Coronary Intimal Thickening: Once Again

In a letter to the Editor, Briana and Malamitsi-Puchner1 commented our recently published paper in which we showed that intimal thickening already begins in fetal life and progresses through childhood and adolescence.2 Our work is in line with studies by Barker about the fetal origins of adult disease which led to The Barker Hypothesis, indicating that the pathogenesis of cardiovascular (CV) disease begins in utero.3Briana et al.1 recently evaluated cord blood serum for potentially prognostic biomarkers for CV disease in large-for-gestational-age compared with appropriate-for-gestational-age neonates. Among other biomarkers, the authors studied serum cardiotrophin-1, a cardiomyocyte-produced chemokine that plays a fundamental role in fetal heart development and whose expression is increased by hypoxia, mechanical stress and proinflammatory cytokines such as interleukin (IL) 1b. The authors1 also studied serum levels of cardiac myocytesarcomeral protein titin, involved in sensing and responding to myocardial stress. As a result, Briana et al.1 propose that cord blood serum concentrations of both cardiotrophin-1 and titin could represent prognostic biomarkers for future CV disease.4In addition, another study by Milei et al.5 analyzed autopsy heart samples from 22 fetal sudden intrauterine death and 36 sudden infant death victims, all between the 32nd week of gestation and 1year of age. In 28 out of 58 cases, the mothers were smokers. Coronary lesions were detected in 10 of 12 fetuses and in 15 of 16 infants whose mothers smoked, while only 5cases (2 of 10 fetuses and 3 of 20 infants) arterial lesions were found in cases of nonsmoking mothers (p 1 artery, compared with 25% in the CoHD patients without surgery (p<0.001). Hence, these results suggest a higher rate of coronary intimal hyperplasia in surgically repaired CoHD patients as compared with non-repaired ones.6 This high incidence was correlated with intimal decrease in estrogen receptor α (ERα) expression, an increment in transforming growth factor β1 (TGF-β1) expression and in apolipoprotein B (apoB) deposition, which allowed us to conclude that a decrease in ERα and augmented expression of TGF-β1 expression may contribute to the development of atherosclerotic coronary artery disease in CoHD patients.6,7 A case report illustrating our findings described an aneurysm in the left main coronary artery of a 2-year-old patient. This aneurysm presented intimal hyperplasia and strong apoB deposition.8As mentioned in the Briana and Malamitsi-Puchner letter,1 it is important to search for early biomarkers of CV disease at an early age in order to implement preventive strategies. In this regard, we suggest that special attention should be given to children of smoking mothers and to CoHD patients, particularly if they underwent reparative surgery.Fil: Castilla Lozano, Maria del Rocio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Cardiológicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Cardiológicas; ArgentinaFil: Gutierrez, Christopher P. A.. Universidad de Buenos Aires; ArgentinaFil: Azzato, Francisco. Universidad de Buenos Aires; ArgentinaFil: Ambrosio, Giuseppe. Università di Perugia; ItaliaFil: Milei, Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Cardiológicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Cardiológicas; Argentin

Perceived Social Support and Risk of Cyberbullying in Adolescents: A Systematic Review

This article analyzes the main findings of studies investigating the relationship between perceived social support and cyberbullying in adolescents. We reviewed research papers published between January 2015 and January 2020, included in the Web of Science, Scopus, PUBMED, and Science Direct databases. The protocol was previously registered on the PROSPERO International Systematic Reviews database (CRD42020176938). The article follows the PRISMA guidelines for systematic reviews (Moher et al., 2015). Out of 1929 surveyed articles, 23 met the inclusion criteria and quality standards of scientific evidence set by Downs and Black (1998). Results reveal the types and characteristics of studies and instruments used in assessing social support and cyberbullying and show the relationship between social support and cyberbullying

Use of cinacalcet for the management of hyperparathyroidism in patients with different degrees of renal failure

