IL-23 receptor (IL-23R) gene protects against pediatric Crohn's disease

BACKGROUND: The IL-23 receptor (IL-23R) has been found to be associated with small bowel Crohn's disease (CD) in a whole genome association study. Specifically, the rare allele of the R381Q single nucleotide polymorphism (SNP) conferred protection against CD. It is unknown whether IL-23R is associated with IBD in children. The aim was to examine the association of IL-23R with susceptibility to IBD in pediatric patients. METHODS: DNA was collected from 609 subjects (151 CD and 52 ulcerative colitis [UC] trios). Trios were genotyped for the R381Q SNP of the IL-23R gene and SNP8, SNP12, SNP13, of the CARD15 gene using Taqman. The transmission disequilibrium test (TDT) was used for association to disease using GENEHUNTER 2.0. RESULTS: The rare allele of R381Q SNP was present in 2.7% of CD and 2.9% UC probands. The CARD15 frequency was 31.5% (CD) and 18% (UC). The IL-23R allele was negatively associated with inflammatory bowel disease (IBD): the R381Q SNP was undertransmitted in children with IBD (8 transmitted [T] versus 27 untransmitted [UT]; P = 0.001). This association was significant for all CD patients (6 T versus 19 UT; P = 0.009), especially for non-Jewish CD patients (2 T versus 17 UT; P = 0.0006). TDT showed a borderline association for UC (2 T versus 8 UT; P = 0.06). As expected, CARD15 was associated with CD in children by the TDT (58 T versus 22 UT P = 0.00006), but not with UC. CONCLUSIONS: The protective IL-23R R381Q variant was particularly associated with CD in non-Jewish children. Thus, the initial whole genome association study based on ileal CD in adults has been extended to the pediatric population and beyond small bowel CD.     

X-ray Thermo-Diffraction Study of the Aluminum-Based Multicomponent Alloy Al58Zn28Si8Mg6

Newly designed multicomponent light alloys are giving rise to non-conventional microstructures that need to be thoroughly studied before determining their potential applications. In this study, the novel Al₅₈Zn₂₈Si₈Mg₆ alloy, previously studied with CALPHAD methods, was cast and heat-treated under several conditions. An analysis of the phase evolution was carried out with in situ X-ray diffraction supported by differential scanning calorimetry and electron microscopy. A total of eight phases were identified in the alloy in the temperature range from 30 to 380 °C: α-Al, α’-Al, Zn, Si, Mg₂Si, MgZn₂, Mg₂Zn₁₁, and SrZn₁₃. Several thermal transitions below 360 °C were determined, and the natural precipitation of the Zn phase was confirmed after nine months. The study showed that the thermal history can strongly affect the presence of the MgZn₂ and Mg₂Zn₁₁ phases. The combination of X-ray thermo-diffraction with CALPHAD methods, differential scanning calorimetry, and electron microscopy offered us a satisfactory understanding of the alloy behavior at different temperatures.     

A clinical example of extreme dose exposure for an implanted cardioverter–defibrillator

Introduction

Considering that the number of malignant diseases in patients over 65 years of age is increasing, it often occurs that patients who carry a cardiac implanted electronic device must undergo radiotherapy. Ionizing radiation can disturb the function of the implantable cardioverter–defibrillator (ICD). As a result of this, an update of the DEGRO/DKG guidelines for radiotherapy of this patient group has been published.

Methods

We report the case of a patient with an ICD and T?lymphoblastic lymphoma with cardiac involvement, who received i.a. a total body irradiation with 8?Gy followed by a consolidating radiotherapy of the pericardium with 14?Gy as well as additional radiotherapy courses after consecutive recurrences. For the purposes of the treatment, the antitachyarrhythmia (ATA) therapy was deactivated and temporarily replaced through a life vest.

Results

According to the current DEGRO guidelines for irradiation of patients with cardiac implanted electronic devices, a categorization of the patient in the “high-risk” group was made. Furthermore, regular telemetric checks of the ICD device were performed before and after treatment. Despite unavailable declaration of the manufacturer regarding the cumulative tolerable dose and DEGRO recommendation for a cumulative dose <2?Gy, the aftercare was unproblematic and normal values were assessed for all relevant ICD parameters, despite a cumulative dose >10?Gy in the device.

