Enhanced T-Helper-1 Lymphocyte Activation Patterns in Acute Coronary Syndromes

ObjectivesWe sought to determine whether different stages of coronary artery disease (CAD) are associated with distinct differentiation patterns of activated T cells.BackgroundAtherosclerosis is an inflammatory disease. However, little is known about specific inflammatory cell activation in atherosclerosis, for example, the T-helper (Th)1/Th2-balance.MethodsWe studied 18 patients with stable angina (SA), 28 patients with acute coronary syndrome (ACS) (16 with unstable angina pectoris and 12 with ST-segment elevation myocardial infarction), 19 patients with unheralded myocardial infarction (UH), and 16 control patients. Cytokine patterns and transcription factor signaling pathways of circulating T cells were characterized using reverse transcription polymerase chain reaction and flow cytometry.ResultsAlthough interferon (IFN)-γ+/CD3+T cells were ∼2-fold greater in patients with SA or UH than in control subjects, there was a massive expansion of Th1 cells in patients with ACS (p < 0.001). This increase was paralleled by significantly increased mRNA transcript levels for signal-transducer-and-activator-4 (ACS 1.17 ± 0.14 relative units [RU]; control patients 0.44 ± 0.09 RU; SA 0.67 ± 0.12 RU; UH 0.61 ± 0.17 RU), interleukin-2 (ACS 1.55 ± 0.51 RU; control patients 0.21 ± 0.09 RU; SA 0.54 ± 0.18 RU; UH 0.45 ± 0.16 RU), and IFN-γ in ACS (1.27 ± 0.39 RU; control patients 0.35 ± 0.09 RU; SA 0.58 ± 0.11 RU; UH 0.53 ± 0.24 RU; p < 0.002). Th2 and Th0 cells were not different across patient subsets. The burden of CAD was identical between SA (1.4 ± 0.2 diseased vessels, 68 ± 13% diameter stenosis) and ACS (1.4 ± 0.2 diseased vessels, 64 ± 17% diameter stenosis) but significantly greater in patients with UH (2.5 ± 0.5 diseased vessels, 95 ± 7% diameter stenosis; p < 0.05).ConclusionsPatients with UH have a greater burden of obstructive CAD than SA but no greater T-cell activation. Patients with ACS have the same extent of CAD than SA but significantly greater activation of Th1 cells that may contribute to the increasing instability. Differences in circulating Th1 cells might indicate different pathogenic components, leading to ACS and UH

"Le jeu savant" : luce e oscurità nell'architettura del XX secolo = light and darkness in 20th century architecture

«L’architecture est le jeu savant, correct et magnifique des volumes assemblés sous la lumière». Alluding to Le Corbusier’s famous statement of 1923, this collection of essays solicits critical reflection on the relationship between light and architecture, on both theoretical and practical levels. Beginning with a discussion of the problem of how to represent light and its effects within architectural space in different media (drawing, photography, film), it then examines the relationship between planning and hygiene-theories, focusing in particular on those which exercised their influence on the choice of orientation and exposure of buildings to the sun. On the technological front, finally, attention is turned to projects making use of the various devices, and then new, for the modulation of natural light, as well as to the many possibilities offered to designers by new technologies of artificial illumination.«L’architecture est le jeu savant, correct et magnifique des volumes assemblés sous la lumière». Alludendo alla celeberrima affermazione di Le Corbusier del 1923, questa raccolta di saggi sollecita una riflessione critica sulla relazione tra luce e architettura, a livello teorico e progettuale. L’avvio è dato da una discussione sui problemi della rappresentazione, nei diversi media (disegno, fotografia, cinema), degli effetti luministici nello spazio architettonico. Si prende poi in esame il rapporto tra progettazione e teorie igieniste, soffermandosi in particolare su quelle che maggiormente esercitarono il loro influsso sulla scelta dell’orientamento e dell’esposizione alla luce dell’edificio. Sul fronte tecnologico, infine, lo sguardo è volto agli esiti progettuali seguiti all’introduzione di diversi dispositivi di modulazione della luce naturale, come pure alle molteplici possibilità offerte ai progettisti dalle nuove tecnologie per l’illuminazione artificiale

