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Background:The most frequent mutation of Friedreich ataxia (FRDA) is the abnormal expansion of a GAA repeat located within the first intron of FXN gene. It is known that the length of GAA is directly correlated with disease severity. The effect of mutation is a severe reduction of mRNA. Recently, a link among aberrant CpG methylation, chromatin organisation and GAA repeat was proposed.Methods:In this study, using pyrosequencing technology, we have performed a quantitative analysis of the methylation status of five CpG sites located within the region upstream of GAA repeat, in 67 FRDA patients.Results:We confirm previous observation about differences in the methylation degree between FRDA individuals and controls. We showed a direct correlation between CpG methylation and triplet expansion size. Significant differences were found for each CpG tested (ANOVA p<0.001). These differences were largest for CpG1 and CpG2: 84.45% and 76.80%, respectively, in FRDA patients compared to 19.65% and 23.34% in the controls. Most importantly, we found a strong inverse correlation between CpG2 methylation degree and age of onset (Spearman’s ρ  =  −0.550, p<0.001).Conclusion:Because epigenetic changes may cause or contribute to gene silencing, our data may have relevance for the therapeutic approach to FRDA. Since the analysis can be performed in peripheral blood leucocytes (PBL), evaluation of the methylation status of specific CpG sites in FRDA patients could be a convenient biomarker.

HMGA1 proteins exert their major physiological function during embryonic development and play a critical role in neoplastic transformation. Here, we show that Hand1 gene, which codes for a transcription factor crucial for differentiation of trophoblast giant cells and heart development, is upregulated in hmga1 minus embryonic stem cells. We demonstrate that HMGA1 proteins bind directly to Hand1 promoter both in vitro and in vivo and inhibit Hand1 promoter activity. We have also investigated HAND1 expression in human thyroid carcinoma cell lines and tissues, in which HMGA proteins are overexpressed, with respect to normal thyroid; an inverse correlation between HMGA1 and HAND1 expression was found in all thyroid tumor histotypes. A correlation between HAND1 gene repression and promoter hypermethylation was found in anaplastic carcinomas but not in other thyroid tumor histotypes. Therefore, we can hypothesize that HMGA1 overexpression plays a key role on HAND1 silencing in differentiated thyroid carcinomas and that promoter hypermethylation occurs in later stages of thyroid tumor progression. Finally, the restoration of the HAND1 gene expression reduces the clonogenic ability of two human thyroid carcinoma-derived cell lines, suggesting that HAND1 downregulation may have a role in the process of thyroid carcinogenesis.

Background Mentalizing, the mental capacity to understand oneself and others in terms of mental states, has been found to be reduced in some mental disorders such as Borderline Personality Disorder (BPD). Some studies have suggested that Eating Disorders (EDs) may also be associated with impairments in mentalizing, but studies have not always yielded consistent results. This is the first study to systematically investigate mentalizing impairments in patients with Bulimia Nervosa (BN) compared with controls. In addition, we investigated whether impairments in mentalizing were related to BPD features, rather than BN per se, given the high comorbidity between BPD and BN. Methods Patients with BN ( n  = 53) and healthy controls (HCs; n  = 87) completed a battery of measures assessing mentalizing including the Reflective Function Questionnaires (RFQ), the Object Relations Inventory (ORI; Differentiation-Relatedness Scales) and the Reading The Mind in The Eyes Test (RMET). Results Patients with BN scored significantly lower than HCs on all tests of mentalizing, with moderate to large between-group effect sizes. These differences were partially accounted for by BPD features as assessed with the Zanarini Rating Scale for Borderline Personality Disorder (ZAN-BPD), and partially by bulimic symptoms measured with the Eating Disorder Examination Questionnaire (EDE-Q). Conclusions Patients with BN have significantly lower levels of mentalizing as assessed with a broad range of tests compared to HCs. These differences were related to both bulimic symptoms and BPD features. Although further research in larger samples is needed, if replicated, these findings suggest that poor mentalizing may be a significant factor in BN patients and should be addressed in treatment, regardless of the presence of BPD features.

We evaluated the prevalence and clinical associations of amenorrhea in 298 female juvenile systemic lupus erythematosus (JSLE) patients (ACR criteria) followed in 12 Brazilian Paediatric Rheumatology centres. Amenorrhea was observed in 35 patients (11.7%) with a mean duration of 7.2 ± 3.6 months. The hormones were performed in 32/35 patients and none of them had FSH and LH levels above and estradiol below the normal range according to pubertal changes. JSLE patients with amenorrhea were younger (15.04 ± 2.5 versus 17.8 ± 3.1 years; P = 0.001), and had a shorter period of time between menarche and current age (3.4 ± 2.9 versus 6.7 ± 5.4 years; P = 0.001). Interestingly, the frequency, cumulative dose, number of pulses and duration of intravenous cyclophosphamide treatment were alike in patients with and without amenorrhea (P > 0.05). In contrast, patients with amenorrhea had significantly higher SLEDAI (P = 0.01) and SLICC/ACR-DI (P = 0.024) scores compared to those without this condition. Independent risk factors identified by multivariate analysis were higher SLEDAI (OR = 1.059; CI = 1.004—1.116; P = 0.034) and SLICC/ACR-DI (OR = 2.125; IC = 1.373—3.291; P = 0.001) scores. Our data suggest that in spite of immunosuppressive therapy, JSLE patients have an adequate ovarian follicular reserve and amenorrhea is particularly associated with disease activity and damage. Lupus (2007) 16, 531—536.

