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Introduction: Kagami-Ogata syndrome (KOS14) and Temple syndrome (TS14) are two disorders associated with reciprocal alterations within the chr14q32 imprinted domain. Here, we present a work-up strategy for preimplantation genetic testing (PGT) to avoid the transmission of a causative micro-deletion., Methods: We analysed DNA from the KOS14 index case and parents using methylation-sensitive ligation-mediated probe amplification and methylation pyrosequencing. The extent of the deletion was mapped using SNP arrays. PGT was performed in trophectoderm samples in order to identify unaffected embryos. Samples were amplified using multiple displacement amplification, followed by genome-wide SNP genotyping to determine the at-risk haplotype and next-generation sequencing to determine aneuploidies., Results: A fully methylated pattern at the normally paternally methylated IG-DMR and MEG3 DMR in the KOS14 proband, accompanied by an unmethylated profile in the TS14 mother was consistent with maternal and paternal transmission of a deletion, respectively. Further analysis revealed a 108 kb deletion in both cases. The inheritance of the deletion on different parental alleles was consistent with the opposing phenotypes. In vitro fertilisation with intracytoplasmatic sperm injection and PGT were used to screen for deletion status and to transfer an unaffected embryo in this couple. A single euploid-unaffected embryo was identified resulting in a healthy baby born., Discussion: We identify a microdeletion responsible for multigeneration KOS14 and TS14 within a single family where carriers have a 50% risk of transmitting the deletion to their offspring. We show that PGT can successfully be offered to couples with IDs caused by genetic anomalies., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Establishing the safety of non-caloric sweetener consumption in humans is a difficult task, since many contradictory results have been reported. The objective of this study was to compare the effect of frequent intake of sucrose, sucralose or steviol glycosides, on selected anthropometric, biochemical and immunological parameters in healthy, young adults. 38 individuals with normal body mass index were recruited and randomly divided into three experimental groups. After a washout week (where food with added sweeteners was restricted), each group was supplemented with sucrose (8 × 5 g packets/day), sucralose or steviol glycosides (4 × 1 g packets/day each) for 6 weeks. Selected variables were measured before and after treatment in each group and differences within and among groups were assessed. Our results showed that, compared to baseline, there was a modest but significant increase in weight (p = 0.0293) in the sucralose group, while the steviol glycosides group reduced their fat mass (p = 0.0390). No differences were observed in glycaemia; however, there was a significant increase in serum triglycerides (77.8-110.8 mg/dL) and cholesterol (162.0-172.3 mg/dL) in the sucrose group, whereas the steviol glycosides group presented lower triglycerides (104.7-92.8 mg/dL) and TNF-α concentrations (51.1-47.5 pg/mL). Comparison among groups showed differences in serum triglycerides (p = 0.0226), TNF-α (p = 0.0460) and IL-β (p = 0.0008). Our results suggest that, even in a short time span, frequent intake of steviol glycosides may have positive effects on metabolic parameters that may be relevant for human health.