Background: The effects of cinacalcet in persistent and/or hypercalcaemia-associated secondary hyperparathyroidism (SHPT) have been described in patients on dialysis. Objectives: To evaluate the efficacy and safety of cinacalcet in SHPT not on dialysis and its effects on bone turnover markers. Methods: Non-randomised, longitudinal, observational, analytical study of patients with chronic kidney disease (CKD) and SHPT (PTH> 80 pg/mL) as well as normo- or hypercalcaemia (≥8.5mg/dL), treated with cinacalcet. Results: Mean cinacalcet dose was 30mg/day in 66.7%. We studied 15 patients (10 women), aged 66.0±17.93years. The aetiology was unknown in 20% of cases. Sociodemographic variables and renal function parameters were recorded. We compared values at baseline as well as after 6 and 12 months. Calcium (10.3±0.55 vs. 9.4±1.04) and iPTH (392.4±317.65 vs. 141.8±59.26) levels decreased. Increased levels of phosphorus (3.7±1.06 vs. 3.9±0.85) and ß-CTX (884.2±797.22 vs. 1053.6±999.00) were detected, although there were no significant changes in GFR, urinary calcium or other bone markers. Two patients withdrew from the study (gastrointestinal intolerance and parathyroidectomy, respectively). Conclusions: Cinacalcet at low doses is effective in the management of SHPT in CKD patients who are not on dialysis. Its use reduces iPTH and calcaemia, without causing serious side effects or significant changes in renal function. Keywords: Bone turnover markers; Calcio; Calcium; Chronic kidney disease; Cinacalcet; Enfermedad renal crónica; Fósforo; Hiperparatiroidismo secundario; Hormona paratiroidea; Marcadores de recambio óseo; Parathyroid hormone; Phosphorus; Secondary hyperparathyroidism

Methylation alterations are not a major cause of PTTG1 missregulation

Background: On its physiological cellular context, PTTG1 controls sister chromatid segregation during mitosis. Within its crosstalk to the cellular arrest machinery, relies a checkpoint of integrity for which gained the over name of securin. PTTG1 was found to promote malignant transformation in 3T3 fibroblasts, and further found to be overexpressed in different tumor types. More recently, PTTG1 has been also related to different processes such as DNA repair and found to trans-activate different cellular pathways involving c-myc, bax or p53, among others. PTTG1 over-expression has been correlated to a worse prognosis in thyroid, lung, colorectal cancer patients, and it can not be excluded that this effect may also occur in other tumor types. Despite the clinical relevance and the increasing molecular characterization of PTTG1, the reason for its up-regulation remains unclear. Method: We analysed PTTG1 differential expression in PC-3, DU-145 and LNCaP tumor cell lines, cultured in the presence of the methyl-transferase inhibitor 5-Aza-2'-deoxycytidine. We also tested whether the CpG island mapping PTTG1 proximal promoter evidenced a differential methylation pattern in differentiated thyroid cancer biopsies concordant to their PTTG1 immunohistochemistry status. Finally, we performed whole-genome LOH studies using Affymetix 50 K microarray technology and FRET analysis to search for allelic imbalances comprising the PTTG1 locus. Conclusion: Our data suggest that neither methylation alterations nor LOH are involved in PTTG1 over-expression. These data, together with those previously reported, point towards a post-transcriptional level of missregulation associated to PTTG1 over-expression.This project was funded by The Fundación de Investigación Biomédica Mutua Madrileña Automovilista. Neocodex have been partially funded by the Ministerio de Educación y Ciencia of Spain (FIT-010000-2004-69, PTQ04-1-0006, PTQ2003-0549, PTQ2003-0546 and PTQ2003-0783). MAJ was also supported by SAF2005- 07713-C03-03 and CS by FIS 06/757

Ratones knock-out del receptor lpa1 de ácido lisofosfatídico presentan un acusado déficit de la isoenzima glutaminasa KGA (GLS) y una morfología alterada en las espinas dendríticas de hipocampo y corteza

Objectives: The objective of the present study was to utilize mice with knocked-down lysophosphatidic acid 1 (LPA1) receptor to ascertain changes in glutamatergic transmission that may help to explain part of the cognitive and memory deficits shown by these KO-LPA1 mice. Material & methods: A well characterized KO-LPA1 mouse strain was used as animal model and compared with wild-type (WT) and heterozygous animals. Expression studies were implemented by immunohistochemistry and Western analysis of mouse brain regions, real-time quantitative RT-PCR of GA isoforms, enzymatic analysis of regional GA activity and Golgi staining to assess dendritic spine morphology and density. Results: A strong reduction of KGA immunoreactivity was mostly revealed in cerebral cortex and hippocampus of KO-LPA1 mice versus WT and heterozygous animals. In contrast, neither mRNA levels nor enzyme activity were significantly altered in KO mice suggesting compensatory mechanisms for neurotransmitter Glu synthesis. Interestingly, Golgi staining of hippocampal and cortical neurons revealed a clear morphology change toward a less-mature undifferentiated spine phenotype, without changes in the total number of spines. Conclusions: The molecular mechanisms underlying KGA downregulation in null LPA1 mutant mice are unknown. However, LPA increases neuronal differentiation, arborization and neurite outgrowth of developing neurons, while Gln-derived Glu, through GA reaction, has been also involved in neuronal growth and differentiation. It is tempting to speculate that downregulation of KGA protein in KO-LPA1 mice induce morphological changes in dendritic spines of cortical and hippocampal neurons which, in turn, may account for memory and cognitive deficits shown by KO-LPA1 mice.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech. Acknowledgements: Red de Trastornos Adictivos, RTA, (RD12/0028/0013/) RETICS, ISCIII, y Consejería Innovación, Ciencia y Empresa, Junta de Andalucía (Proyecto de Excelencia CVI-6656)

