Natural Glycoforms of Human Interleukin 6 show atypical plasma clearance

A library of glycoforms of human interleukin 6 (IL‐6) comprising complex and mannosidic N‐glycans was generated by semisynthesis. The three segments were connected by sequential native chemical ligation followed by two‐step refolding. The central glycopeptide segments were assembled by pseudoproline‐assisted Lansbury aspartylation and subsequent enzymatic elongation of complex N‐glycans. Nine IL‐6 glycoforms were synthesized, seven of which were evaluated for in vivo plasma clearance in rats and compared to non‐glycosylated recombinant IL‐6 from E. coli. Each IL‐6 glycoform was tested in three animals and reproducibly showed individual serum clearances depending on the structure of the N‐glycan. The clearance rates were atypical, since the 2,6‐sialylated glycoforms of IL‐6 cleared faster than the corresponding asialo IL‐6 with terminal galactoses. Compared to non‐glycosylated IL‐6 the plasma clearance of IL‐6 glycoforms was delayed in the presence of larger and multibranched N‐glycans in most case

Impact of age and comorbidities on health-related quality of life for patients with prostate cancer: evaluation before a curative treatment

<p>Abstract</p> <p>Background</p> <p>Interpretation of comparative health-related quality of life (HRQOL) studies following different prostate cancer treatments is often difficult due to differing patient ages. Furthermore, age-related changes can hardly be discriminated from therapy-related changes. The evaluation of age-and comorbidity-related changes was in focus of this study.</p> <p>Methods</p> <p>HRQOL of 528 prostate cancer patients was analysed using a validated questionnaire (Expanded Prostate Cancer Index Composite) before a curative treatment. Patients were divided into age groups ≤65, 6670, 7175 and >75 years. The impact of specific comorbidities and the Charlson Comorbidity Index (CCI) were evaluated. The questionnaire comprises 50 items concerning the urinary, bowel, sexual and hormonal domains for function and bother. For assessment of sexual and hormonal domains, only patients without prior hormonal treatment were included (n = 336).</p> <p>Results</p> <p>Urinary incontinence was observed increasingly with higher age (mean function scores of 92/88/85/87 for patients ≤65, 6670, 7175 and >75 years) complete urinary control in 78%/72%/64%/58% (p < 0.01). Sexual function scores decreased particularly (48/43/35/30), with erections sufficient for intercourse in 68%/50%/36%/32% (p < 0.01) a decrease of more than a third comparing patients ≤65 vs. 6670 (36%) and 6670 vs. 7175 years (39%). The percentage of patients with comorbidities was lowest in the youngest group (48% vs. 66%/68%/63% for ages 6670/7175/>75 years; p < 0.05). A multivariate analysis revealed an independent influence of both age and comorbidities on urinary incontinence, specifically diabetes on urinary bother, and both age and diabetes on sexual function/bother. Rectal domain scores were not significantly influenced by age or comorbidities. A CCI>5 particularly predisposed for lower urinary and sexual HRQOL scores.</p> <p>Conclusion</p> <p>Urinary continence and sexual function are the crucial HRQOL domains with age-related and independently comorbidity-related decreasing scores. The results need to be considered for the interpretation of comparative studies or longitudinal changes after a curative treatment.</p

Insulating improper ferroelectric domain walls as robust barrier layer capacitors

We report the dielectric properties of improper ferroelectric hexagonal (h-)ErMnO3. From the bulk characterization, we observe a temperature and frequency range with two distinct relaxation-like features, leading to high and even “colossal” values for the dielectric permittivity. One feature trivially originates from the formation of a Schottky barrier at the electrode–sample interface, whereas the second one relates to an internal barrier layer capacitance (BLC). The calculated volume fraction of the internal BLC (of 8%) is in good agreement with the observed volume fraction of insulating domain walls (DWs). While it is established that insulating DWs can give rise to high dielectric constants, studies typically focused on proper ferroelectrics where electric fields can remove the DWs. In h-ErMnO3, by contrast, the insulating DWs are topologically protected, facilitating operation under substantially higher electric fields. Our findings provide the basis for a conceptually new approach to engineer materials exhibiting colossal dielectric permittivities using domain walls in improper ferroelectrics

An extract from the Atlantic brown algae Saccorhiza polyschides counteracts diet-induced obesity in mice via a gut related multi-factorial mechanisms

In this study we addressed the questions whether an Atlantic brown algae extract (BAE) affects diet induced obesity in mice and which would be the primary targets and underlying key mechanisms. Male C57 BL/6 mice were fed a hypercaloric diet, referred to as high fat diet (HFD), supplemented with a freeze-dried aqueous BAE from Saccorhiza polyschides (5 %) for 8 months. Compared to the control group, dietary BAE supplementation significantly attenuated increase in body weight and fat mass. We observed apparent metabolic improvement including normalization of blood glucose, reduced plasma leptin, reduced fecal bile salt hydrolase activity with lower microbial production of toxic bile acid metabolites in the gut and increased systemic bile acid circulation in BAE-fed mice counteracting adverse effects of long term HFD feeding. Survival of mice receiving dietary BAE supplementation appeared slightly enhanced; however, median and maximal life spans as well as hepatic mTOR activation were not significantly different between BAE and control mice. We suggest that the beneficial metabolic effects of our BAE are at least partly mediated by alterations in gut microbiota associated with fermentation of indigestible polysaccharides that are major components of brown algae such as alginates and fucoidans. We moreover propose a multi-factorial mechanism that involves profound alterations in bile acid homeostasis, changes in intestinal and systemic glucose metabolism likely including increased intestinal gluconeogenesis, increased activity of the intestinally derived hormone GLP-1 contributing to promote systemic insulin sensitivity, and inhibition of α-amylase activity, which expectably limits dietary carbohydrate digestion and glucose release

