OBJECTIVES: The 2016 ACR-EULAR Response Criteria for JDM was developed as a composite measure with differential weights of six core set measures (CSMs) to calculate a Total Improvement Score (TIS). We assessed the contribution of each CSM, representation of muscle-related and patient-reported CSMs towards improvement, and frequency of CSM worsening across myositis response criteria (MRC) categories in validation of MRC. METHODS: Data from JDM patients in the Rituximab in Myositis trial (n = 48), PRINTO JDM trial (n = 139), and consensus patient profiles (n = 273) were included. Observed vs expected CSM contributions were compared using Sign test. Characteristics of MRC categories were compared by Wilcoxon tests with Bonferroni adjustment. Spearman correlation of changes in TIS and individual CSMs were examined. Agreement between physician-assessed change and MRC categories was evaluated by weighted Cohen's kappa. RESULTS: Of 457 JDM patients with IMACS CSMs and 380 with PRINTO CSMs, 9-13% had minimal, 19-23% had moderate and 41-50% had major improvement. The number of improved and absolute percentage change of CSMs increased by MRC improvement level. Patients with minimal improvement by MRC had a median of 0-1 CSM worsened, and those with moderate/major improvement had a median of zero worsening CSMs. Of patients improved by MRC, 94-95% had improvement in muscle strength and 93-95% had improvement in ≥1 patient-reported CSM. IMACS and PRINTO CSMs performed similarly. Physician-rated change and MRC improvement categories had moderate-to-substantial agreement (Kappa 0.5-0.7). CONCLUSION: The ACR-EULAR MRC perform consistently across multiple studies, supporting its further use as an efficacy end point in JDM trials.
Tuberous sclerosis complex (TSC) is a monogenetic disease that arises due to mutations in either the TSC1 or TSC2 gene and affects multiple organ systems. One of the hallmark manifestations of TSC are cortical malformations referred to as cortical tubers. These tubers are frequently associated with treatment-resistant epilepsy. Some of these patients are candidates for epilepsy surgery. White matter abnormalities, such as loss of myelin and oligodendroglia, have been described in a small subset of resected tubers but mechanisms underlying this phenomenon are unclear. Herein, we analyzed a variety of neuropathologic and immunohistochemical features in gray and white matter areas of resected cortical tubers from 46 TSC patients using semi-automated quantitative image analysis. We observed divergent amounts of myelin basic protein as well as numbers of oligodendroglia in both gray and white matter when compared with matched controls. Analyses of clinical data indicated that reduced numbers of oligodendroglia were associated with lower numbers on the intelligence quotient scale and that lower amounts of myelin-associated oligodendrocyte basic protein were associated with the presence of autism-spectrum disorder. In conclusion, myelin pathology in cortical tubers extends beyond the white matter and may be linked to cognitive dysfunction in TSC patients.
- MeSH
- bílá hmota patologie MeSH
- lidé MeSH
- mozková kůra patologie MeSH
- myelinová pochva patologie MeSH
- oligodendroglie patologie MeSH
- šedá hmota patologie MeSH
- tuberózní skleróza patologie MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Neuronal intranuclear inclusion disease (NIID) is a progressive neurodegenerative disorder categorized into 3 phenotypic variants: infantile, juvenile, and adult. Four recent reports have linked NIID to CGG expansions in the NOTCH2NLC gene in adult NIID (aNIID) and several juvenile patients. Infantile NIID (iNIID) is an extremely rare neuropediatric condition. We present a 7-year-old male patient with severe progressive neurodegenerative disease that included cerebellar symptoms with cerebellar atrophy on brain MRI, psychomotor developmental regression, pseudobulbar syndrome, and polyneuropathy. The diagnosis of iNIID was established through a postmortem neuropathology work-up. We performed long-read sequencing of the critical NOTCH2NLC repeat motif and found no expansion in the patient. We also re-evaluated an antemortem skin biopsy that was collected when the patient was 2 years and 8 months old and did not identify the intranuclear inclusions. In our report, we highlight that the 2 methods (skin biopsy and CGG expansion testing in NOTCH2NLC) used to identify aNIID patients may provide negative results in iNIID patients.
- MeSH
- biopsie MeSH
- dítě MeSH
- intranukleární inkluzní tělíska genetika patologie MeSH
- kojenec MeSH
- kůže patologie MeSH
- lidé MeSH
- mícha patologie MeSH
- mozek patologie MeSH
- neurodegenerativní nemoci diagnóza genetika patologie MeSH
- novorozenec MeSH
- předškolní dítě MeSH
- receptor Notch2 genetika MeSH
- trinukleotidové repetice genetika MeSH
- Check Tag
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- mužské pohlaví MeSH
- novorozenec MeSH
- předškolní dítě MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
- práce podpořená grantem MeSH
Aberrant DNA methylation at specific genetic loci is a key molecular feature of juvenile myelomonocytic leukemia (JMML) with poor prognosis. Using quantitative high-resolution mass spectrometry, we identified RASA4 isoform 2, which maps to chromosome 7 and encodes a member of the GAP1 family of GTPase-activating proteins for small G proteins, as a recurrent target of isoform-specific DNA hypermethylation in JMML (51% of 125 patients analyzed). RASA4 isoform 2 promoter methylation correlated with clinical parameters predicting poor prognosis (older age, elevated fetal hemoglobin), with higher risk of relapse after hematopoietic stem cell transplantation, and with PTPN11 mutation. The level of isoform 2 methylation increased in relapsed cases after transplantation. Interestingly, most JMML cases with monosomy 7 exhibited hypermethylation on the remaining RASA4 allele. The results corroborate the significance of epigenetic modifications in the phenotype of aggressive JMML.