Evolving minimum standards in responsible international sperm donor offspring quota

An international working group was established with the aim of making recommendations on the number of offspring for a sperm donor that should be allowable in cases of international use of his sperm. Considerations from genetic, psychosocial, operational and ethical points of view were debated. For these considerations, it was assumed that current developments in genetic testing and Internet possibilities mean that, now, all donors are potentially identifiable by their offspring, so no distinction was made between anonymous and non-anonymous donation. Genetic considerations did not lead to restrictive limits (indicating that up to 200 offspring or more per donor may be acceptable except in isolated social-minority situations). Psychosocial considerations on the other hand led to proposals of rather restrictive limits (10 families per donor or less). Operational and ethical considerations did not lead to more or less concrete limits per donor, but seemed to lie in-between those resulting from the aforementioned ways of viewing the issue. In the end, no unifying agreed figure could be reached; however the consensus was that the number should never exceed 100 families. The conclusions of the group are summarized in three recommendation

Response to Novel Drugs before and after Allogeneic Stem Cell Transplantation in Patients with Relapsed Multiple Myeloma

Multiple myeloma (MM) remains as an incurable disease and, although allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative approach, most patients ultimately relapse, and their treatment remains challenging. Because allo-HSCT can modify not only the biology of the disease, but also the immune system and the microenvironment, it can potentially enhance the response to rescue therapies. Information on the efficacy and safety of novel drugs in patients relapsing after allo-HSCT is lacking, however. The objectives of this study were to evaluate the efficacy and toxicity of rescue therapies in patients with MM who relapsed after allo-HSCT, as well as to compare their efficacy before and after allo-HSCT. This retrospective multicenter study included 126 consecutive patients with MM who underwent allo-HSCT between 2000 and 2013 at 8 Spanish centers. All patients engrafted. The incidence of grade II-IV acute graft-versus-host disease (GVHD) was 47%, and nonrelapse mortality within the first 100 days post-transplantation was 13%. After a median follow-up of 92 months, overall survival (OS) was 51% at 2 years and 43% at 5 years. The median progression-free survival after allo-HSCT was 7 months, whereas the median OS after relapse was 33 months. Patients relapsing in the first 6 months after transplantation had a dismal prognosis compared with those who relapsed later (median OS, 11 months versus 120 months; P <.001). The absence of chronic GVHD was associated with reduced OS after relapse (hazard ratio, 3.44; P <.001). Most patients responded to rescue therapies, including proteasome inhibitors (PIs; 62%) and immunomodulatory drugs (IMiDs; 77%), with a good toxicity profile. An in-depth evaluation, including the type and intensity of PI- and IMiD-based combinations used before and after allo-HSCT, showed that the overall response rate and duration of response after allo-HSCT were similar to those seen in the pretransplantation period. Patients with MM who relapse after allo-HSCT should be considered candidates for therapy with new drugs, which can achieve similar response rates with similar durability as seen in the pretransplantation period. This pattern does not follow the usual course of the disease outside the transplantation setting, where response rates and time to progression decreases with each consecutive line of treatment

Association between pre-diagnostic circulating lipid metabolites and colorectal cancer risk: a nested case–control study in the European Prospective Investigation into Cancer and Nutrition (EPIC)