Microphthalmia in Texel Sheep Is Associated with a Missense Mutation in the Paired-Like Homeodomain 3 (PITX3) Gene

Microphthalmia in sheep is an autosomal recessive inherited congenital anomaly found within the Texel breed. It is characterized by extremely small or absent eyes and affected lambs are absolutely blind. For the first time, we use a genome-wide ovine SNP array for positional cloning of a Mendelian trait in sheep. Genotyping 23 cases and 23 controls using Illumina's OvineSNP50 BeadChip allowed us to localize the causative mutation for microphthalmia to a 2.4 Mb interval on sheep chromosome 22 by association and homozygosity mapping. The PITX3 gene is located within this interval and encodes a homeodomain-containing transcription factor involved in vertebrate lens formation. An abnormal development of the lens vesicle was shown to be the primary event in ovine microphthalmia. Therefore, we considered PITX3 a positional and functional candidate gene. An ovine BAC clone was sequenced, and after full-length cDNA cloning the PITX3 gene was annotated. Here we show that the ovine microphthalmia phenotype is perfectly associated with a missense mutation (c.338G>C, p.R113P) in the evolutionary conserved homeodomain of PITX3. Selection against this candidate causative mutation can now be used to eliminate microphthalmia from Texel sheep in production systems. Furthermore, the identification of a naturally occurring PITX3 mutation offers the opportunity to use the Texel as a genetically characterized large animal model for human microphthalmia

Blood sampling methodology is crucial for precise measurement of plasma catecholamines concentrations in mice

Epinephrine (E) and norepinephrine (NE) play a major role in regulating metabolism and cardiovascular physiology. Both are secreted in response to stress and their measurement in plasma allows the study of sympathoadrenal function. Several studies investigating sympathoadrenal physiology are conducted using mice. Review of the literature revealed that basal mouse NE and E plasma concentrations range within 4-140nM depending on the blood sampling method. Such variability doesn't allow study comparison and may conceal catecholamine variations in response to stress. Therefore, our aim was to determine a reliable sampling method to measure mouse plasma catecholamine concentrations. Results showed that arterial catheterization is the most accurate sampling method: E and NE basal levels were similar to those found in humans (1.1±0.3nM and 4.1±0.5nM, respectively). Retro-orbital bleeding led to analogous results. On the contrary, decapitation was stressful for mice and consequently NE and E concentrations were high (24.6±2.7nM and 27.3±3.8nM, respectively). These different bleeding methods were compared in terms of their ability to detect sympathoadrenal system stimulation (cold-pressure test). With catheter and retro-orbital samplings the expected increase in NE and E levels was easily perceived. In contrast, with decapitation no significant change in E was detected. In conclusion, arterial-catheter and retro-orbital blood sampling methods appear to be the most accurate procedures for studying the sympathetic nervous system in mice in both unstressed and stressed condition

Comprehensive behavioral testing in the R6/2 mouse model of Huntington's disease shows no benefit from CoQ10 or minocycline

Previous studies of the effects of coenzyme Q10 and minocycline on mouse models of Huntington’s disease have produced conflicting results regarding their efficacy in behavioral tests. Using our recently published best practices for husbandry and testing for mouse models of Huntington’s disease, we report that neither coenzyme Q10 nor minocycline had significant beneficial effects on measures of motor function, general health (open field, rotarod, grip strength, rearing-climbing, body weight and survival) in the R6/2 mouse model. The higher doses of minocycline, on the contrary, reduced survival. We were thus unable to confirm the previously reported benefits for these two drugs, and we discuss potential reasons for these discrepancies, such as the effects of husbandry and nutrition

Exploring health-related needs of elderly people (70+) at home : a qualitative study from Switzerland

Background: The elderly represents the fastest growing group in our population. Since there is a close relationship between the number of older people and health care expenditure, promoting healthy aging has become an important topic. However, it is essential to understand first the needs of this population in order to create suitable programs and activities. Methods: A qualitative design was used in this study to explore the subjective views of elderly people and to learn more about their health-related needs. A total of 12 participants were recruited using a consecutive sampling strategy. The data were collected through semi-structured interviews and analyzed by employing a summarizing content analysis. Results: This study has identified 4 areas of health-related needs: Independence and autonomy, social security, structure in daily life and community and belonging, where all categories are interrelated and interact with one other. Conclusion: Focusing more on community-based approaches would support creating a conducive environment. Also, home visits undertaken by a specialized nurse focused on health risks and disabilities could be an adequate approach to support the elderly population in an efficient way and to offer targeted programs and activities

