Sirkadiaaninen lämpötila-amplitudi muokkaa unen määrää nuoruudessa

Tavoitteet. Tämän tutkimuksen tavoitteena oli tarkastella unen ja sisäisen vuorokausirytmin normatiivista kehittymistä nuoruuden aikana. Aiemmissa tutkimuksissa on löydetty, että unen kokonaismäärä vähenee ikääntymisen myötä, ja erityisesti nuoruudessa unen ajoitus muuttuu myöhemmäksi, mihin vaikuttaa sekä fysiologisia että psykologisia tekijöitä. Uni on yhteydessä nuorten sisäiseen vuorokausirytmiin, mitä on yleisesti tutkittu melatoniinin erityksen kautta. On epäselvää, kuinka uni on yhteydessä kehon lämpötilan vuorokausirytmiin nuoruudessa. Menetelmät. Tämä tutkimus oli osa Sleep & Mind -tutkimusryhmän SleepHelsinki! kohorttitutkimusta. Nuorten unta mitattiin aktigrafialla, kun taas lämpötilan vuorokausirytmi sisälsi ihon pintalämpötilan mittaamisen. Lämpötilan vuorokausirytmiä tarkasteltiin rytmin pituudella, ihon keskiarvoisella lämpötilalla sekä vuorokauden aikana tapahtuvan vaihtelun suuruudella eli amplitudilla. Lähtömittaukseen osallistui 215 (71.6 % tyttöjä) nuorta (16–18 vuotta). Vuoden kuluttua 156 (76.3 % tyttöjä) nuorta osallistui seurantamittaukseen. Muutoksia unessa ja lämpötilan vuorokausirytmissä testattiin toistettujen mittausten sekamallilla, mikä tehtiin erikseen tytöille ja pojille. Sukupuolten välisiä eroja testattiin yksisuuntaisella varianssianalyysillä. Seurantamittauksen unta ja vuorokausirytmiä ennustettiin lähtömittauksen arvoilla ja sukupuolella; testaukseen käytettiin sekä lineaarisia että ordinaalista regressiomalleja. Tulokset ja johtopäätökset. Vuoden aikana nuorten unen kokonaismäärä kasvoi viikon aikana, mutta viikonlopun unen määrä väheni. Tämä muutos oli kuitenkin tilastollisesti merkitsevä pelkästään tytöillä. Unen ajoitus myöhästyi sekä tytöillä että pojilla, sillä unen alkamisaika, keskikohta sekä heräämisaika muuttuivat myöhäisemmiksi. Ihon lämpötilan vuorokausirytmi puolestaan muuttui pelkästään pojilla, sillä heidän keskiarvoinen iholämpötilansa kasvoi ja lämpötilan vaihtelun suuruus väheni. Seurantamittauksessa poikien lämpötilan amplitudi oli myös selvästi pienempi kuin tytöillä, ja tytöillä oli 5.85-kertainen todennäköisyys korkeaan amplitudiin poikiin verrattuna. Lämpötilan amplitudi oli yhteydessä viikon unen määrään, sillä lämpötilan amplitudi vaikutti muutoksiin unen määrässä: korkeampi amplitudi lämpötilassa ennusti unen määrän kasvamista. Kuitenkin aiempi unen määrä vaikutti todennäkösyyteen, että nuorella oli pitkä unen kesto vuoden kuluttua.Aims of the study. The aim of this study was to examine normative development of sleep patterns and circadian rhythmicity during adolescence. Previous studies have found that sleep duration shortens across the lifespan, and especially adolescents’ sleep timing shifts later due to physiological and psychological factors. Sleep patterns in adolescence are connected to individual’s endogenous circadian rhythms, usually measured by delayed melatonin secretion in the evening. There is a lack of understanding how sleep patterns are related to circadian body temperature rhythms during adolescence. Methods. This study was part of SleepHelsinki! cohort study of the Sleep & Mind Research Group. Adolescents’ sleep patterns were measured with actigraphies, whereas circadian body temperature was measured from the skin surface. Circadian temperature rhythmicity was inspected by circadian period length, the mesor of skin surface temperature and the amplitude of daily changes within the rhythm. Baseline measurements were measured from 215 (71.6 % girls) adolescents aged 16–18 years. At one-year follow-up, 156 (76.3 % girls) adolescents were measured again. Mixed models for repeated measures were used to examine changes over the year in sleep patterns and endogenous circadian temperature rhythm, separately for both girls and boys. Sex differences were tested with one-way variance analysis. Linear and ordinal regressions were used to predict sleep and circadian rhythm over the year. Results and conclusions. Over the year, adolescents’ sleep duration became longer during the week, while weekend sleep shortened. However, this change was only significant for girls. Sleep schedule became more delayed for both girls and boys during the week, as sleep onset, midpoint and offset occurred at a later time. Circadian rhythm changed for boys, as their average skin surface temperature increased, and their circadian temperature amplitude became smaller. Boys also had significantly lower circadian temperature amplitude than girls at the follow-up. Compared to boys, girls were 5.85 times more likely to have a high circadian temperature amplitude at the follow-up measurement. Changes in sleep length during the week was moderated by temperature amplitude, with higher circadian amplitude predicting sleep duration to become longer. Still, the likelihood to have long sleep duration was affected by past sleep duration