Robotic infant surgery with 3 mm instruments: a study in piglets of less than 10 kg body weight

No data exist concerning the appication of a new robotic system with 3 mm instruments (Senhance®, Transenterix) in infants and small children. Therefore, the aim of this study was to test the system for its feasibility, performance and safety of robotic pediatric abdominal and thoracic surgery in piglets simulating infants with a body weight lower than 10 kg. 34 procedures (from explorative laparoscopy to thoracoscopic esophageal repair) were performed in 12 piglets with a median age of 23 (interquartile range: 12-28) days and a median body weight of 6.9 (6.1-7.3) kg. The Senhance® robotic system was used with 3 mm instruments, a 10 mm 3D 0° or 30° videoscope and advanced energy devices, the setup consisted of the master console and three separate arms. The amount, size, and position of the applied ports, their distance as well as the distance between the three operator arms of the robot, external and internal collisions, and complications of the procedures were recorded and analyzed. We were able to perform all planned surgical procedures with 3 mm robotic instruments in piglets with a median body weight of less than 7 kg. We encountered two non-robot associated complications (bleeding from the inferior caval and hepatic vein) which led to termination of the live procedures. Technical limitations were the reaction time and speed of robotic camera movement with eye tracking, the excessive bending of the 3 mm instruments and intermittent need of re-calibration of the fulcrum point. Robotic newborn and infant surgery appears technically feasible with the Senhance® system. Software adjustments for camera movement and sensitivity of the fulcrum point calibration algorithm to adjust for the increased compliance of the abdominal wall of infants, therefore reducing the bending of the instruments, need to be implemented by the manufacturer as a result of our study. To further evaluate the Senhance® system, prospective trials comparing it to open, laparoscopic and other robotic systems are needed

Mesenchymal stromal cells but not cardiac fibroblasts exert beneficial systemic immunomodulatory effects in experimental myocarditis.

Systemic application of mesenchymal stromal cells (MSCs) in inflammatory cardiomyopathy exerts cardiobeneficial effects. The mode of action is unclear since a sufficient and long-acting cardiac homing of MSCs is unlikely. We therefore investigated the regulation of the immune response in coxsackievirus B3 (CVB3)-induced acute myocarditis after intravenous application of MSCs. Wildtype mice were infected with CVB3 and treated with either PBS, human MSCs or human cardiac fibroblasts intravenously 1 day after infection. Seven days after infection, MSCs could be detected in the spleen, heart, pancreas, liver, lung and kidney, whereby the highest presence was observed in the lung. MSCs increased significantly the myocardial expression of HGF and decreased the expression of the proinflammatory cytokines TNFα, IL1β and IL6 as well as the severity of myocarditis and ameliorated the left ventricular dysfunction measured by conductance catheter. MSCs upregulated the production of IFNγ in CD4+ and CD8+ cells, the number of IL10-producing regulatory T cells and the apoptosis rate of T cells in the spleen. An increased number of CD4+CD25+FoxP3 could be found in the spleen as well as in the circulation. In contrast, application of human cardiac fibroblasts had no effect on the severity of myocarditis and the systemic immune response observed after MSCs-administration. In conclusion, modulation of the immune response in extracardiac organs is associated with cardiobeneficial effects in experimental inflammatory cardiomyopathy after systemic application of MSCs

Natural Glycoforms of Human Interleukin 6 Show Atypical Plasma Clearance

A library of glycoforms of human interleukin 6 (IL‐6) comprising complex and mannosidic N‐glycans was generated by semisynthesis. The three segments were connected by sequential native chemical ligation followed by two‐step refolding. The central glycopeptide segments were assembled by pseudoproline‐assisted Lansbury aspartylation and subsequent enzymatic elongation of complex N‐glycans. Nine IL‐6 glycoforms were synthesized, seven of which were evaluated for in vivo plasma clearance in rats and compared to non‐glycosylated recombinant IL‐6 from E. coli. Each IL‐6 glycoform was tested in three animals and reproducibly showed individual serum clearances depending on the structure of the N‐glycan. The clearance rates were atypical, since the 2,6‐sialylated glycoforms of IL‐6 cleared faster than the corresponding asialo IL‐6 with terminal galactoses. Compared to non‐glycosylated IL‐6 the plasma clearance of IL‐6 glycoforms was delayed in the presence of larger and multibranched N‐glycans in most case

Effects of MSCs on fibroblasts and collagen production during myocarditis.

<p>a. Serious red analysis of collagen production by murine fibroblasts co-cultured with splenocytes from infected and healthy mice treated with PBS, MSCs or cardiac fibroblasts. Splenocytes from infected animals induced an increased production of collagen in the fibroblasts compared to those from non-infected mice. However, splenocytes from MSC-treated mice led to a significantly lower activation of murine fibroblasts as measured by their collagen production. b-c. Immunohistochemical analysis of the collagen I and III amount in the myocardium showed a significantly lower myocardial fibrosis after MSC-treatment compared to PBS and fibroblasts and confirmed our in vitro experiments. *p<0.05 vs PBS-treated mice with same infection status, § p<0.05 vs respective control-group, # p<0.05 vs. MSC-treated mice with same infection status, & p<0.05 vs. murine fibroblasts in basal conditions (cultured alone).</p