Correction to: Oncogene (2009) 28, 876–885; doi:10.1038/onc.2008.438 Shown are raw images from a replicate experiment in support of the results shown in the Figure 1a of this article. Readers will note that these results confirm those shown in Figure 1a of the published article. Indeed, the HAND1 gene mRNA is virtually absent in the wild-type ES +/+ cells, while it is clearly detected in the ES HMGA1 +/− (roughly 50%dosage) and in the ES HMGA1 −/− (null) cells.

Peripheral T-cell lymphomas not otherwise specified (PTCLs/NOS) are rare and aggressive tumours whose molecular pathogenesis and diagnosis are still challenging. The microRNA (miRNA) profile of 23 PTCLs/NOS was generated and compared with that of normal T-lymphocytes (CD4+, CD8+, naive, activated). The differentially expressed miRNA signature was compared with the gene expression profile (GEP) of the same neoplasms. The obtained gene patterns were tested in an independent cohort of PTCLs/NOS. The miRNA profile of PTCLs/NOS then was compared with that of 10 angioimmunoblastic T-cell lymphomas (AITLs), 6 anaplastic large-cell lymphomas (ALCLs)/ALK+ and 6 ALCLs/ALK−. Differentially expressed miRNAs were validated in an independent set of 20 PTCLs/NOS, 20 AITLs, 19 ALCLs/ALK− and 15 ALCLs/ALK+. Two hundred and thirty-six miRNAs were found to differentiate PTCLs/NOS from activated T-lymphocytes. To assess which miRNAs impacted on GEP, a multistep analysis was performed, which identified all miRNAs inversely correlated to different potential target genes. One of the most discriminant miRNAs was selected and its expression was found to affect the global GEP of the tumours. Moreover, two sets of miRNAs were identified distinguishing PTCL/NOS from AITL and ALCL/ALK−, respectively. The diagnostic accuracy of this tool was very high (83.54%) and its prognostic value validated.

BackgroundData of diffuse alveolar hemorrhage (DAH) in childhood-onset systemic lupus erythematosus (cSLE) patients are limited due to the small representation of this complication in previous case series or the focus on the comparison to adult SLE, precluding an accurate analysis of associated factors and outcomes in patients with and without this severe complication.ObjectivesTo evaluate prevalence, clinical manifestations, laboratory abnormalities and treatment in a multicenter cohort study including 847 cSLE patients with and without diffuse DAH, as well as concomitant parameters of severity.MethodsDAH was defined as the presence of at least three respiratory symptoms or signs associated with diffuse interstitial/alveolar infiltrates on chest x-ray or high-resolution computer tomography and sudden drop in hemoglobin levels with no other source of bleeding. Holm-Bonferroni correction for multiple comparisons was performed adjusting the significance level (p<0.0022).ResultsDAH was evidenced in 19/847 (2.2%) cSLE patients. Cough/dyspnea/tachycardia/hypoxemia occurred in all cSLE patients with DAH. Concomitant parameters of severity observed were: mechanical ventilation in 14/19 (74%), hemoptysis 12/19 (63%), macrophage activation syndrome 2/19 (10%) and death 9/19 (47%). Further analysis of cSLE patients at DAH diagnosis compared to 76 cSLE control patients without DAH with same disease duration [3 (1–151) vs. 4 (1–151) months, p=0.335], showed higher frequencies of constitutional involvement (74% vs. 10%, p<0.0001), serositis (63% vs. 6%, p<0.0001) and sepsis (53% vs. 9%, p<0.0001) in the DAH group. The median of disease activity score (SLEDAI-2K) was significantly higher in cSLE patients with DAH [18 (5–40) vs. 6 (0–44), p<0.0001]. The frequencies of thrombocytopenia (53% vs. 12%, p<0.0001), intravenous methylprednisolone (95% vs. 16%, p<0.0001) and intravenous cyclophosphamide (47% vs. 8%, p<0.0001) were also significantly higher in DAH patients.ConclusionsThis is the largest study to evaluate DAH. This complication, although not a disease activity score descriptor, occurs in the context of significant moderate/severe cSLE flare. Importantly, we identified that this condition is associated with serious disease flare complicated by sepsis and with high mortality rate.AcknowledgementsThis study was supported by research grants from Conselho Nacional de Desenvolvimento Científico e Tecnolόgico (CNPq 301805/2013-0 to RMRP, 303752/2015-7 to MTT, 301479/2015-1 to CSM, 305068/2014-8 to EB and 303422/2015-7 to CAS), Federico Foundation (to EB, RMRP and CAS) and by Núcleo de Apoio à Pesquisa “Saúde da Criança e do Adolescente” da USP (NAP-CriAd) to CAS.Disclosure of Interest: None declared

The microstructural characteristics were evaluated of two types of Italian Farro (Triticum turgidum ssp. dicoccum) with spring and autumn growth habits, the former with a vitreous tendency and the latter with a floury tendency. Common wheat flours and grains (Triticum aestivum) were used as controls. Protein fractions such as glutenin and gliadin were extracted from Triticum turgidum ssp. dicoccum flours and studied by SDS-PAGE in order to make a comparison between the electrophoretic analyses and microstructural studies which were conducted on the same samples using Scanning Electron Microscopy (SEM and Cryo-SEM). The results obtained by SDS-PAGE showed that the gliadin patterns of both emmer samples were similar, while the common wheat gliadins showed a band at 90 kDa that was not present in the gliadin fraction of emmer. When the glutenin patterns were analysed, the autumn emmer did not show the low molecular weight protein bands (16-23 kDa) whilst spring emmer wheat appeared more similar to common wheat. Regarding the microstructural characteristics of the kernels, spring (vitreous tendency) emmer showed starch granules covered by protein to a higher extent than autumn emmer. These differences were also observed in flours. The gluten of spring emmer wheat was observed as a homogeneous structure showing similarities with common wheat gluten, while autumnal emmer gluten appeared more heterogeneous and lacking in structure.