Major histocompatibility complex and other allergy-related candidate genes associated with insect bite hypersensitivity in Icelandic horses

Insect bite hypersensitivity (IBH) is an allergic dermatitis of horses caused by bites of insects. IBH is a multifactorial disease with contribution of genetic and environmental factors. Candidate gene association analysis of IBH was performed in a group of 89 Icelandic horses all born in Iceland and imported to Europe. Horses were classified in IBH-affected and non-affected based on clinical signs and history of recurrent dermatitis, and on the results of an in vitro sulfidoleukotriene (sLT)-release assay with Culicoides nubeculosus and Simulium vittatum extract. Different genetic markers were tested for association with IBH by the Fisher's exact test. The effect of the major histocompatibility complex (MHC) gene region was studied by genotyping five microsatellites spanning the MHC region (COR112, COR113, COR114, UM011 and UMN-JH34-2), and exon 2 polymorphisms of the class II Eqca-DRA gene. Associations with Eqca-DRA and COR113 were identified (p < 0.05). In addition, a panel of 20 single nucleotide polymorphisms (SNPs) in 17 candidate allergy-related genes was tested. During the initial screen, no marker from the panel was significantly (p < 0.05) associated with IBH. Five SNPs associated with IBH at p < 0.10 were therefore used for analysis of combined genotypes. Out of them, SNPs located in the genes coding for the CD14 receptor (CD14), interleukin 23 receptor (IL23R), thymic stromal lymphopoietin (TSLP) and transforming growth factor beta 3 (TGFB3) molecules were associated with IBH as parts of complex genotypes. These results are supported by similar associations and by expression data from different horse populations and from human studies.

Current Regulating and Supporting Services: Nutrient Cycles

The study forest regulates nutrient cycles as a supporting ecosystem service mainly via retention in the biosphere and the soil organic layer. How tight the nutrient cycles are depends on environmental conditions. In this chapter, we focus on the roles of (1) deposition from the atmosphere, (2) soil moisture regime, and (3) conversion to pasture in the nutrient cycle. Between 1998 and 2010, there were a seasonal deposition of salpetric acid, an episodic deposition of Ca and Mg from Sahara dusts, and a continuous increase in reactive N inputs related to Amazonian forest fires, the El Niño Southern Oscillation cycle, and the economic development, respectively. Simultaneously, soils became increasingly drier enhancing nutrient release by mineralization. An increasing number of rain storms could considerably increase the export of N and base metals (K, Ca, Mg) via fast surface-near lateral transport in soil. Land-use change from forest to pasture introduces alkaline ashes and grass-derived organic matter. The resulting increases in soil pH and nutrient and substrate supply increase nutrient cycling rates because of enhanced microbial activity.

Atopic conditions and brain tumor risk in children and adolescents--an international case-control study (CEFALO)

BACKGROUND A number of epidemiological studies indicate an inverse association between atopy and brain tumors in adults, particularly gliomas. We investigated the association between atopic disorders and intracranial brain tumors in children and adolescents, using international collaborative CEFALO data. PATIENTS AND METHODS CEFALO is a population-based case-control study conducted in Denmark, Norway, Sweden, and Switzerland, including all children and adolescents in the age range 7-19 years diagnosed with a primary brain tumor between 2004 and 2008. Two controls per case were randomly selected from population registers matched on age, sex, and geographic region. Information about atopic conditions and potential confounders was collected through personal interviews. RESULTS In total, 352 cases (83%) and 646 controls (71%) participated in the study. For all brain tumors combined, there was no association between ever having had an atopic disorder and brain tumor risk [odds ratio 1.03; 95% confidence interval (CI) 0.70-1.34]. The OR was 0.76 (95% CI 0.53-1.11) for a current atopic condition (in the year before diagnosis) and 1.22 (95% CI 0.86-1.74) for an atopic condition in the past. Similar results were observed for glioma. CONCLUSIONS There was no association between atopic conditions and risk of all brain tumors combined or of glioma in particular. Stratification on current or past atopic conditions suggested the possibility of reverse causality, but may also the result of random variation because of small numbers in subgroups. In addition, an ongoing tumor treatment may affect the manifestation of atopic conditions, which could possibly affect recall when reporting about a history of atopic diseases. Only a few studies on atopic conditions and pediatric brain tumors are currently available, and the evidence is conflicting.

Perceived malleability of self versus the world and its impact on youths’ control orientation and well-being in the US, Germany, and India

Primary control is defined as changing the world to fit the self, while secondary control is defined as changing the self to fit the world. To understand why different individuals prefer different kinds of control processes, we proposed a research project looking at US, German and Indian young adults. We hypothesize that theories of self and the world (fixed vs. malleable; Dweck, 1999) affect the prevailing mode of control used. Furthermore, adolescents’ cultural background is assumed to affect their self-world theories as well as the adaptiveness of specific modes of control. For example, in the US, where the self is tended to be seen as fixed and the world as malleable, primary control prevails and is more adaptive than secondary control while the reverse is expected for India. We present the theoretical outline and methodology of the study as well as first results.

