndromes/chromosomal abnormalities. Hearing loss was moderate to profound in all cases. All patients had bilateral semicircular canal deformities, with usually identical anatomical pattern on each side. Of the eight cases, six had normal cochlear development; malformations in the tympanic membrane and external auditory canal were only found in one; changes in ossicular chain were found in three patients; vestibules and vestibular aqueduct were normal in most cases; and abnormalities of oval window development and hypoplasia were found in two cases.
The present study shows that a correlation between the severity and type of hearing loss and radiographic abnormalities is difficult to establish. Hearing loss associated with semicircular canal dysplasia is more likely due to anomalous membranous labyrinth development, which is not radiologically detectable by computerized tomography scan.info:eu-repo/semantics/publishedVersio
Calyceal migration of vascular embolization coils used to treat massive hemorrhage following percutaneous nephrolithotomy: an endoscopic finding during repeat percutaneous nephrolithotomy
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Urticária crónica espontânea em idade pediátrica
Get PDFIntroduction: Chronic spontaneous urticaria is characterized by emergence of pruritic maculopapular cutaneous lesions recurring for more than six weeks, without known triggering factor. Association with autoimmunity is sometimes present, with urticaria preceding the onset of autoimmune disease.
Clinical case: A five-year-old female with a personal history of allergic asthma and family history of thyroid disease was referred to the Immunoallergology consultation for cutaneous complaints compatible with urticaria with more than three years of evolution. Inducible urticaria forms were excluded. Analytical study revealed positive antinuclear antibodies with a 1/320 titer and positive basophil activation test after stimulation with autologous serum. Control of cutaneous manifestations was achieved with full dose antihistaminic H1.
Conclusion: Chronic spontaneous urticaria associated with autoimmunity is rare in children. Clinical follow-up should be maintained to evaluate disease control and enable early recognition of other autoimmunity manifestations.info:eu-repo/semantics/publishedVersio
Effectiveness of Tocilizumab in the Treatment of Fasciitis with Eosinophilia: Two Case Reports
Get PDFFasciitis with eosinophilia (FE) is a rare connective tissue disease. Due to its rarity, large-scale studies are lacking, which makes its treatment challenging. Systemic corticosteroids (SCSs) are the cornerstone of treatment; however, additional immunosuppressive drugs (ISDs) are frequently necessary (usually methotrexate). We report 2 patients, for whom an SCS and methotrexate were not a viable long-term option. In the first case, we were unable to taper the SCS dose without symptom relapse, the patient showed only a partial response to methotrexate and presented side effects. The second case never fully responded to the SCS and methotrexate and demonstrated serious SCS adverse effects. Both patients were started on tocilizumab with extremely favourable results, making this drug a potential therapeutic weapon for these patients.
Learning points: The treatment of FE is challenging and mainly based on retrospective reviews, open-label trials and case reports, all of which included a small number of patients.Currently, systemic corticosteroids are the mainstay of treatment; however, other ISDs are frequently necessary.Cases showing a favourable clinical response to tocilizumab have recently been described in patients with corticosteroid-refractory disease, suggesting that this drug may potentially become a therapeutic weapon for these patients.info:eu-repo/semantics/publishedVersio
Pancreatite e cetoacidose diabética numa adolescente tratada com sertralina
Get PDFAcute pancreatitis (AP) is a rare entity in pediatric age. Reports of AP in the context of diabetic ketoacidosis (DKA) have established the role of transient hyperlipemia as a consequent factor.
Pharmacological etiology is responsible for 0.3−1.4% of AP cases, with no case reports of an association with the use of sertraline in the pediatric population to date.
Herein is described the case of a 15-year-old girl with poorly controlled type 1 diabetes, taking sertraline for a depressive disorder, who developed AP associated with DKA.