Background: Altered lipid metabolism is a hallmark of cancer development. However, the role of specific lipid metabolites in colorectal cancer development is uncertain. Methods: In a case–control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC), we examined associations between pre-diagnostic circulating concentrations of 97 lipid metabolites (acylcarnitines, glycerophospholipids and sphingolipids) and colorectal cancer risk. Circulating lipids were measured using targeted mass spectrometry in 1591 incident colorectal cancer cases (55% women) and 1591 matched controls. Multivariable conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for associations between concentrations of individual lipid metabolites and metabolite patterns with colorectal cancer risk. Findings: Of the 97 assayed lipids, 24 were inversely associated (nominally p < 0.05) with colorectal cancer risk. Hydroxysphingomyelin (SM (OH)) C22:2 (ORper doubling 0.60, 95% CI 0.47–0.77) and acylakyl-phosphatidylcholine (PC ae) C34:3 (ORper doubling 0.71, 95% CI 0.59–0.87) remained associated after multiple comparisons correction. These associations were unaltered after excluding the first 5 years of follow-up after blood collection and were consistent according to sex, age at diagnosis, BMI, and colorectal subsite. Two lipid patterns, one including 26 phosphatidylcholines and all sphingolipids, and another 30 phosphatidylcholines, were weakly inversely associated with colorectal cancer. Interpretation: Elevated pre-diagnostic circulating levels of SM (OH) C22:2 and PC ae C34:3 and lipid patterns including phosphatidylcholines and sphingolipids were associated with lower colorectal cancer risk. This study may provide insight into potential links between specific lipids and colorectal cancer development. Additional prospective studies are needed to validate the observed associations

Using surveillance data to estimate pandemic vaccine effectiveness against laboratory confirmed influenza A(H1N1)2009 infection : two case-control studies, Spain, season 2009-2010

Background: Physicians of the Spanish Influenza Sentinel Surveillance System report and systematically swab patients attended to their practices for influenza-like illness (ILI). Within the surveillance system, some Spanish regions also participated in an observational study aiming at estimating influenza vaccine effectiveness (cycEVA study). During the season 2009-2010, we estimated pandemic influenza vaccine effectiveness using both the influenza surveillance data and the cycEVA study. Methods: We conducted two case-control studies using the test-negative design, between weeks 48/2009 and 8/2010 of the pandemic season. The surveillance-based study included all swabbed patients in the sentinel surveillance system. The cycEVA study included swabbed patients from seven Spanish regions. Cases were laboratory-confirmed pandemic influenza A(H1N1)2009. Controls were ILI patients testing negative for any type of influenza. Variables collected in both studies included demographic data, vaccination status, laboratory results, chronic conditions, and pregnancy. Additionally, cycEVA questionnaire collected data on previous influenza vaccination, smoking, functional status, hospitalisations, visits to the general practitioners, and obesity. We used logistic regression to calculate adjusted odds ratios (OR), computing pandemic influenza vaccine effectiveness as (1-OR *100. Results: We included 331 cases and 995 controls in the surveillance-based study and 85 cases and 351 controls in the cycEVA study. We detected nine (2.7%) and two (2.4%) vaccine failures in the surveillance-based and cycEVA studies, respectively. Adjusting for variables collected in surveillance database and swabbing month, pandemic influenza vaccine effectiveness was 62% (95% confidence interval (CI): -5; 87). The cycEVA vaccine effectiveness was 64% (95%CI: -225; 96) when adjusting for common variables with the surveillance system and 75% (95%CI: -293; 98) adjusting for all variables collected. Conclusion: Point estimates of the pandemic influenza vaccine effectiveness suggested a protective effect of the pandemic vaccine against laboratory-confirmed influenza A(H1N1)2009 in the season 2009-2010. Both studies were limited by the low vaccine coverage and the late start of the vaccination campaign. Routine influenza surveillance provides reliable estimates and could be used for influenza vaccine effectiveness studies in future seasons taken into account the surveillance system limitations

Standards recommendations for the Earth BioGenome Project

A global international initiative, such as the Earth BioGenome Project (EBP), requires both agreement and coordination on standards to ensure that the collective effort generates rapid progress toward its goals. To this end, the EBP initiated five technical standards committees comprising volunteer members from the global genomics scientific community: Sample Collection and Processing, Sequencing and Assembly, Annotation, Analysis, and IT and Informatics. The current versions of the resulting standards documents are available on the EBP website, with the recognition that opportunities, technologies, and challenges may improve or change in the future, requiring flexibility for the EBP to meet its goals. Here, we describe some highlights from the proposed standards, and areas where additional challenges will need to be met