Effects of angiotensin II blockade on cardiomyocyte regeneration after myocardial infarction in rats

Peer reviewe

Inhibition of let-7c Regulates Cardiac Regeneration after Cryoinjury in Adult Zebrafish

The let-7c family of micro-RNAs (miRNAs) is expressed during embryonic development and plays an important role in cell differentiation. We have investigated the role of let-7c in heart regeneration after injury in adult zebrafish. let-7c antagomir or scramble injections were given at one day after cryoinjury (1 dpi). Tissue samples were collected at 7 dpi, 14 dpi and 28 dpi and cardiac function was assessed before cryoinjury, 1 dpi, 7 dpi, 14 dpi and 28 dpi. Inhibition of let-7c increased the rate of fibrinolysis, increased the number of proliferating cell nuclear antigen (PCNA) positive cardiomyocytes at 7 dpi and increased the expression of the epicardial marker raldh2 at 7 dpi. Additionally, cardiac function measured with echocardiography recovered slightly more rapidly after inhibition of let-7c. These results reveal a beneficial role of let-7c inhibition in adult zebrafish heart regeneration

Urinary Biomarkers Indicative of Apoptosis and Acute Kidney Injury in the Critically Ill

Background Apoptosis is a key mechanism involved in ischemic acute kidney injury (AKI), but its role in septic AKI is controversial. Biomarkers indicative of apoptosis could potentially detect developing AKI prior to its clinical diagnosis. Methods As a part of the multicenter, observational FINNAKI study, we performed a pilot study among critically ill patients who developed AKI (n = 30) matched to critically ill patients without AKI (n = 30). We explored the urine and plasma levels of cytokeratin-18 neoepitope M30 (CK-18 M30), cell-free DNA, and heat shock protein 70 (HSP70) at intensive care unit (ICU) admission and 24h thereafter, before the clinical diagnosis of AKI defined by the Kidney Disease: Improving Global Outcomes - creatinine and urine output criteria. Furthermore, we performed a validation study in 197 consecutive patients in the FINNAKI cohort and analyzed the urine sample at ICU admission for CK-18 M30 levels. Results In the pilot study, the urine or plasma levels of measured biomarkers at ICU admission, at 24h, or their maximum value did not differ significantly between AKI and non-AKI patients. Among 20 AKI patients without severe sepsis, the urine CK-18 M30 levels were significantly higher at 24h (median 116.0, IQR [32.3-233.0] U/L) than among those 20 patients who did not develop AKI (46.0 [0.0-54.0] U/L), P = 0.020. Neither urine cell-free DNA nor HSP70 levels significantly differed between AKI and non-AKI patients regardless of the presence of severe sepsis. In the validation study, urine CK-18 M30 level at ICU admission was not significantly higher among patients developing AKI compared to non-AKI patients regardless of the presence of severe sepsis or CKD. Conclusions Our findings do not support that apoptosis detected with CK-18 M30 level would be useful in assessing the development of AKI in the critically ill. Urine HSP or cell-free DNA levels did not differ between AKI and non-AKI patients.Peer reviewe

Alterations of Cardiac Protein Kinases in Cyclic Nucleotide-Dependent Signaling Pathways in Human Ischemic Heart Failure