- MeSH
- chemorezistence * MeSH
- CpG ostrůvky MeSH
- dítě MeSH
- juvenilní myelomonocytární leukemie diagnóza metabolismus patologie MeSH
- kojenec MeSH
- lidé MeSH
- lidské chromozomy, pár 7 MeSH
- metylace DNA * MeSH
- mladiství MeSH
- monozomie MeSH
- mutace MeSH
- předškolní dítě MeSH
- prognóza MeSH
- promotorové oblasti (genetika) MeSH
- protein - isoformy genetika metabolismus MeSH
- proteiny aktivující GTPasu ras genetika metabolismus MeSH
- tyrosinfosfatasa nereceptorového typu 11 genetika metabolismus MeSH
- umlčování genů MeSH
- Check Tag
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Inflammatory bowel diseases (IBD) are emerging globally, indicating that environmental factors may be important in their pathogenesis. Colonic mucosal epigenetic changes, such as DNA methylation, can occur in response to the environment and have been implicated in IBD pathology. However, mucosal DNA methylation has not been examined in treatment-naïve patients. We studied DNA methylation in untreated, left sided colonic biopsy specimens using the Infinium HumanMethylation450 BeadChip array. We analyzed 22 control (C) patients, 15 untreated Crohn's disease (CD) patients, and 9 untreated ulcerative colitis (UC) patients from two cohorts. Samples obtained at the time of clinical remission from two of the treatment-naïve UC patients were also included into the analysis. UC-specific gene expression was interrogated in a subset of adjacent samples (5 C and 5 UC) using the Affymetrix GeneChip PrimeView Human Gene Expression Arrays. Only treatment-naïve UC separated from control. One-hundred-and-twenty genes with significant expression change in UC (> 2-fold, P<0.05) were associated with differentially methylated regions (DMRs). Epigenetically associated gene expression changes (including gene expression changes in the IFITM1, ITGB2, S100A9, SLPI, SAA1, and STAT3 genes) were linked to colonic mucosal immune and defense responses. These findings underscore the relationship between epigenetic changes and inflammation in pediatric treatment-naïve UC and may have potential etiologic, diagnostic, and therapeutic relevance for IBD.
- MeSH
- Crohnova nemoc genetika imunologie MeSH
- dítě MeSH
- epigeneze genetická MeSH
- exprese genu MeSH
- kolon imunologie MeSH
- lidé MeSH
- metylace DNA imunologie MeSH
- mladiství MeSH
- mladý dospělý MeSH
- předškolní dítě MeSH
- slizniční imunita MeSH
- střevní sliznice imunologie MeSH
- studie případů a kontrol MeSH
- ulcerózní kolitida genetika imunologie MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
Abnormalities in CD4+CD25+ regulatory T cells (Treg) may contribute to type 1 diabetes (T1D) development. First-degree relatives of T1D patients are at increased risk especially when they carry certain HLA II haplotypes. Using two novel markers of CD4+CD25+ Treg (CD127- and FoxP3+ respectively), we evaluated number and function of Treg after specific stimulation with diabetogeneic autoantigens in 11 high-risk (according to HLA-linked risk) relatives of T1D patients and 14 age-matched healthy controls using a cytokine secretion assay based on interferon-gamma (IFN-gamma) production. High-risk relatives of T1D patients had significantly lower pre- and post-stimulatory number of CD127- Treg than that of healthy controls (P < 0.05). Labelling Treg with FoxP3+ demonstrated similar trend but did not reach statistical significance. Although the stimulation with diabetogenic autoantigens did not lead to a significant change in number of Treg in both groups, the defective function of Treg was performed by significantly higher activation of diabetogeneic T cells in high-risk relatives of T1D patients compared to healthy controls (P < or = 0.02). Individuals at increased HLA-associated genetic risk for T1D showed defects in Treg.
- MeSH
- antigeny CD4 analýza MeSH
- diabetes mellitus 1. typu imunologie MeSH
- dospělí MeSH
- financování organizované MeSH
- forkhead transkripční faktory analýza MeSH
- kultivované buňky MeSH
- lidé MeSH
- mladiství MeSH
- počet lymfocytů MeSH
- průtoková cytometrie MeSH
- receptor interleukinu-2 - alfa-podjednotka analýza MeSH
- receptor interleukinu-7 - alfa-podjednotka analýza MeSH
- regulační T-lymfocyty imunologie MeSH
- rizikové faktory MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- MeSH
- aberace pohlavních chromozomů MeSH
- karyotypizace MeSH
- lidé MeSH
- mladiství MeSH
- schizofrenie genetika MeSH
- tělesná výška MeSH
- XYY karyotyp diagnóza MeSH
- Check Tag
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
- MeSH
- chromozomální aberace MeSH
- dítě MeSH
- dospělí MeSH
- Downův syndrom genetika imunologie MeSH
- imunoglobuliny MeSH
- lidé MeSH
- mladiství MeSH
- Turnerův syndrom genetika imunologie MeSH
- tvorba protilátek MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
