Brain energy rescue:an emerging therapeutic concept for neurodegenerative disorders of ageing

The brain requires a continuous supply of energy in the form of ATP, most of which is produced from glucose by oxidative phosphorylation in mitochondria, complemented by aerobic glycolysis in the cytoplasm. When glucose levels are limited, ketone bodies generated in the liver and lactate derived from exercising skeletal muscle can also become important energy substrates for the brain. In neurodegenerative disorders of ageing, brain glucose metabolism deteriorates in a progressive, region-specific and disease-specific manner — a problem that is best characterized in Alzheimer disease, where it begins presymptomatically. This Review discusses the status and prospects of therapeutic strategies for countering neurodegenerative disorders of ageing by improving, preserving or rescuing brain energetics. The approaches described include restoring oxidative phosphorylation and glycolysis, increasing insulin sensitivity, correcting mitochondrial dysfunction, ketone-based interventions, acting via hormones that modulate cerebral energetics, RNA therapeutics and complementary multimodal lifestyle changes

Genetic Variation in the Platelet Endothelial Aggregation Receptor 1 Gene Results in Endothelial Dysfunction

We gratefully acknowledge our Amish liaisons and field workers and the extraordinary cooperation and support of the Amish community, without which these studies would not have been possible. We also acknowledge Dr. Alan Shuldiner for his impactful insights and guidance.Platelet Endothelial Aggregation Receptor 1 (PEAR1) is a newly identified membrane protein reported to be involved in multiple vascular and thrombotic processes. While most studies to date have focused on the effects of this receptor in platelets, PEAR1 is located in multiple tissues including the endothelium, where it is most highly expressed. Our first objective was to evaluate the role of PEAR1 in endothelial function by examining flow-mediated dilation of the brachial artery in 641 participants from the Heredity and Phenotype Intervention Heart Study. Our second objective was to further define the impact of PEAR1 on cardiovascular disease computationally through meta-analysis of 75,000 microarrays, yielding insights regarding PEAR1 function, and predictions of phenotypes and diseases affected by PEAR1 dysregulation. Based on the results of this meta-analysis we examined whether genetic variation in PEAR1 influences endothelial function using an ex vivo assay of endothelial cell migration. We observed a significant association between rs12041331 and flow-mediated dilation in participants of the Heredity and Phenotype Intervention Heart Study (P = 0.02). Meta-analysis results revealed that PEAR1 expression is highly correlated with several genes (e.g. ANG2, ACVRL1, ENG) and phenotypes (e.g. endothelial cell migration, angiogenesis) that are integral to endothelial function. Functional validation of these results revealed that PEAR1 rs12041331 is significantly associated with endothelial migration (P = 0.04). Our results suggest for the first time that genetic variation of PEAR1 is a significant determinant of endothelial function through pathways implicated in cardiovascular disease.Yeshttp://www.plosone.org/static/editorial#pee

Effects of alirocumab on types of myocardial infarction: insights from the ODYSSEY OUTCOMES trial

Aims  The third Universal Definition of Myocardial Infarction (MI) Task Force classified MIs into five types: Type 1, spontaneous; Type 2, related to oxygen supply/demand imbalance; Type 3, fatal without ascertainment of cardiac biomarkers; Type 4, related to percutaneous coronary intervention; and Type 5, related to coronary artery bypass surgery. Low-density lipoprotein cholesterol (LDL-C) reduction with statins and proprotein convertase subtilisin–kexin Type 9 (PCSK9) inhibitors reduces risk of MI, but less is known about effects on types of MI. ODYSSEY OUTCOMES compared the PCSK9 inhibitor alirocumab with placebo in 18 924 patients with recent acute coronary syndrome (ACS) and elevated LDL-C (≥1.8 mmol/L) despite intensive statin therapy. In a pre-specified analysis, we assessed the effects of alirocumab on types of MI. Methods and results  Median follow-up was 2.8 years. Myocardial infarction types were prospectively adjudicated and classified. Of 1860 total MIs, 1223 (65.8%) were adjudicated as Type 1, 386 (20.8%) as Type 2, and 244 (13.1%) as Type 4. Few events were Type 3 (n = 2) or Type 5 (n = 5). Alirocumab reduced first MIs [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.77–0.95; P = 0.003], with reductions in both Type 1 (HR 0.87, 95% CI 0.77–0.99; P = 0.032) and Type 2 (0.77, 0.61–0.97; P = 0.025), but not Type 4 MI. Conclusion  After ACS, alirocumab added to intensive statin therapy favourably impacted on Type 1 and 2 MIs. The data indicate for the first time that a lipid-lowering therapy can attenuate the risk of Type 2 MI. Low-density lipoprotein cholesterol reduction below levels achievable with statins is an effective preventive strategy for both MI types.For complete list of authors see http://dx.doi.org/10.1093/eurheartj/ehz299</p

Effect of alirocumab on mortality after acute coronary syndromes. An analysis of the ODYSSEY OUTCOMES randomized clinical trial

