Abstract Objective Despite advances in the revascularisation techniques their net clinical benefit differs substantially between patients presenting with myocardial infarction (ACS) and chronic coronary syndrome (CCS) due to obstructive coronary atherosclerosis. Considering that leukocytes represents a key pathophysiological component of myocardial ischaemia, exploration of mononuclear blood cell (PBMC) gene expression profile in CCS and ACS setting could reveal clinically relevant transcriptomic signals. The aim of the present study was to identify differences in PBMC transcriptome between ACS and CCS patients which are linked to mortality after revascularisation. Methods and Results We analysed PBMC transcriptomes from719 ACS and 486 CCS patients creating discovery cohort. The results of transcriptomic analysis were verified in replication cohort (ACS: N=682 for CCS: N=489) generated based on propensity score matching. Median time from revascularisation to blood collection (IQR) was 15.68 (-4.52, 23.23) hrs. Patients with ACS showed consistent differential expression of 8173 genes (4544 upregulated, 3629 downregulated) when compared with CCS patients. The subsequent pathway analysis also showed significant enrichment of several canonical pathways involved in major cardiovascular pathologies i.e. atherosclerosis (p = 1.22-06, enrichment = 3.39), vascular endothelial growth factor production (p = 1.16-06, enrichment = 16.73), positive regulation of vascular development (p = 2.78-06, enrichment = 5.30) and heterotopic cell adhesion including gene desmocollin 2 (DSC2, p = 3.64-04, enrichment = 6.30). In der multivariate survival analysis with differentially expressed genes, increased expression of DCS2, lamin A/C (LMNA), and UGGT2, and decreased expression of SNRNP70 predicted poor survival over the median follow-up 11.35 yrs. Consistently, controlling the false discovery rate at ≤ 5% these genes enriched pathways involved in cardiomyopathies such as arrhythmogenic right-ventricular cardiomyopathy (p = 4.19x10-4, enrichment = 58.9) and collagen disease (p = 2.29x10-3, enrichment = 23.8). Conclusion We found altered PBMC expression of multiple genes in patients requiring revascularisation for ACS versus CCS. Several differentially expressed genes included in cardiomyopathy pathways predicted long-term all-cause mortality in these patients.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Background: Heat induces a thermoregulatory strain that impairs cardiopulmonary exercise capacity. The aim of the current study is to elucidate the effect of isolated dehydration on cardiopulmonary exercise capacity in a model of preparticipating hypohydration. Methods: Healthy recreational athletes underwent a standardised fluid deprivation test. Hypohydration was assessed by bioelectrical impedance analysis (BIA) and laboratory testing of electrolytes and retention parameters in the blood and urine. The participants underwent cardiopulmonary exercise testing (CPET) with a cycle ramp protocol. Each participant served as their own control undergoing CPET in a hypohydrated [HYH] and euhydrated [EUH] state. Results: Fluid deprivation caused a mild (2%) but significant reduction of body water (38.6 [36.6; 40.7] vs. 39.4 [37.4; 41.5] %; p < 0.01) and an increase of urine osmolality (767 [694; 839] vs. 537 [445; 629] mosm/kg; p < 0.01). Hypohydration was without alterations of electrolytes, serum osmolality or hematocrit. The oxygen uptake was significantly lower after hypohydration (−4.8%; p = 0.02 at ventilatory threshold1; −2.0%; p < 0.01 at maximum power), with a corresponding decrease of minute ventilation (−4% at ventilatory threshold1; p = 0.01, −3.3% at maximum power; p < 0.01). The power output was lower in hypohydration (−6.8%; p < 0.01 at ventilatory threshold1; −2.2%; p = 0.01 at maximum power). Conclusion: Isolated hypohydration causes impairment of workload as well as peak oxygen uptake in recreational athletes. Our findings might indicate an important role of hypohydration in the heat-induced reduction of exercise capacity.