ObjectivesImpaired protein kinase signaling is a hallmark of ischemic heart disease (IHD). Inadequate understanding of the pathological mechanisms limits the development of therapeutic approaches. We aimed to identify the key cardiac kinases and signaling pathways in patients with IHD with an effort to discover potential therapeutic strategies.MethodsCardiac kinase activity in IHD left ventricle (LV) and the related signaling pathways were investigated by kinomics, transcriptomics, proteomics, and integrated multi-omics approach.ResultsProtein kinase A (PKA) and protein kinase G (PKG) ranked on top in the activity shift among the cardiac kinases. In the IHD LVs, PKA activity decreased markedly compared with that of controls (62% reduction, p = 0.0034), whereas PKG activity remained stable, although the amount of PKG protein increased remarkably (65%, p = 0.003). mRNA levels of adenylate cyclases (ADCY 1, 3, 5, 9) and cAMP-hydrolysing phosphodiesterases (PDE4A, PDE4D) decreased significantly, although no statistically significant alterations were observed in that of PKGs (PRKG1 and PRKG2) and guanylate cyclases (GUCYs). The gene expression of natriuretic peptide CNP decreased remarkably, whereas those of BNP, ANP, and neprilysin increased significantly in the IHD LVs. Proteomics analysis revealed a significant reduction in protein levels of “Energy metabolism” and “Muscle contraction” in the patients. Multi-omics integration highlighted intracellular signaling by second messengers as the top enriched Reactome pathway.ConclusionThe deficiency in cAMP/PKA signaling pathway is strongly implicated in the pathogenesis of IHD. Natriuretic peptide CNP could be a potential therapeutic target for the modulation of cGMP/PKG signaling.Peer reviewe

Tankyrase Inhibition Attenuates Cardiac Dilatation and Dysfunction in Ischemic Heart Failure

Hyperactive poly(ADP-ribose) polymerases (PARP) promote ischemic heart failure (IHF) after myocardial infarction (MI). However, the role of tankyrases (TNKSs), members of the PARP family, in pathogenesis of IHF remains unknown. We investigated the expression and activation of TNKSs in myocardium of IHF patients and MI rats. We explored the cardioprotective effect of TNKS inhibition in an isoproterenol-induced zebrafish HF model. In IHF patients, we observed elevated TNKS2 and DICER and concomitant upregulation of miR-34a-5p and miR-21-5p in non-infarcted myocardium. In a rat MI model, we found augmented TNKS2 and DICER in the border and infarct areas at the early stage of post-MI. We also observed consistently increased TNKS1 in the border and infarct areas and destabilized AXIN in the infarct area from 4 weeks onward, which in turn triggered Wnt/β-catenin signaling. In an isoproterenol-induced HF zebrafish model, inhibition of TNKS activity with XAV939, a TNKSs-specific inhibitor, protected against ventricular dilatation and cardiac dysfunction and abrogated overactivation of Wnt/β-catenin signaling and dysregulation of miR-34a-5p induced by isoproterenol. Our study unravels a potential role of TNKSs in the pathogenesis of IHF by regulating Wnt/β-catenin signaling and possibly modulating miRNAs and highlights the pharmacotherapeutic potential of TNKS inhibition for prevention of IHF

Vezf1 regulates cardiac structure and contractile function

Background Vascular endothelial zinc finger 1 (Vezf1) is a transcription factor previously shown to regulate vasculogenesis and angiogenesis. We aimed to investigate the role of Vezf1 in the postnatal heart. Methods The role of Vezf1 in regulating cardiac growth and contractile function was studied in zebrafish and in primary cardiomyocytes. Findings We find that expression of Vezf1 is decreased in diseased human myocardium and mouse hearts. Our experimental data shows that knockdown of zebrafish Vezf1 reduces cardiac growth and results in impaired ventricular contractile response to β-adrenergic stimuli. However, Vezf1 knockdown is not associated with dysregulation of cardiomyocyte Ca2+ transient kinetics. Gene ontology enrichment analysis indicates that Vezf1 regulates cardiac muscle contraction and dilated cardiomyopathy related genes and we identify cardiomyocyte Myh7/β-MHC as key target for Vezf1. We further identify a key role for an MCAT binding site in the Myh7 promoter regulating the response to Vezf1 knockdown and show that TEAD-1 is a binding partner of Vezf1. Interpretation We demonstrate a role for Vezf1 in regulation of compensatory cardiac growth and cardiomyocyte contractile function, which may be relevant in human cardiac disease.Peer reviewe