Conclusion

This case shows that if the cardiac implanted electronic devices are not directly irradiated und the energy used is reduced to 6 MV, irradiation-induced damage is less likely and can possibly be prevented.

     

New Data on Cylindrospermopsin Toxicity

Cylindrospermopsin (CYN) is a widely spread cyanotoxin that can occur in fresh water and food. This research aims to investigate CYN toxicity by studying the effects of drinking 0.25 nM of CYN-contaminated water from a natural source, and of the direct application of moderate concentrations of CYN on different animal targets. The chosen structures and activities are rat mitochondria inner membrane permeability, mitochondrial ATP synthase (ATPase) and rat liver diamine oxidase (DAO) activities (EC 1.4.3.22.), the force of the contraction of an excised frog heart preparation with functional innervation, and the viability of a human intestinal epithelial cell line (HIEC-6). The oral exposure to CYN decreased the reverse (hydrolase) activity of rat liver ATPase whereas its short-term, in vitro application was without significant effect on this organelle, DAO activity, heart contractions, and their neuronal regulation. The application of CYN reduced HIEC-6 cells’ viability dose dependently. It was concluded that CYN is moderately toxic for the human intestinal epithelial cells, where the regeneration of the epithelial layer can be suppressed by CYN. This result suggests that CYN may provoke pathological changes in the human gastrointestinal tract.     

Correlation between the in vitro antioxidant activity and polyphenol content of aqueous extracts from Bulgarian herbs

The water phase antioxidant activity of extracts from 23 Bulgarian medicinal plants was studied in relation to their polyphenol content in comparison with mate, black tea, honeybush and rooibos foreign species. Antioxidant activity was measured by the ABTS (2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid)) cation radical decolorization assay, and the total polyphenol content was assayed according to the Folin-Ciocalteu method. Five Bulgarian plant extracts exhibited higher antioxidant activity than that of mate, which is 21.7% of all Bulgarian herbs included in this study. These were Alchemilla vulgaris L. (4.79 +/- 0.14 mm), Sambucus ebulus L. (4.03 +/- 0.07 mm), Mentha spicata L. (3.90 +/- 0.03 mm), Fragaria vesca L. (3.74 +/- 0.06 mm), Crataegus monogyna Jacq. (3.63 +/- 0.05 mm). Another eight Bulgarian medicinal plant extracts exhibited an intermediate antioxidant activity - lower than that of mate and higher than that of honeybush, which makes 34.8% of all Bulgarian herbs included in the study. More than half of the herbal extracts included in the present study exhibited antioxidant activity higher than or comparable to the reference foreign plants. A positive correlation (r = 0.92) between antioxidant activity and polyphenol content was found, suggesting that the antioxidant capacity of the aqueous plant extracts is due to a great extent to their polyphenols.     

Two-stage genome-wide linkage scan in keratoconus sib pair families

PURPOSE: To identify susceptibility gene loci for keratoconus. METHODS: A genome-wide linkage analysis was performed with data from 67 keratoconus sib pair families with 110 affected sib pairs of white or Hispanic origin. A total of 351 subjects were genotyped for 380 microsatellite markers along the genome at approximately 10-cM density. An additional 58 microsatellite markers at approximately 2-cM density in the identified linkage regions on chromosomes 4, 5, 9, 12, and 14 were also genotyped. Multipoint linkage analysis was performed in all pedigrees by nonparametric methods and maximum likelihood estimates of identity by descent sharing as implemented in GeneHunter (http://linkage.rockefeller.edu/soft/gh/ provided in the public domain by Rockefeller University, New York, NY). RESULTS: The strongest evidence of linkage was observed at the telomere (159 cM) of chromosome 9 (lod = 4.5) in all pedigrees. Other regions suggestive of linkage were identified at 176 cM of chromosome 4 (lod = 2.7), 143 cM of chromosome 5 (lod = 2.0), 7 cM of chromosome 9 (lod = 2.8), 12 cM of chromosome 11 (lod = 2.3), 27 cM of chromosome 12 (lod = 2.3), and 14 cM of chromosome 14 (lod = 2.9). Two significant linkage regions were also observed on chromosomes 17 at 86 cM (lod = 3.9) and 9 at 34 cM (lod = 3.8) in the Hispanic subjects only. After fine mapping these regions (with the exception of chromosomes 11 and 17), most linkage peaks remained similar (lod = 2.2 at 176 cM on chromosome 4; lod = 1.7 at 146 cM on chromosome 5; lod = 3.5 at 160 cM on chromosome 9; lod = 2.5 at 7 cM on chromosome 12; and lod = 2.6 at 19 cM on chromosome 14). CONCLUSIONS: These results indicate that one or more loci may contribute to keratoconus susceptibility.     