The discovery of regulatory noncoding RNA molecules (ncRNA) revolutionized our previous understanding of gene expression. As shown by extensive sequencing projects from earlier times, ncRNA occurs in the human transcriptome in a previously unforeseen number and diversity, whereas mRNA coding for proteins only makes up a small proportion of the human transcriptome. In addition to structurally important ncRNA, tens of thousands of regulatory ncRNAs were identified in humans, of which microRNAs, long noncoding RNAs and the recently discovered circular RNAs are important groups. Members of this joint project have already contributed essential knowledge on the role, the mechanisms and the target structures of ncRNAs in the cardiovascular (CV) system. Furthermore, they have shown the feasibility of treatment based on the manipulation of ncRNA in cardiovascular diseases. Although a fascinating new field of research has opened up with ncRNAs, the enormous number of RNA transcripts, their different mechanisms of action and the complex methods necessary for their investigation represent major challenges. The tasks are now 1) to determine those ncRNAs which are essential for the development and homeostasis as well as the development and progression of diseases in the cardiovascular system and 2) to mechanistically understand their mode of functioning, with the aim to derive target structures and their manipulation to develop urgently needed new therapies.

Background and Aims: The discovery of microRNAs targeting gene pathways involved in HDL and LDL metabolism illuminated the potent role of non-coding RNAs in the regulation of cholesterol homeostasis. Long non-coding RNAs (lncRNA) have also been identified as crucial regulators of gene expression; however, few have been fully characterized.

Objectives: Little is known about molecular processes leading to the development of Hypoplastic Left Heart Syndrome (HLHS). To understand gene regulatory networks affected during early embryogenesis, we conducted a comparative transcriptome analysis between human induced pluripotent stem cell (hiPS) lines derived from HLHS patients and healthy controls.

Prognostic relevant pathways of leukocyte involvement in human myocardial ischemic-reperfusion injury are largely unknown. We enrolled 136 patients with ST-elevation myocardial infarction (STEMI) after primary angioplasty within 12 h after onset of symptoms. Following reperfusion, whole blood was collected within a median time interval of 20 h (interquartile range: 15–25 h) for genome-wide gene expression analysis. Subsequent CMR scans were performed using a standard protocol to determine infarct size (IS), area at risk (AAR), myocardial salvage index (MSI) and the extent of late microvascular obstruction (lateMO). We found 398 genes associated with lateMO and two genes with IS. Neither AAR, nor MSI showed significant correlations with gene expression. Genes correlating with lateMO were strongly related to several canonical pathways, including positive regulation of T-cell activation (p = 3.44 × 10−5), and regulation of inflammatory response (p = 1.86 × 10−3). Network analysis of multiple gene expression alterations associated with larger lateMO identified the following functional consequences: facilitated utilisation and decreased concentration of free fatty acid, repressed cell differentiation, enhanced phagocyte movement, increased cell death, vascular disease and compensatory vasculogenesis. In conclusion, the extent of lateMO after acute, reperfused STEMI correlated with altered activation of multiple genes related to fatty acid utilisation, lymphocyte differentiation, phagocyte mobilisation, cell survival, and vascular dysfunction.

Limited cleavage promotes the aggregation propensity of protein tau in neurodegenerative tauopathies. Cathepsin S (CatS) is overexpressed in brains of patients suffering from tauopathies such as Alzheimer’s disease (AD). Furthermore, CatS serum levels correlate with survival in the elderly. The current study investigates whether limited cleavage by CatS promotes tau aggregation, and whether CatS serum levels may correlate with disease severity in tauopathies. Oligomer formation of fluorescently labeled protein tau was monitored by single particle fluorescence spectroscopy after coincubation with CatS. Tau cleavage patterns were investigated by SDS-PAGE. For serum analyses, samples were collected from 42 patients with probable progressive supranuclear palsy (PSP) according to NINDS-PSP criteria. Disease severity was assessed by PSP rating scale (PSP-RS), PSP staging system (PSP-S) and Schwab and England Activities of Daily Living (SEADL). CatS, cystatin C (CysC) and interleukin 6 (IL-6) serum levels were determined by ELISA, ECLIA and turbidimetry, respectively. SDS-PAGE demonstrated a distinct cleavage pattern of protein tau after coincubation with CatS. Furthermore, tau oligomer formation was increased 2.4-fold (p < 0.05) after limited cleavage. Serum CatS and CysC levels did not correlate with disease severity in PSP. Of note, IL-6 correlated with PSP-S (r = 0.41; 95% CI 0.11–0.65; p = 0.008), SEADL (r = −0.37; 95% CI −0.61 to −0.06; p = 0.017) and the history and gait/midline subdomains of the PSP-RS. While CatS facilitates tau aggregation in vitro, serum levels of CatS appear not to correlate with disease severity. The observed correlation of IL-6 with disease severity warrants further investigation of inflammatory markers in PSP.

