Fundamental Improvement of Creep Resistance of New-Generation Nano-Oxide Strengthened Alloys via Hot Rotary Swaging Consolidation

New-generation oxide dispersion-strengthened (ODS) alloys with a high volume fraction of nano-oxides of 5% are intended to become the leading creep- and oxidation-resistant alloys for applications at 1100–1300 °C. Hot consolidation of mechanically alloyed powders by intensive plastic deformation followed by heat treatment of the alloys are the key aspects for achieving top creep properties, typically ensured by a coarse-grained microstructure strengthened with homogeneously dispersed, very stable yttrium nano-oxides. The rotary swaging method proves to be favourable for hot consolidation of the new-generation ODS alloy presented. Compared to specimens consolidated by hot rolling, consolidation by hot rotary swaging predetermines the formation of coarse grains with a very high aspect ratio during subsequent secondary recrystallization. Such a grain morphology increases the creep strength of the new-generation ODS alloy considerably.     

Zoonotic Dirofilaria repens (Nematoda: Filarioidea) in Aedes vexans mosquitoes,Czech Republic

The surveillance of vectors for arthropod-borne pathogens is nowadays an important tool in surveillance programmes throughout Europe. Whereas many studies have been performed to screen arthropods for viruses or bacterial pathogens, only limited information is available concerning the geographical distribution and vector range of pathogenic filariae in Central Europe. To consider the prevalence of filarial parasites in mosquito vectors, we performed a molecular survey of mosquitoes for filarial DNA. Mosquito collection was conducted at six study sites in the South Moravian region (Czech Republic) close to the borders with Slovakia and Austria from 2009 to 2011. Molecular screening of mosquitoes was conducted using conventional PCR with primers designed to amplify the mitochondrial cytochromoxidase subunit I gene as well as the partial 5.8S ribosomal RNA gene. A total of 13,222 mosquitoes belonging to six species were captured and distributed into 237 pools with different numbers of individuals. Overall, four pools were positive for Dirofilaria repens (a minimum infection rate 0.03 %) at two study sites (both natural and urban). Another filarial parasite detected during a study into Aedes vexans mosquitoes revealed the closest homology to Setaria spp. We detected specific D. repens DNA in Ae. vexans mosquitoes for the first time in the Czech Republic and confirmed the circulation of Dirofilaria spp. in a natural focus of infection providing an epidemiological link between autochthonous canine cases and mosquito vectors in the area studied.     

The effect of healing phenotype-inducing cytokine formulations within soft hydrogels on encapsulated monocytes and incoming immune cells

The adverse immune responses to implantable biomedical devices is a general problem with important consequences for the functionality of implants. Immunomodulatory soft hydrogel-based interfaces between the implant and the host can attenuate these reactions. Moreover, encapsulation of the patient''s own immune cells into these interfaces can lead to the personalisation of implants from the immune reaction point of view. Herein, we described a co-crosslinkable composite hydrogel (composed of gelatin and hyaluronic acid), which could be used for the encapsulation of macrophages in the presence of an anti-inflammatory phenotype-fixing cytokine cocktail. To mimick the incoming immune cells on the coating surface in vivo, peripheral blood mononuclear cells were seeded on the hydrogels. The encapsulation of monocytic cells into the composite hydrogels in the presence of cytokine cocktails at 5× or 10× concentrations led to the spreading of the encapsulated cells instead of the formation of clusters. Moreover, the secretion of the anti-inflammatory cytokines IL-1RA and CCL-18 was significantly increased. The attachment of PBMC to the surface of the hydrogel is dependent on the hydrogel composition and also significantly increased in the presence of the cytokine cocktail together with the number of CD68+ cells on the hydrogel surface. Our study demonstrates that the delivery of a polarisation cocktail with biocompatible hydrogels can control the initial response by the incoming immune cells. This effect can be improved by the encapsulation of autologous monocytes that are also polarised by the cytokine cocktail and secrete additional anti-inflammatory cytokines. This interface can fine tune the initial immune response to an implanted biomaterial in a personalised manner.

Hydrogels made from the derivatives of gelatin and hyaluronic acid were used as coatings to control the immune responses.     

De novo mutations of GCK,HNF1A and HNF4A may be more frequent in MODY than previously assumed

Aims/hypothesis

MODY is mainly characterised by an early onset of diabetes and a positive family history of diabetes with an autosomal dominant mode of inheritance. However, de novo mutations have been reported anecdotally. The aim of this study was to systematically revisit a large collection of MODY patients to determine the minimum prevalence of de novo mutations in the most prevalent MODY genes (i.e. GCK, HNF1A, HNF4A).

Methods

Analysis of 922 patients from two national MODY centres (Slovakia and the Czech Republic) identified 150 probands (16%) who came from pedigrees that did not fulfil the criterion of two generations with diabetes but did fulfil the remaining criteria. The GCK, HNF1A and HNF4A genes were analysed by direct sequencing.

