Long-term methylphenidate exposure and 24-hours blood pressure and left ventricular mass in adolescents and young adults with attention deficit hyperactivity disorder

Blood pressure; Echocardiography; MethylphenidatePresión arterial; Ecocardiografía; MetilfenidatoPressió arterial; Ecocardiografia; MetilfenidatYoung people with attention deficit hyperactivity disorder (ADHD) are now being treated with psychostimulant medication for longer than was previously the case and are increasingly likely to remain on methylphenidate into adolescence and adulthood. This study was designed to determine whether the long-term use of methylphenidate (MPH, immediate release or extended release) increases blood pressure and left ventricular mass (LVM) identified by echocardiography in adolescents and young adults with ADHD aged 12-25 years. In a five-site cross-sectional design two groups were compared for 24- hour blood pressure and heart rate (HR) registrations and LVM: 1) adolescents and young adults with ADHD who had been treated with MPH for > 2 years (N=162, age mean (SD) 15.6 (3.0)), and 2) adolescents and young adults with ADHD who had never been treated with methylphenidate (N=71, age mean 17.4 (4.2)). The analyses were controlled for propensity scores derived from age, sex, height, weight, and 19 relevant background variables. A blood pressure indicative of hypertension (>95th percentile) was observed in 12.2% (95% confidence interval 7.3 – 18.9%) of the participants in the MPH treated group and in 9.6% (95%CI 3.2 – 21.0%) of the MPH naïve group, with overlapping intervals. The 24-hour recorded systolic blood pressure (SBP) and HR were significantly higher during daytime in medicated individuals with ADHD than in those with unmedicated ADHD, but were similar in both groups during the night. 24-hour diastolic blood pressure (DBP) did not differ between both groups during either daytime or at night. LVM, corrected for body-surface area (LVMBSA), also did not differ between the two groups (p=0.20, controlling for confounders). Further, MPH daily dose and duration of treatment were unrelated to LVMBSA, SBP, and DBP. Long-term MPH use in adolescents and young adults with ADHD is associated with small but significant increases of SBP and HR during daytime. Given the current sample size, the proportions of hypertension do not differ significantly between MPH treated and MPH-naïve individuals with ADHD. Future studies with larger samples, longer treatment duration, and/or with within-subject designs are necessary. The results do, however, further support recommendations that highlight the importance of monitoring blood pressure and HR during MPH treatment.This work was supported by the European Union 7th framework grant “Attention Deficit Hyperactivity Disorder Drugs Use Chronic Effects” (ADDUCE, grant no. 260576). The funder had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. Any views expressed are those of the authors and not necessarily those of the funder

A Community in Life and Death: The Late Neolithic Megalithic Tomb at Alto de Reinoso (Burgos, Spain)

The analysis of the human remains from the megalithic tomb at Alto de Reinoso represents the widest integrative study of a Neolithic collective burial in Spain. Combining archaeology, osteology, molecular genetics and stable isotope analysis (87Sr/86Sr, δ15N, δ13C) it provides a wealth of information on the minimum number of individuals, age, sex, body height, pathologies, mitochondrial DNA profiles, kinship relations, mobility, and diet. The grave was in use for approximately one hundred years around 3700 cal BC, thus dating from the Late Neolithic of the Iberian chronology. At the bottom of the collective tomb, six complete and six partial skeletons lay in anatomically correct positions. Above them, further bodies represented a subsequent and different use of the tomb, with almost all of the skeletons exhibiting signs of manipulation such as missing skeletal parts, especially skulls. The megalithic monument comprised at least 47 individuals, including males, females, and subadults, although children aged 0–6 years were underrepresented. The skeletal remains exhibited a moderate number of pathologies, such as degenerative joint diseases, healed fractures, cranial trauma, and a low intensity of caries. The mitochondrial DNA profiles revealed a pattern pointing to a closely related local community with matrilineal kinship patterns. In some cases adjacent individuals in the bottom layer showed familial relationships. According to their strontium isotope ratios, only a few individuals were likely to have spent their early childhood in a different geological environment, whilst the majority of individuals grew up locally. Carbon and nitrogen isotope analysis, which was undertaken to reconstruct the dietary habits, indicated that this was a homogeneous group with egalitarian access to food. Cereals and small ruminants were the principal sources of nutrition. These data fit in well with a lifestyle typical of sedentary farming populations in the Spanish Meseta during this period of the Neolithi