TNFSF15 is an ethnic-specific IBD gene

BACKGROUND: Inflammatory bowel disease (IBD) is a clinically and, likely, genetically heterogeneous group of disorders. A recent report suggests that genetic variations in the TNFSF15 gene contribute to the susceptibility of IBD in both Japanese and Caucasian populations. The aim was to confirm the association between TNFSF15 high- and low-risk haplotypes and IBD in a Caucasian population. METHODS: Five single-nucleotide polymorphisms (SNPs) that comprise the 2 common haplotypes were genotyped in 599 Caucasian patients with Crohn's disease (CD), 382 Caucasian patients with ulcerative colitis (UC), and 230 ethnically matched healthy controls, including both Jews and non-Jews. RESULTS: The previously reported 'risk' haplotype was not associated with CD or UC (88.2% in CD cases versus 88.3% in controls, P = 0.96; 88.1% in UC cases versus 88.3% in controls, P = 0.78). We did, however, observe an increased frequency of the "protective" haplotype in non-Jewish controls for both CD and UC (38.8% CD cases versus 50% controls, P = 0.01; 37.3% UC cases versus 50% controls, P = 0.01) with no such effect observed in the Jewish samples. There was an interactive effect between ethnicity and the protective haplotype in CD (P = 0.04). CONCLUSIONS: We observed a protective haplotype, consisting of the minor alleles for all 5 markers, to have a higher frequency in the non-Jewish controls than in CD and UC. Of further interest, the haplotype frequency was in the opposite direction in our Jewish case-control panels (both CD and UC), leading us to conclude 1) that TNFSF15 is indeed an IBD susceptibility gene, and 2) the disease susceptibility is ethnic-specific.     

The cytoskeletal protein septin 11 is associated with human obesity and is involved in adipocyte lipid storage and metabolism

Aims/hypothesis

Septins are newly identified members of the cytoskeleton that have been proposed as biomarkers of a number of diseases. However, septins have not been characterised in adipose tissue and their relationship with obesity and insulin resistance remains unknown. Herein, we characterised a member of this family, septin 11 (SEPT11), in human adipose tissue and analysed its potential involvement in the regulation of adipocyte metabolism.

Methods

Gene and protein expression levels of SEPT11 were analysed in human adipose tissue. SEPT11 distribution was evaluated by immunocytochemistry, electron microscopy and subcellular fractionation techniques. Glutathione S-transferase (GST) pull-down, immunoprecipitation and yeast two-hybrid screening were used to identify the SEPT11 interactome. Gene silencing was used to assess the role of SEPT11 in the regulation of insulin signalling and lipid metabolism in adipocytes.

Results

We demonstrate the expression of SEPT11 in human adipocytes and its upregulation in obese individuals, with SEPT11 mRNA content positively correlating with variables of insulin resistance in subcutaneous adipose tissue. SEPT11 content was regulated by lipogenic, lipolytic and proinflammatory stimuli in human adipocytes. SEPT11 associated with caveolae in mature adipocytes and interacted with both caveolin-1 and the intracellular fatty acid chaperone, fatty acid binding protein 5 (FABP5). Lipid loading of adipocytes caused the association of the three proteins with the surface of lipid droplets. SEPT11 silencing impaired insulin signalling and insulin-induced lipid accumulation in adipocytes.

Conclusions/interpretation

Our findings support a role for SEPT11 in lipid traffic and metabolism in adipocytes and open new avenues for research on the control of lipid storage in obesity and insulin resistance.