Early and long-term outcome of elective stenting of the infarct-related artery in patients with viability in the infarct-area: Rationale and design of the Viability-guided Angioplasty after acute Myocardial Infarction-trial (The VIAMI-trial)

BACKGROUND: Although percutaneous coronary intervention (PCI) is becoming the standard therapy in ST-segment elevation myocardial infarction (STEMI), to date most patients, even in developed countries, are reperfused with intravenous thrombolysis or do not receive a reperfusion therapy at all. In the post-lysis period these patients are at high risk for recurrent ischemic events. Early identification of these patients is mandatory as this subgroup could possibly benefit from an angioplasty of the infarct-related artery. Since viability seems to be related to ischemic adverse events, we initiated a clinical trial to investigate the benefits of PCI with stenting of the infarct-related artery in patients with viability detected early after acute myocardial infarction. METHODS: The VIAMI-study is designed as a prospective, multicenter, randomized, controlled clinical trial. Patients who are hospitalized with an acute myocardial infarction and who did not have primary or rescue PCI, undergo viability testing by low-dose dobutamine echocardiography (LDDE) within 3 days of admission. Consequently, patients with demonstrated viability are randomized to an invasive or conservative strategy. In the invasive strategy patients undergo coronary angiography with the intention to perform PCI with stenting of the infarct-related coronary artery and concomitant use of abciximab. In the conservative group an ischemia-guided approach is adopted (standard optimal care). The primary end point is the composite of death from any cause, reinfarction and unstable angina during a follow-up period of three years. CONCLUSION: The primary objective of the VIAMI-trial is to demonstrate that angioplasty of the infarct-related coronary artery with stenting and concomitant use of abciximab results in a clinically important risk reduction of future cardiac events in patients with viability in the infarct-area, detected early after myocardial infarction

The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies

Despite the clinical significance of balanced chromosomal abnormalities (BCAs), their characterization has largely been restricted to cytogenetic resolution. We explored the landscape of BCAs at nucleotide resolution in 273 subjects with a spectrum of congenital anomalies. Whole-genome sequencing revised 93% of karyotypes and demonstrated complexity that was cryptic to karyotyping in 21% of BCAs, highlighting the limitations of conventional cytogenetic approaches. At least 33.9% of BCAs resulted in gene disruption that likely contributed to the developmental phenotype, 5.2% were associated with pathogenic genomic imbalances, and 7.3% disrupted topologically associated domains (TADs) encompassing known syndromic loci. Remarkably, BCA breakpoints in eight subjects altered a single TAD encompassing MEF2C, a known driver of 5q14.3 microdeletion syndrome, resulting in decreased MEF2C expression. We propose that sequence-level resolution dramatically improves prediction of clinical outcomes for balanced rearrangements and provides insight into new pathogenic mechanisms, such as altered regulation due to changes in chromosome topology

Bright light therapy versus physical exercise to prevent co-morbid depression and obesity in adolescents and young adults with attention-deficit/hyperactivity disorder: study protocol for a randomized controlled trial

Background: The risk for major depression and obesity is increased in adolescents and adults with attention-deficit / hyperactivity disorder (ADHD) and adolescent ADHD predicts adult depression and obesity. Non-pharmacological interventions to treat and prevent these co-morbidities are urgently needed. Bright light therapy (BLT) improves day– night rhythm and is an emerging therapy for major depression. Exercise intervention (EI) reduces obesity and improves depressive symptoms. To date, no randomized controlled trial (RCT) has been performed to establish feasibility and efficacy of these interventions targeting the prevention of co-morbid depression and obesity in ADHD. We hypothesize that the two manualized interventions in combination with mobile health-based monitoring and reinforcement will result in less depressive symptoms and obesity compared to treatment as usual in adolescents and young adults with ADHD. Methods: This trial is a prospective, pilot phase-IIa, parallel-group RCT with three arms (two add-on treatment groups [BLT, EI] and one treatment as usual [TAU] control group). The primary outcome variable is change in the Inventory of Depressive Symptomatology total score (observer-blinded assessment) between baseline and ten weeks of intervention. This variable is analyzed with a mixed model for repeated measures approach investigating the treatment effect with respect to all three groups. A total of 330 participants with ADHD, aged 14 – < 30 years, will be screened at the four study centers. To establish effect sizes, the sample size was planned at the liberal significance level of α = 0.10 (two-sided) and the power of 1-β = 80% in order to find medium effects. Secondary outcomes measures including change in obesity, ADHD symptoms, general psychopathology, health-related quality of life, neurocognitive function, chronotype, and physical fitness are explored after the end of the intervention and at the 12-week follow-up. This is the first pilot RCT on the use of BLT and EI in combination with mobile health-based monitoring and reinforcement targeting the prevention of co-morbid depression and obesity in adolescents and young adults with ADHD. If at least medium effects can be established with regard to the prevention of depressive symptoms and obesity, a larger scale confirmatory phase-III trial may be warranted.The trial is funded by the EU Framework Programme for Research and Innovation, Horizon 2020 (Project no. 667302). Funding period: January 2016–December 2020. This funding source had no role in the design of this study and will not have any role during its execution, analyses, interpretation of the data, or decision to submit results. Some local funds additionally contributed to carry out this study, especially for the preparation of the interventions: FBO research activity is by the Spanish Ministry of Economy and Competitiveness – MINECO (RYC-2011-09011) and by the University of Granada, Plan Propio de Investigación 2016, Excellence actions: Unit of Excellence on Exercise and Health (UCEES)