PERSPECTIVES OVER THE ECONOMIC TRANSITION AND DEMOGRAPHIC AGING IN EASTERN EUROPE

The countries of Eastern Europe represent a particular case from the demographic and economic point of view, as their demographic transition overlapped the economic development process. This represents a major challenge for the sustainability of their health and pension systems and has resulted in reforms and measures to support economic growth and increase the birth rate. Two categories of countries from Eastern Europe were analysed, Romania and Poland as representatives of the ex-Communist countries that joined the European Union and the Russian Federation as representative of the former Soviet Union. The Russian Federation experienced the most profound changes after 1990, being the only country in the Eastern bloc that is close to the generational replacement threshold, the only country with a positive migration balance, but also the only country with the lowest life expectancy

Effects of granulocyte-colony stimulating factor on bone marrow morphology following cyclophosphamide induced neutropenia in rats

Granulocyte-colony stimulating factor is a glycoprotein that stimulates synthesis of granulocytes, especially of neutrophiles. It can be used to correct myelosupression associated with long-term chemotherapy or in the treatment of neutropenia. The aim of our study was to assess the effects of G-CSF on bone marrow after cyclophosphamide induced neutropenia in rats. The study was conducted on 24 female Wistar rats divided in 3 experimental groups; the control group, group of cyclophoshamide treated animals and the group of animals that were treated with Granulocyte-colony stimulating factor after neutropenia induction with cyclophosphamide. Cytological exam of bone marrow aspirates and histological exam from sternal bone marrow were realized using routine techniques. Examination of the aspirates taken from the femoral bone marrow and of the histological sections taken from the sternum showed a dramatic reduction in the number of myeloid precursors in individuals of group 2 which have been subjected to cyclophosphamide-induced myelosuppression, while the administration of G-CSF to the individuals of group 3 induced marked proliferation of the myeloid precursor cells, correcting the myelosuppressive effect of the cyclophosphamide In conclusion, G-CSF can be used for the stimulation and mobilization of myeloid progenitor cells from the bone marrow

The maternal genetic make-up of the Iberian Peninsula between the Neolithic and the Early Bronze Age

Agriculture first reached the Iberian Peninsula around 5700 BCE. However, little is known about the genetic structure and changes of prehistoric populations in different geographic areas of Iberia. In our study, we focus on the maternal genetic makeup of the Neolithic (~ 5500–3000 BCE), Chalcolithic (~ 3000–2200 BCE) and Early Bronze Age (~ 2200–1500 BCE). We report ancient mitochondrial DNA results of 213 individuals (151 HVS-I sequences) from the northeast, central, southeast and southwest regions and thus on the largest archaeogenetic dataset from the Peninsula to date. Similar to other parts of Europe, we observe a discontinuity between hunter-gatherers and the first farmers of the Neolithic. During the subsequent periods, we detect regional continuity of Early Neolithic lineages across Iberia, however the genetic contribution of hunter-gatherers is generally higher than in other parts of Europe and varies regionally. In contrast to ancient DNA findings from Central Europe, we do not observe a major turnover in the mtDNA record of the Iberian Late Chalcolithic and Early Bronze Age, suggesting that the population history of the Iberian Peninsula is distinct in character

Dhx34 and Nbas function in the NMD pathway and are required for embryonic development in zebrafish