UNLABELLED:Effects of the dietary glycaemic load on postprandial blood glucose and insulin response might be of importance for fat deposition and risk of obesity. We aimed to investigate the metabolic effects, acceptance and tolerance of a follow-on formula containing the low glycaemic and low insulinaemic carbohydrate isomaltulose replacing high glycaemic maltodextrin. Healthy term infants aged 4 to 8 completed months (n = 50) were randomized to receive the intervention follow-on formula (IF, 2.1g isomaltulose (Palatinose™)/100mL) or an isocaloric conventional formula (CF) providing 2.1g maltodextrin/100mL for four weeks. Plasma insulinaemia 60 min after start of feeding (primary outcome) was not statistically different, while glycaemia adjusted for age and time for drinking/volume of meal 60 min after start of feeding was 122(105,140) mg/dL in IF (median, interquartile range) and 111(100,123) in CF (p = 0.01). Urinary c-peptide:creatinine ratio did not differ (IF:81.5(44.7, 96.0) vs. CF:56.8(37.5, 129),p = 0.43). Urinary c-peptide:creatinine ratio was correlated total intake of energy (R = 0.31,p = 0.045), protein (R = 0.42,p = 0.006) and fat (R = 0.40,p = 0.01) but not with carbohydrate intake (R = 0.22,p = 0.16). Both formulae were well accepted without differences in time of crying, flatulence, stool characteristics and the occurrence of adverse events. The expected lower postprandial plasma insulin and blood glucose level due to replacement of high glycaemic maltodextrin by low glycaemic isomaltulose were not observed in the single time-point blood analysis. In infants aged 4 to 8 completed months fed a liquid formula, peak blood glucose might be reached earlier than 60 min after start of feeding. Non-invasive urinary c-peptide measurements may be a suitable marker of nutritional intake during the previous four days in infants.TRIAL REGISTRATION:ClinicalTrials.gov NCT01627015.

Hintergrund: Mangelnde Vorhersagemöglichkeiten über die verbleibende Lebenszeit von Patienten in der Palliativbehandlung stellen oftmals eine große Herausforderung für Patienten und Familien, aber auch für die Planung der weiteren Versorgung dar. In der letzten Zeit wurden Serummarker identifiziert, die mit der verbleibenden Lebenszeit von alten und hochalten Menschen korrelieren. Ziel dieser Untersuchung war die Ermittlung des prädiktiven Werts für die Lebenszeit bei Patienten in der palliativen Phase.

Common marmosets are suitable non-human primate models for many human diseases. Standard values for blood parameters are required to evaluate physiological and pathological situations. Two studies were conducted: study I to determine standard values and study II to examine these under changed housing conditions. In study I, all parameters for clinical chemistry were similar in range for both genders with these specifics: male marmosets had significantly higher total and LDL cholesterol levels than females, whereas the mean corpuscular volume and the mean corpuscular haemoglobin were significantly lower than in females. In study II, glucose, lymphocytes and salivary cortisol were significantly lower, and faecal cortisol was increased during the change of housing conditions. In conclusion, standard values for haematology and clinical chemistry for the common marmoset were determined. Further on, parameters that are influenced by relocation stress and its importance for experimental results are described.

Genetic polymorphisms in alleles of the cytochrome P450 enzymes (CYP) 2D6 and 2C19 can result in intermediate (IM) or poor metabolizer (PM) status which may affect the plasma levels of antidepressants. We investigated a case series focussing on the connection between CYP genotypes and plasma levels of antidepressants and report whether this information was helpful for the pharmacological decision. Plasma levels of psychopharmacological substances were examined in 22 subjects treated with mainly escitalopram, mirtazapine or both in order to discover drug levels out of therapeutic range as a reason for lack of improvement or increased side effects. Genotyping results for CYP 2D6 (*3,*4,*5,*6) or CYP 2C19 (*2) were examined for interpretation of drug levels. For example, mirtazapine drug levels were diminished in one patient showing *3 CYP 2D6 heterozygosity which would have rather lead to IM status and therefore elevated plasma levels. This was a patient suffering from colitis ulcerosa, which may have led to insufficient uptake of mirtazapine from the bowel. The change from mirtazapine capsule to a disintegrating tablet of mirtazapine led to a sufficient increase in plasma levels and to remission of the patient. The cases demonstrate the high impact of therapeutic drug monitoring in order to evaluate shortcomings in therapeutic response. CYP genotyping can be of clinical relevance during therapy if additional clinical and pharmacokinetic information is taken into account.