Rationale & Objective: In Central America, there is a high prevalence of chronic kidney disease (CKD) of nontraditional etiology often observed among agricultural workers. Few studies have assessed CKD prevalence among workers in nonagricultural occupations, which was the objective of this investigation., Study Design: Prospective cohort study., Setting & Participants: Male and female workers (n = 224) employed by artisanal brickmaking facilities in La Paz Centro, Nicaragua., Predictors: Age, sex, education, smoking status, body mass index, alcohol consumption, water consumption, first-degree relative(s) with CKD, years worked, hours worked per week, job category, study visit (baseline and follow-up), and self-reported hypertension and diabetes., Outcomes: CKD defined as estimated glomerular filtration rate (eGFR) < 60mL/min/1.73m 2 at 2 time points 4 months apart and CKD stage., Analytical Approach: A linear mixed-effects model with an unstructured covariance matrix was used to evaluate the association between demographics, occupational risk factors, and eGFR at baseline. The interaction between risk factors and time with change in eGFR was also evaluated. Multivariable logistic regression models were used to evaluate predictors of CKD., Results: The CKD prevalence was 12.1% (n = 27), 100% of cases were male, 30% had stage 5 CKD (eGFR < 15mL/min/1.73m 2 ), and 22% were younger than 35 years. Proportions of participants with eGFRs < 60mL/min/1.73m 2 at baseline and follow-up were 13.8% and 15.2%, respectively. Linear regression analysis demonstrated significant predictors of lower kidney function at baseline including oven work, older age, lack of education, and having an immediate family member with CKD. Predictors of CKD identified using logistic regression analysis included oven work and lack of education., Limitations: Crude job classification measures, loss to follow-up, self-reported exposures., Conclusions: The prevalence of CKD is high in this population of brick workers, suggesting that the epidemic of CKD affecting Mesoamerica is not limited to agricultural workers. These results are consistent with the hypothesis that occupational heat exposure is a risk factor for kidney disease in this region., (Copyright © 2019 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Genome-wide studies have begun to link subtle variations in both allelic DNA methylation and parent-of-origin genetic effects with early development. Numerous reports have highlighted that the placenta plays a critical role in coordinating fetal growth, with many key functions regulated by genomic imprinting. With the recent description of wide-spread polymorphic placenta-specific imprinting, the molecular mechanisms leading to this curious polymorphic epigenetic phenomenon is unknown, as is their involvement in pregnancies complications., Results: Profiling of 35 ubiquitous and 112 placenta-specific imprinted differentially methylated regions (DMRs) using high-density methylation arrays and pyrosequencing revealed isolated aberrant methylation at ubiquitous DMRs as well as abundant hypomethylation at placenta-specific DMRs. Analysis of the underlying chromatin state revealed that the polymorphic nature is not only evident at the level of allelic methylation, but DMRs can also adopt an unusual epigenetic signature where the underlying histones are biallelically enrichment of H3K4 methylation, a modification normally mutually exclusive with DNA methylation. Quantitative expression analysis in placenta identified two genes, GPR1-AS1 and ZDBF2, that were differentially expressed between IUGRs and control samples after adjusting for clinical factors, revealing coordinated deregulation at the chromosome 2q33 imprinted locus., Conclusions: DNA methylation is less stable at placenta-specific imprinted DMRs compared to ubiquitous DMRs and contributes to privileged state of the placenta epigenome. IUGR-associated expression differences were identified for several imprinted transcripts independent of allelic methylation. Further work is required to determine if these differences are the cause IUGR or reflect unique adaption by the placenta to developmental stresses.

The Chilean physician Hans Betzhold published the book Eugenesia (Eugenics) in 1939, which was a work that received multiple awards and ran to a second edition in 1942. Both editions and the participation of Betzhold at the Second Peruvian Conference on Eugenics in 1943 attest to the fact that he was an important actor in the field of Chilean eugenics. This paper analyzes his transition from the publication of Eugenesia, in which he proposes a National Eugenics Department combining existing projects and laws to make the eugenic ideal a reality until its intervention, in the year 1943, when his optimism yields to disillusion regarding the task of creating a "Chilean superman."

Aim: This study aimed to establish a catalog of probes corresponding to imprinted differentially methylated regions (DMRs) on the Infinium HumanMethylationEPIC BeadChip., Materials & Methods: Reciprocal uniparental diploidies with low normal biparental mosaic contribution, together with normal diploid controls, were subjected to EPIC BeadChip hybridization. The methylation profiles were assessed for imprinted differential methylation. Top candidates were validated using locus-specific PCR-based assays., Results: Seven hundred and eighty-nine CpG probes coincided with 50 known imprinted DMRs and 467 CpG probes corresponding to 124 novel imprinted DMR candidates were identified. Validation led to identification of several subtle DMRs within known imprinted domains as well as novel maternally methylated regions associated with PTCHD3 and JAKMIP1., Conclusion: Our comprehensive list of bona fide-imprinted DMR probes will simplify and facilitate methylation profiling of individuals with imprinting disorders and is applicable to other diseases in which aberrant imprinting has been implicated, such as cancer and fetal growth.