Revisiting the structure of subjective well-being in middle-aged adults

Abstract Subjective well-being is a broad, multifaceted construct comprising general satisfaction with life, satisfaction with life domains (health, family, people, free time, self, housing, work, and finances), positive affect, and negative affect. Drawing on representative data from middle-aged adults (N = 738), the authors used three different structural models to analyze the interrelationships among these facets of subjective well-being. In a top-down model, a single factor representing global subjective well-being explained the correlations found among the more specific facets of subjective well-being and exerted the strongest influence on general satisfaction with life, satisfaction with health, and satisfaction with finances. In a bottom-up model, satisfaction with the latter two domains had the strongest effect on global subjective well-being. The authors discuss the implications of their findings for research on subjective well-being

Chemistry Pharmacology And Behavioral Studies Identify Chiral Cyclopropanes As Selective α4β2-Nicotinic Acetylcholine Receptor Partial Agonists Exhibiting An Antidepressant Profile. Part II

A 3-pyridyl ether scaffold bearing a cyclopropane-containing side chain was recently identified in our efforts to create novel antidepressants that act as partial agonists at α4β2-nicotinic acetylcholine receptors. In this study, a systematic structure-activity relationship investigation was carried out on both the azetidine moiety present in compound 3 and its right-hand side chain, thereby discovering a variety of novel nicotinic ligands that retain bioactivity and feature improved chemical stability. The most promising compounds, 24, 26, and 30, demonstrated comparable or enhanced pharmacological profiles compared to the parent compound 4, and the N-methylpyrrolidine analogue 26 also exhibited robust antidepressant-like efficacy in the mouse forced swim test. The favorable ADMET profile and chemical stability of 26 further indicate this compound to be a promising lead as a drug candidate warranting further advancement down the drug discovery pipeline. © 2013 American Chemical Society

A retrospective study on disease management in children and adolescents with phenylketonuria during the Covid-19 pandemic lockdown in Austria

BACKGROUND In classical phenylketonuria (PKU) phenylalanine (Phe) accumulates due to functional impairment of the enzyme phenylalanine hydroxylase caused by pathogenic variants in the PAH gene. PKU treatment prevents severe cognitive impairment. Blood Phe concentration is the main biochemical monitoring parameter. Between appointments and venous blood sampling, Austrian PKU patients send dried blood spots (DBS) for Phe measurements to their centre. Coronavirus disease-19 (COVID-19), caused by the SARS CoV-2 virus, was classified as a pandemic by the World Health Organization in March 2020. In Austria, two nationwide lockdowns were installed during the first and second pandemic wave with variable regional and national restrictions in between. This retrospective questionnaire study compared the frequency of Phe measurements and Phe concentrations during lockdown with the respective period of the previous year in children and adolescents with PKU and explored potential influencing factors. RESULTS 77 patients (30 female, 47 male; mean age 12.4 [8-19] years in 2020) from five centres were included. The decline of venous samples taken on appointments in 2020 did not reach significance but the number of patients with none or only one DBS tripled from 4 (5.2%) in 2019 to 12 (15.6%) in 2020. Significantly more patients had a decline than a rise in the number of DBS sent in between 2019 and 2020 (p < 0.001; Chi$^{2}$ = 14.79). Especially patients ≥ 16 years sent significantly less DBS in 2020 (T = 156, p = 0.02, r = 0.49). In patients who adhered to DBS measurements, Phe concentrations remained stable. Male or female sex and dietary only versus dietary plus sapropterin treatment did not influence frequency of measurements and median Phe. CONCLUSION During the COVID pandemic, the number of PKU patients who stopped sending DBS to their metabolic centre increased significantly, especially among those older than 16 years. Those who kept up sending DBS maintained stable Phe concentrations. Our follow-up system, which is based on DBS sent in by patients to trigger communication with the metabolic team served adherent patients well. It failed, however, to actively retrieve patients who stopped or reduced Phe measurements