Background: Previous trials of PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitors demonstrated reductions in major adverse cardiovascular events, but not death. We assessed the effects of alirocumab on death after index acute coronary syndrome. Methods: ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) was a double-blind, randomized comparison of alirocumab or placebo in 18 924 patients who had an ACS 1 to 12 months previously and elevated atherogenic lipoproteins despite intensive statin therapy. Alirocumab dose was blindly titrated to target achieved low-density lipoprotein cholesterol (LDL-C) between 25 and 50 mg/dL. We examined the effects of treatment on all-cause death and its components, cardiovascular and noncardiovascular death, with log-rank testing. Joint semiparametric models tested associations between nonfatal cardiovascular events and cardiovascular or noncardiovascular death. Results: Median follow-up was 2.8 years. Death occurred in 334 (3.5%) and 392 (4.1%) patients, respectively, in the alirocumab and placebo groups (hazard ratio [HR], 0.85; 95% CI, 0.73 to 0.98; P=0.03, nominal P value). This resulted from nonsignificantly fewer cardiovascular (240 [2.5%] vs 271 [2.9%]; HR, 0.88; 95% CI, 0.74 to 1.05; P=0.15) and noncardiovascular (94 [1.0%] vs 121 [1.3%]; HR, 0.77; 95% CI, 0.59 to 1.01; P=0.06) deaths with alirocumab. In a prespecified analysis of 8242 patients eligible for ≥3 years follow-up, alirocumab reduced death (HR, 0.78; 95% CI, 0.65 to 0.94; P=0.01). Patients with nonfatal cardiovascular events were at increased risk for cardiovascular and noncardiovascular deaths (P<0.0001 for the associations). Alirocumab reduced total nonfatal cardiovascular events (P<0.001) and thereby may have attenuated the number of cardiovascular and noncardiovascular deaths. A post hoc analysis found that, compared to patients with lower LDL-C, patients with baseline LDL-C ≥100 mg/dL (2.59 mmol/L) had a greater absolute risk of death and a larger mortality benefit from alirocumab (HR, 0.71; 95% CI, 0.56 to 0.90; Pinteraction=0.007). In the alirocumab group, all-cause death declined wit h achieved LDL-C at 4 months of treatment, to a level of approximately 30 mg/dL (adjusted P=0.017 for linear trend). Conclusions: Alirocumab added to intensive statin therapy has the potential to reduce death after acute coronary syndrome, particularly if treatment is maintained for ≥3 years, if baseline LDL-C is ≥100 mg/dL, or if achieved LDL-C is low. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01663402

Ammattiosaamisen näytöt yrityksen ja ammattiopiston yhteistyössä

Opinnäytetyön aiheena oli selvittää, miten ammattiosaamisen näytöt toimivat paikallisen osuuskaupan ja ammattiopiston yhteistyössä koskien ravintolan salipuolen tarjoilijoita. Ammattiosaamisen näytöt ovat olleet käytössä työssäoppijoiden arvioinnissa viisi vuotta. Tavoitteena oli saada tietoa näyttöjen hyödyistä työantajanäkökulmasta katsottuna sekä löytää mahdollisia kehittämiskohteita. Opinnäytetyön teoreettisessa osassa selvennettiin työssäoppimisen ja ammattiosaamisen näytön käsitteitä, mikä on niiden merkitys ammattikoulutuksessa ja toisaalta niiden merkitys työelämälle. Lisäksi selvitettiin yritysten rekrytointikäytäntöjä ja sitä, mitä on työelämän ja oppilaitosten yhteistyö. Tutkimuksen empiirisessä osassa käytettiin puolistrukturoitua teemahaastattelua. Haastateltavat olivat paikallisen osuuskaupan ravintoloiden esimiehiä, ja haastattelut tehtiin kuudelle henkilölle. Haastattelut nauhoitettiin ja litteroitiin sanasta sanaan tietokoneelle jatkoanalyysia varten. Tutkimuksen tuloksena vahvistui se, että ammattiosaamisen näytöt ovat kaikille selkeä asia ja niistä on hyötyä sekä työnantajalle että opiskelijalle. Yhteistyö osuuskaupan ja ammattiopiton kanssa toimii hyvin, eivätkä näyttötilanteet ole aiheuttaneet suurempia ongelmia. Ainoastaan työssäoppijan osaamisen arviointi koetaan hankalana nykyisellä asteikolla. Alan ammattiopistotasoista koulutusta tarvitaan edelleen Joensuun alueella, ja tutkimuksen mukaan sitä pitäisi jopa lisätä. Koulutetun työvoiman puute ei vielä ole maakunnassa suuri ongelma verrattuna pääkaupunkiseutuun, mutta uhkakuvia on jo nyt havaittavissa. Tähän tulisi yhteistyökumppaneiden kiinnittää huomiota, jotta jatkossa Joensuun alueella koulutetaan riittävästi työvoimaa alalle.The purpose of the thesis was to find out how the collaboration between a company and vocational college works concerning vocational skills demonstrations of restaurant waiters. In addition, the task was to examine if there is any benefit of skills demonstrations for the company, and how to develop co-operation. Partners for the study are a local hotel and restaurant company and a local vocational college. The information was gathered from literature, journals, the Internet and by interviewing. In the theoretical part of the study the main issue was to explain what on-the-job learning is and what vocational skills demonstrations are, and what their consequence is for vocational education and for work life. Also how companies carry out their recruitment was clarified. Data for this study were collected by interviewing six supervisors in partner restaurants. The results of the study show that vocational skills demonstrations are perceived well without any complexities. Rather the results indicate more utilities for students, for the company and for the vocational school. The final result of this thesis was that it is important to keep on vocational education in Joensuu and even to enhance it. Now the lack of trained waiters is a fact in southern Finland. A vision is that it will be a threat also in eastern Finland in the future. To ensure professional labour for hotel and restaurant business, companies support for vocational education is essential