Objective: To compare sensitivity, specificity and predictive value of Deauville score (DS) vs. ΔSUVmax in interim-treatment PET (iPET) and end-treatment PET (ePET), in patients with diffuse large B cell lymphoma (DLBCL), Hodgkin lymphoma (HL), and follicular lymphoma (FL)., Method: Retrospective longitudinal multicentre study including 138 patients (46 DLBCL, 46 HL, 46 FL), on whom 3 18 F-FDG PET/CT were performed: baseline, iPET, and ePET. Visual (DS) and semi-quantitative (ΔSUVmax) parameters were determined for iPET and ePET. Predictive value was determined in relation to disease-free interval., Results: Statistical analysis. iPET for DLBCL, HL, and FL: 1) sensitivity of DS: 76.92/83.33/61.53%; specificity: 78.78/85/81.81%; 2) sensitivity of ΔSUVmax: 53.84/83.33/61.53%; specificity: 87.87/87.50/78.78%. ePET for DLBCL, HL and FL: 1) sensitivity of DS: 61.53/83.33/69.23%; specificity: 90.90/85/87.87%; 2) sensitivity of ΔSUVmax: 69.23/83.33/69.23%; specificity: 90.90/87.50/84.84%. Predictive assessment. iPET study: in DLBCL, DS resulted in 10.3% recurrence of negative iPET, and 17.1% in ΔSUVmax at disease-free interval; in HL, both parameters showed a 2.8% recurrence of negative iPET; in FL, DS resulted in 15.6% recurrence of negative iPET, and 16.1% in ΔSUVmax, with no statistical significance. ePET study: in DLBCL, DS resulted in 14.3% recurrence of negative ePET, and 11.8% in ΔSUVmax at disease-free interval; in HL and FL, both methods showed 2.8 and 12.5% recurrence in negative ePET, respectively., Conclusion: DS and ΔSUVmax did not show significant differences in DLBCL, HL and FL. Their predictive value also did not show significant differences in HL and FL. In DLBCL, DS was higher in iPET, and ΔSUVmax in ePET., (Copyright © 2017 Elsevier España, S.L.U. y SEMNIM. All rights reserved.)

Acute lymphoblastic leukemia (ALL) following solid organ or hematologic malignancy (secondary ALL, s-ALL) is not well characterized. We analyzed the characteristics and outcome of patients with s-ALL and compared them with those of patients with de novo- ALL. Of 448 patients, 24 (5%) had previous neoplasia. Sixteen patients had received previous cytotoxic therapy (therapy-associated ALL, t-ALL), and eight had not (antecedent-malignancy ALL, am-ALL). Except for more advanced age in patients with s-ALL, no statistically significant differences were observed in WBC count, CNS involvement, immunophenotype or cytogenetics between the groups, nor in complete remission (t-ALL: 94%; am-ALL: 75%; de novo-ALL: 85%), 3-year remission duration (58%; 50%; 72%), overall survival (71%; 38%; 60%) or event-free survival (53%, 38%; 53%). Our study did not show poor clinical or cytogenetic features or inferior outcome in ALL patients with antecedent neoplastic disease, irrespective of the type of treatment received for the neoplasia.

Rejuvenation was a chapter of critical importance for the worldwide development of endocrinology in the 1920s. This work explores the acceptance of these techniques in Chile. Starting in the late 19th century, the Chilean Medical Journal (Revista Médica de Chile) incorporated references to experiments with endocrine gland preparations that were being conducted in Europe at the time. An appropriation of the experiments by the Austrian Eugen Steinach began in 1920, with prominent figures such as the Italian professor Juan Noe Crevani and the young Chilean student Ottmar Wilhelm. Between 1922 and 1924, Wilhelm developed a series of experiments on dogs, bulls, pigs, rats and Welfare Board patients through the so-called Steinach operation, which consisted of the sectioning of the efferent channel in one of the testicles. Professor Noe's scientific patronage policy and Wilhelm's strategy of succession in the field led the latter to hold a chair in the new School of Medicine of Universidad de Concepci6n at the age of 25. From this position, the. figure of Wilhelm was fundamental for the development of a line of endocrinological research that was able to position Universidad de Concepci6n as a scientific development centre, which was strengthened by the arrival of another disciple of Steinach in Chile, the Latvian professor Alejandro Lipschütz.