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

Health effects of high and low vitamin A intake in the Netherlands : What knowledge is available and what is missing

In Nederland komt het voor dat mensen weinig vitamine A innemen. Sommigen krijgen er juist veel van binnen, vooral kinderen (bijvoorbeeld als zij veel smeerleverworst eten). Met de huidige stand van de wetenschap is nog niet duidelijk of dit schadelijk is voor de gezondheid. Er zijn bijvoorbeeld aanwijzingen dat er een samenhang is tussen een hoge inname van vitamine A (retinol), een lagere botdichtheid en een verhoogd risico op botbreuken. Sluitend bewijs daarvoor ontbreekt. Vitamine A kan worden gegeten in de vorm van retinol, dat veel in dierlijke producten zit, en als caroteen, dat vooral in plantaardige producten zit. Bij een hoge inname gaat het om een teveel aan retinol; bij een lage inname is de totale vitamine A-inname van belang. Dit blijkt uit literatuuronderzoek van het RIVM waarin de stand van zaken in de wetenschappelijke literatuur sinds 2008 in kaart is gebracht. Aanleiding is de aanbeveling van de Gezondheidsraad uit 2008 om te onderzoeken of een lage en hoge inname van vitamine A in Nederland daadwerkelijk een gezondheidsprobleem vormt. Een specifieke vraag betreft de relatie tussen hoge vitamine A-inname en botgezondheid. Sinds 2008 is er geen onderzoek gepubliceerd dat deze vragen beantwoordt. De resultaten van beschikbare onderzoeken naar de inname van vitamine A betreffen situaties die niet representatief zijn voor de situatie in Nederland. De bestudeerde innames liggen namelijk ver boven of ver onder de inname van vitamine A die in Nederland voorkomt. Verder zijn de resultaten van onderzoek naar de relatie tussen vitamine A-inname en botgezondheid niet eenduidig. Er zijn verschillende methoden om de vitamine A-status te meten en de botgezondheid te bepalen. Ook worden factoren die van invloed kunnen zijn op de vitamine A-status of botgezondheid, bijvoorbeeld overgewicht of vitamine D-inname, niet altijd meegenomen. Onderzoek naar de hoeveelheid vitamine A in het lichaam kan duidelijk maken of een lage of hoge inname daadwerkelijk problemen veroorzaakt. De hoeveelheid vitamine A is echter lastig te bepalen bij grote groepen, omdat dit niet eenvoudig in bijvoorbeeld een bloedmonster kan worden gemeten. Voor de meest geschikte methode is een stukje uit de lever (biopt) nodig. Onderzoek naar de mogelijke gezondheidseffecten van een lage of hoge vitamine A-inname in Nederland zou zich in eerste instantie kunnen richten op groepen waarvan, op basis van het voedingspatroon, een lage dan wel hoge vitamine A-inname verwacht wordt.In the Netherlands, some people consume little vitamin A. On the other hand, some people, especially children, consume high amounts (for example, if they eat a lot of liver sausage). Regarding current scientific evidence, it is not yet clear whether this is harmful to health. There are indications, for example, that there is a correlation between a high intake of vitamin A (retinol) and a lower bone density and increased risk of bone fractures. The evidence, however, is not conclusive. Vitamin A can be consumed in the form of retinol, which is found at high levels in animal products, and as carotene, which is mainly found in vegetable products. When referring to high intake, this concerns too much retinol; with a low intake, the total vitamin A intake is important. This is evident from a literature review by the National Institute for Public Health and the Environment (RIVM) using the scientific literature from 2008 onwards. The reason for this research is the recommendation of the Health Council of 2008 to investigate whether a low and high intake of vitamin A in the Netherlands is actually a health problem. A specific question concerns the relationship between high vitamin A intake and bone health. Since 2008, no research has been published that answers these questions. The results of available studies on the intake of vitamin A concern situations that are not representative of the situation in the Netherlands. The studied intakes are far above or far below the intake of vitamin A that occurs in the Netherlands. Furthermore, the results of research into the relationship between vitamin A intake and bone health are ambiguous. There are several methods to measure vitamin A status and to determine bone health. In addition, factors that may influence vitamin A status or bone health, for example being overweight or vitamin D intake, are not always included. Research into the amount of vitamin A in the body can make clear whether a low or high intake actually causes health problems. The amount of vitamin A, however, is difficult to determine in large groups, because this cannot easily be measured in, for example, a blood sample. A piece from the liver (biopsy) is required for the most suitable method. Research into the possible health effects of a low or high vitamin A intake in the Netherlands could initially focus on groups of which, based on their dietary pattern, a low or high vitamin A intake is expected.Ministerie van VW