The nonsense-mediated mRNA decay (NMD) pathway is a highly conserved surveillance mechanism that is present in all eukaryotes. It prevents the synthesis of truncated proteins by selectively degrading mRNAs harbouring premature termination codons (PTCs). The core NMD effectors were originally identified in genetic screens in Saccharomyces cerevisae and in the nematode Caenorhabditis elegans, and subsequently by homology searches in other metazoans. A genome-wide RNAi screen in C. elegans resulted in the identification of two novel NMD genes that are essential for proper embryonic development. Their human orthologues, DHX34 and NAG/NBAS, are required for NMD in human cells. Here, we find that the zebrafish genome encodes orthologues of DHX34 and NAG/NBAS. We show that the morpholino-induced depletion of zebrafish Dhx34 and Nbas proteins results in severe developmental defects and reduced embryonic viability. We also found that Dhx34 and Nbas are required for degradation of PTC-containing mRNAs in zebrafish embryos. The phenotypes observed in both Dhx34 and Nbas morphants are similar to defects in Upf1, Smg-5- or Smg-6- depleted embryos, suggesting that these factors affect the same pathway and confirming that zebrafish embryogenesis requires an active NMD pathway

The Beaker phenomenon and the genomic transformation of northwest Europe

From around 2750 to 2500 bc, Bell Beaker pottery became widespread across western and central Europe, before it disappeared between 2200 and 1800 bc. The forces that propelled its expansion are a matter of long-standing debate, and there is support for both cultural diffusion and migration having a role in this process. Here we present genome-wide data from 400 Neolithic, Copper Age and Bronze Age Europeans, including 226 individuals associated with Beaker-complex artefacts. We detected limited genetic affinity between Beaker-complex-associated individuals from Iberia and central Europe, and thus exclude migration as an important mechanism of spread between these two regions. However, migration had a key role in the further dissemination of the Beaker complex. We document this phenomenon most clearly in Britain, where the spread of the Beaker complex introduced high levels of steppe-related ancestry and was associated with the replacement of approximately 90% of Britain’s gene pool within a few hundred years, continuing the east-to-west expansion that had brought steppe-related ancestry into central and northern Europe over the previous centuries

Epigenetic regulation of astrocytic dysfunction in depression and suicide

Major depressive disorder (MDD) affects close to 1.8 million Canadians (~5% of the population) annually, and is the third most burdensome disease worldwide. Although over 50 years of drug therapy and research has implicated multiple brain regions and systems, our understanding of the pathophysiology of MDD remains incomplete. Research into astrocytic dysfunction in MDD has generated consistent and replicable findings and has been bolstered by our increased understanding of the multiple active roles of astrocytes in normal brain function. Several lines of evidence also suggest that DNA methylation and histone modifications are involved in the pathogenesis of neuropsychiatric disorders, including MDD; however, the epigenetic mediators linking astrocytic dysfunction and depression remain largely unexplored. This doctoral thesis describes experiments conducted in post-mortem brain tissue of individuals who display astrocytic dysfunction and who were diagnosed with MDD. Together, this work supports the role of epigenetic regulation in astrocytic dysfunction and contributes to the growing understanding of the complexities in human astrocytes. In addition, these studies provide important information towards elucidating the etiopathogenesis of MDD.Le trouble dépressif majeur (TDM) touche près de 1,8 million de Canadiens (~ 5% de la population) par an, et se classe au troisième rang des maladies en termes de fardeau mondial. Bien que plus de 50 ans de thérapie médicamenteuse et de recherche ont impliqué plusieurs régions et systèmes cérébraux avec le TDM, notre compréhension de la physiopathologie de cette maladie reste incomplète.La recherche sur le dysfonctionnement des astrocytes dans le TDM a généré des résultats cohérents et reproductibles. Cette association a été renforcée par notre compréhension accrue des rôles actifs multiples des astrocytes dans les fonctions cérébrales de cerveaux sains.De nombreuses preuves suggèrent aussi que la méthylation de l'ADN et les modifications des histones sont impliquées dans la pathogenèse des troubles neuropsychiatriques, y compris le TDM; cependant, les médiateurs épigénétiques reliant la dysfonction astrocytaire et la dépression restent largement inexplorées. Cette thèse de doctorat décrit des expériences menées avec des tissus cérébraux post-mortem de personnes qui présentent un dysfonctionnement astrocytaire et qui ont été diagnostiqués avec un TDM. Ainsi, cette thèse présente le rôle de la régulation épigénétique dans le dysfonctionnement astrocytaire et contribue à la compréhension croissante de la complexité des astrocytes humains. En outre, ces études fournissent des informations importantes pour faire progresser la compréhension de l'étiopathogénie des TDM