DNA methylation is one of the main epigenetic mechanisms that can regulate gene expression and is an important means for creating phenotypic variation. In the present study, we performed methylation profiling of 2 candidate genes for personality traits, namely DRD4 and SERT, in the great tit Parus major to ascertain whether personality traits and behavior within different habitats have evolved with the aid of epigenetic variation. We applied bisulphite PCR and strand-specific sequencing to determine the methylation profile of the CpG dinucleotides in the DRD4 and SERT promoters and also in the CpG island overlapping DRD4 exon 3. Furthermore, we performed pyrosequencing to quantify the total methylation levels at each CpG location. Our results indicated that methylation was ∼1-4% higher in urban than in forest birds, for all loci and tissues analyzed, suggesting that this epigenetic modification is influenced by environmental conditions. Screening of genomic DNA sequence revealed that the SERT promoter is CpG poor region. The methylation at a single CpG dinucleotide located 288 bp from the transcription start site was related to exploration score in urban birds. In addition, the genotypes of the SERT polymorphism SNP234 located within the minimal promoter were significantly correlated with novelty seeking behavior in captivity, with the allele increasing this behavior being more frequent in urban birds. As a conclusion, it seems that both genetic and methylation variability of the SERT gene have an important role in shaping personality traits in great tits, whereas genetic and methylation variation at the DRD4 gene is not strongly involved in behavior and personality traits.

The phenotype overlap between autism spectrum disorders (ASD) & intellectual disabilities (ID) is mirrored at the genetic level, with common genes being reported mutated in variety of developmental disabilities. However despite widespread genetic screening for mutations, in approximately 40-60% of childhood developmental disorders the genetic cause remains unknown. Several genome-wide linkage screens in ASD have identified a locus mapping to distal 8q. We have recently identified a novel brain-specific imprinted cluster at this location, which contains the reciprocally expressed maternal KCNK9 and paternally expressed non-coding PEG13 transcripts, the latter located within an intron of TRAPPC9. Interestingly, mutations of KCNK9 and TRAPPC9 have been reported in Birk-Barel mental retardation and non-syndromic familial forms of ID, respectively. Here, we report a genetic screen for KCNK9 coding mutations and potential epigenetic aberrations that could result in deregulated imprinting in a cohort of 120 ID, 86 ASD and 86 Tourette syndrome patients. Fifteen of the ID patients had clinical characteristics overlapping with Birk-Barel syndrome. Sequencing of the two coding exons of KCNK9 failed to identify pathologic mutations, with only one variant, rs2615374, being present with allele frequencies similar to those described in dbSNP database. DNA methylation profiling of the KCNK9 and TRAPPC9 promoters, the maternally methylated PEG13 DMR and a long-range enhancer region were normal in all patients. Our findings suggest that mutations of KCNK9 or epigenetic disturbances within the PEG13 imprinted cluster do not significantly contribute to the cause of the developmental disabilities tested in this study., (© 2014 Wiley Periodicals, Inc.)

Background and Objectives: Short, intensive multiagent chemotherapy has resulted in significant progress in Burkitt's lymphoma and leukemia. A protocol was designed to treat all adult patients with mature B-cell lymphoma or leukemia with the aims of comparing the response to therapy and survival with regards to their HIV infection status., Design and Methods: Fifty-three adult patients with advanced stage Burkitt's lymphoma or Burkitt's leukemia were treated. Response to therapy, survival and toxicity were evaluated according to their HIV infection status., Results: The median age of the patients was 53 years (range 15-74). There were no differences in CR rates between HIV-negative (77%) and HIV-positive patients (71%). Only age > 60 years was associated with a lower CR rate (OR 0.18, 95%CI 0.04-0.81, p=0.026). The 2-year overall survival (OS) probability was 51% (95%CI, 38%-64%) for the 53 patients. The OS of HIV-negative and HIV-positive patients did not significantly differ. Only age > 60 years was associated with a shorter OS (OR 5.1, 95%CI 2.0-12.7, p=0.001). The 2-year disease free survival (DFS) for the 40 patients achieving CR was 60% (95%CI, 45%-75%). Age > 60 years was the only identified factor associated with a shorter DFS (OR 5.2, 95%CI 1.4-20, p=0.015)., Interpretation and Conclusions: This study confirms the effectiveness of intensive strategies in adult patients with advanced stage Burkitt's lymphoma or leukemia. It also shows the feasibility of these strategies in individuals with HIV infection with comparable results. Advanced age proved to be the main adverse prognostic factor for response to therapy and survival.