Results

Mutations in GCK, HNF1A or HNF4A genes were detected in 58 of 150 individuals. Parents of 28 probands were unavailable for further analysis, and in 19 probands the mutation was inherited from an asymptomatic parent. In 11 probands the mutations arose de novo.

Conclusions/interpretation

In our cohort of MODY patients from two national centres the de novo mutations in GCK, HNF1A and HNF4A were present in 7.3% of the 150 families without a history of diabetes and 1.2% of all of the referrals for MODY testing. This is the largest collection of de novo MODY mutations to date, and our findings indicate a much higher frequency of de novo mutations than previously assumed. Therefore, genetic testing of MODY could be considered for carefully selected individuals without a family history of diabetes.     

The molecular basis of familial hypercholesterolemia in the Czech Republic: Spectrum of LDLR mutations and genotype-phenotype correlations

BackgroundFamilial hypercholesterolemia (FH), a major risk for coronary heart disease, is predominantly associated with mutations in the genes encoding the low-density lipoprotein receptor (LDLR) and its ligand apolipoprotein B (APOB).ResultsIn this study, we characterize the spectrum of mutations causing FH in 2239 Czech probands suspected to have FH. In this set, we found 265 patients (11.8%) with the APOB mutation p.(Arg3527Gln) and 535 patients (23.9%) with a LDLR mutation. In 535 probands carrying the LDLR mutation, 127 unique allelic variants were detected: 70.1% of these variants were DNA substitutions, 16.5% small DNA rearrangements, and 13.4% large DNA rearrangements. Fifty five variants were novel, not described in other FH populations. For lipid profile analyses, FH probands were divided into groups [patients with the LDLR mutation (LDLR+), with the APOB mutation (APOB+), and without a detected mutation (LDLR?/APOB?)], and each group into subgroups according to gender. The statistical analysis of lipid profiles was performed in 1722 probands adjusted for age in which biochemical data were obtained without FH treatment (480 LDLR+ patients, 222 APOB+ patients, and 1020 LDLR?/APOB? patients). Significant gradients in i) total cholesterol (LDLR+ patients > APOB+ patients = LDLR?/APOB? patients) ii) LDL cholesterol (LDLR+ patients > APOB+ patients = LDLR?/APOB? patients in men and LDLR+patients > APOB+ patients >LDLR?/APOB? patients in women), iii) triglycerides (LDLR?/APOB? patients > LDLR+ patients > APOB+ patients), and iv) HDL cholesterol (APOB+ patients > LDLR?/APOB? patients = LDLR+ patients) were shown.ConclusionOur study presents a large set of Czech patients with FH diagnosis in which DNA diagnostics was performed and which allowed statistical analysis of clinical and biochemical data.     

The role of endoglin in atherosclerosis

Endoglin (CD 105, TGF-β receptor III) is a homodimeric transmembrane glycoprotein that plays a regulatory role in TGF-β signaling. Its functional role in the context of atherosclerosis has yet to be defined and should be stated here. Therefore, we focused on the role of endoglin in atherosclerosis in both humans and experimental animals. Endoglin expression was demonstrated in atherosclerotic vessels predominantly in endothelial cells and smooth muscle cells in various types of blood vessels in mice and humans, suggesting its participation in atherogenesis. Endoglin expression was also related to the expression of eNOS in endothelium, repair of the vessel wall, plaque neoangiogenesis, production of collagen and stabilization of atherosclerotic lesions. In addition, increased levels of soluble endoglin were associated with hypercholesterolemia, atherosclerosis, acute myocardial infarction and were related to inhibition of TGF-β signaling in the vessel wall. Moreover, soluble endoglin levels were significantly lowered after a series of extracorporeal eliminations in patients with familial hypercholesterolemia. Additionally, statin treatment decreased levels of soluble endoglin and increased its expression in aorta, which was related to reduced atherosclerosis in mice. In conclusion, we propose that measurement of soluble endoglin might give information about progression of the atherosclerotic process or the efficacy of therapeutic interventions, which is the task that must be answered in clinical trials.     

Decreased serum antioxidant capacity in patients with Wilson disease is associated with neurological symptoms

Background &; Aims

Wilson disease (WD) is an inherited disorder of copper disposition caused by an ATP7B transporter gene mutation, leading to copper accumulation in predisposed tissues. In addition to a genetic predisposition, other factors are likely to contribute to its clinical manifestation. The aim of the study was to assess whether oxidative stress affects the phenotypic manifestation of WD.

Methods

In 56 patients with WD (29 men; 26 with the hepatic form, 22 with the neurologic form, and eight asymptomatic; mean age 38.5?±?12 years), total serum antioxidant capacity (TAC) and inflammatory parameters (hs-CRP, IL-1??, IL-2, IL-6, IL-10, and TNF-??) were analyzed and related to the clinical manifestation, and mutations of the ATP7B gene. The control group for the TAC and inflammatory parameters consisted of 50 age- and gender-matched healthy individuals.

Results

WD patients had a significantly lower TAC (p?Conclusions Data from our study suggest that the increased oxidative stress contributes significantly to the clinical manifestation of WD; as a lower TAC is associated with the neurological symptoms in WD patients.