With this report, the authors intend to emphasize the importance of diagnosing AP in DKA setting. In addition, since the patient had normal serum triglyceride levels and no other risk factors for AP, it is hypothesized that sertraline may have been a triggering event in this context.info:eu-repo/semantics/publishedVersio
Intradermal Tests With Drugs: An Approach to Standardization
Get PDFBackground: Intradermal tests (IDTs) are performed and interpreted differently in drug allergy centers making valid comparison of results difficult. Objective: To reduce method-related and intercenter variability of IDTs by the introduction of a standardized method. Materials and methods: In 11 centers of the European Network for Drug Allergy, IDTs were prospectively performed with saline and with amoxicillin (20 mg/ml) using (1) the local method and (2) the standardized European Network in Drug Allergy (ENDA) method (0.02 ml). The diameters of the initial injection wheal (Wi) for the different volumes and sites injected obtained from each center were analyzed. Results: The most reproducible method was to fill a syringe with test solution, then expel the excess fluid to obtain exactly 0.02 ml. The median Wi diameter with 0.02 ml injection using the standardized method was 5 mm [range 2-10 mm; interquartile range (IQR) 5-5 mm; n = 1,096] for saline and 5 mm (range 2-9 mm; IQR = 4.5-5 mm; n = 240) for amoxicillin. IDT injection sites did not affect the Wi diameter. Training improved precision and reduced the variability of Wi diameters. Conclusion: Using the standardized IDT method described in this multicenter study helped to reduce variability, enabling more reliable comparison of results between individuals and centers.info:eu-repo/semantics/publishedVersio
Novel MAG Variant Causes Cerebellar Ataxia with Oculomotor Apraxia: Molecular Basis and Expanded Clinical Phenotype
Get PDFHomozygous variants in MAG, encoding myelin-associated glycoprotein (MAG), have been associated with complicated forms of hereditary spastic paraplegia (HSP). MAG is a glycoprotein member of the immunoglobulin superfamily, expressed by myelination cells. In this study, we identified a novel homozygous missense variant in MAG (c.124T>C; p.Cys42Arg) in a Portuguese family with early-onset autosomal recessive cerebellar ataxia with neuropathy and oculomotor apraxia. We used homozygosity mapping and exome sequencing to identify the MAG variant, and cellular studies to confirm its detrimental effect. Our results showed that this variant reduces protein stability and impairs the post-translational processing (N-linked glycosylation) and subcellular localization of MAG, thereby associating a loss of protein function with the phenotype. Therefore, MAG variants should be considered in the diagnosis of hereditary cerebellar ataxia with oculomotor apraxia, in addition to spastic paraplegia.This work was funded by National Funds through FCT—Fundação para a Ciência e a Tecnologia, I.P.,under the project UIDB/04293/2020. It was also funded by FEDER funds through the Programa OperacionalFactores de Competitividade—COMPETE 2020 and by Nacional funds through the FCT [COMPETE:POCI-01-0145-FEDER-007440]. This work was also funded in part by the FCT grant FCT-ANR/BEX-GMG/0008/2013and the Porto Neurosciences and Neurologic Disease Research Initiative at the i3S (Norte-01-0145-FEDER-000008),supported by Norte Portugal Regional Operational Programme (NORTE 2020) under the PORTUGAL 2020Partnership Agreement, also through FEDER. The authors also acknowledge the support of the i3S ScientificPlatform Advanced Light Microscopy, member of the PPBI (PPBI-POCI-01-0145-FEDER-022122) and GenomePT(POCI-01-0145-FEDER-022184). MS was the recipient of a fellowship (SFRH/BPD/116046/2016) from the FCTsupported by POPH/MCTES funding.info:eu-repo/semantics/publishedVersio
Neonatal Cholestasis Over Time: Changes in Epidemiology and Outcome in a Cohort of 154 Patients from a Portuguese Tertiary Center
Get PDFIntroduction: In the last two decades there have been advances in the diagnosis and management of neonatal cholestasis, which may have changed its epidemiology, diagnostic accuracy, outcomes, and survival. Our goal was to characterize these changes over time in our setting. Methods: Retrospective cohort study in a tertiary center, enrolling patients born between January 1985 and October 2019. The cohort was divided into two periods, before (A; n = 67) and after (B; n = 87) the year 2000; and in two groups, according to patient's outcome (favorable, unfavorable). Overall survival and survival with and without orthotopic liver transplant (OLT) were evaluated in the two periods (A and B) and in different subgroups of underlying entities. Results: We found that the age of cholestasis recognition decreased significantly from period A to period B [median 43 days and 22 days, respectively, (p < 0.001)]; the changes in epidemiology were relevant, with a significant decrease in alpha-1-antitrypsin deficiency (p < 0.001) and an increase in transient cholestasis (p = 0.004). A next-generation sequencing (NGS) panel available since mid-2017 was applied to 13 patients with contributory results in 7, but, so far, only in 2 patients led to conclusive diagnosis of underlying entities. The number of cases of idiopathic cholestasis did not vary significantly. Over time there was no significant change in the outcome (p = 0.116). Overall survival and survival without OLT had no significant improvement during the period of observation (in periods A and B, 86 vs. 88%, and 85 vs. 87%, respectively). However, in period B, with OLT we achieved the goal of 100% of survival rate. Conclusions: Our data suggest that transient cholestasis became a very important subset of neonatal cholestasis, requiring specific guidance. The NGS panels can provide important inputs on disease diagnosis but, if applied without strict criteria and expertise, they can open a Pandora's box due to misinterpretation. Despite all the advances in accurate diagnosis and timely management-including early recognition of cholestasis-the improvement in patient outcomes and survival were still not significant.This work was supported by Applied Molecular Biosciences Unit (UCIBIO), which was financed by national funds from FCT/MCTES (UID/MULTI/04378/2019)info:eu-repo/semantics/publishedVersio