Prognostic significance of xCT polymorphisms and expression in patients with advanced pancreatic cancer treated with chemotherapy

The plasma membrane xc- cystine/glutamate transporter mediates cellular uptake of cystine in exchange for intracellular glutamate and is highly expressed by pancreatic cancer cells. The xCT gene, encoding the cystine-specific xCT protein subunit of xc-, is important in regulating intracellular glutathione (GSH) levels, critical for cancer cell protection against oxidative stress, tumor growth and resistance to chemotherapeutic agents including platinum. We examined 4 single nucleotide polymorphisms (SNPs) of the xCT gene in 269 advanced pancreatic cancer patients who received first line gemcitabine with or without cisplatin or oxaliplatin. Genotyping was performed using Taqman real-time PCR assays. A statistically significant correlation was noted between the 3' untranslated region (UTR) xCT SNP rs7674870 and overall survival (OS): Median survival time (MST) was 10.9 and 13.6 months, respectively, for the TT and TC/CC genotypes (p = 0.027). Stratified analysis showed the genotype effect was significant in patients receiving gemcitabine in combination with platinum therapy (n = 145): MST was 10.5 versus 14.1 months for the TT and TC/CC genotypes, respectively (p = 0.013). The 3' UTR xCT SNP rs7674870 may correlate with OS in pancreatic cancer patients receiving gemcitabine and platinum combination therapy. Paraffin-embedded core and surgical biopsy tumor specimens from 98 patients with metastatic pancreatic adenocarcinoma were analyzed by immunohistochemistry using an xCT specific antibody. xCT protein IHC expression scores were analyzed in relation to overall survival in 86 patients and genotype in 12 patients and no statistically significant association was found between the level of xCT IHC expression score and overall survival (p = 0.514). When xCT expression was analyzed in terms of treatment response, no statistically significant associations could be determined (p = 0.908). These data suggest that polymorphic variants of xCT may have predictive value, and that the xc- transporter may represent an important target for therapy in pancreatic cancer.

Structure-function analyses of {\it PAX6\/} and the molecular bases of aniridia

PAX6 is a transcription activator that regulates eye development in animals ranging from Drosophila to human. The C-terminal region of PAX6 is proline/serine/threonine-rich (PST) and functions as a potent transactivation domain when attached to a heterologous DNA-binding domain of the yeast transcription factor, GAL4. The PST region comprises 152 amino acids encoded by four exons. The transactivation function of the PST region has not been defined and characterized in detail by in vitro mutagenesis. I dissected the PST domain in two independent systems, a heterologous system using a GAL4 DNA-binding site and the native system of PAX6. In both systems, the results show consistently that all four constituent exons of the PST domain are responsible for the transactivation function. The four exon fragments act cooperatively to stimulate transcription, although none of them can function individually as an independent transactivation domain. Combinations of two or more exon fragments can reconstitute substantial transactivation activity when fused to the DNA-binding domain of GAL4, but they surprisingly do not produce much activity in the context of native PAX6 even though the mutant PAX6 proteins are stable and their DNA-binding function remains unaffected. I conclude that the PAX6 protein contains an unusually large transactivation domain that is evolutionarily conserved to a high degree, and that its full transactivation activity relies on the cooperative action of the four exon fragments.^ Most PAX6 mutations detected in patients with aniridia result in truncations of the protein. Some of the truncation mutations occur in the PST region of PAX6, resulting in mutant proteins that retain their DNA-binding ability but have no significant transactivation activity. It is not clear whether such mutants are true loss-of-function or dominant-negative mutants. I show that these mutants are dominant-negative if they are coexpressed with wild-type PAX6 in cultured cells and that the dominant-negative effects result from enhanced DNA-binding ability of these mutants due to removal of the PST domain. These mutants are able to repress the wild-type PAX6 activity not only at target genes with paired domain binding sites but also at target genes with homeodomain binding sites.^ Mutations in the human PAX6 gene produce various phenotypes, including aniridia, Peters' anomaly, autosomal dominant keratitis, and familial foveal dysplasia. The various phenotypes may arise from different mutations in the same gene. To test this theory, I performed a functional analysis of two missense mutations in the paired domain: the R26G mutation reported in a case of Peters' anomaly, and the I87R mutation identified in a patient with aniridia. While both the R26 and the I87 positions are conserved in the paired boxes of all known PAX genes, X-ray crystallography has shown that only R26 makes contact with DNA. I found that the R26G mutant failed to bind a subset of paired domain binding sites but, surprisingly, bound other sites and successfully transactivated promoters containing those sites. In contrast, the I87R mutant had lost the ability to bind DNA at all tested sites and failed to transactivate promoters. My data support the haploinsufficiency hypothesis of aniridia, and the hypothesis that R26G is a hypomorphic allele. ^

Characterization of dermatan sulfate proteoglycan 3 (DSPG3) and cartilage oligomeric matrix protein (COMP)

This dissertation describes the identification and characterization of human dermatan sulfate proteoglycan 3 (DSPG3) and the characterization of the transcriptional regulation of human cartilage oligomeric matrix protein (COMP) in cartilage, ligament, and tendon cells. DSPG3 and COMP are two extracellular matrix proteins. The function of these ECM proteins is unknown.^ DSPG3 was cloned, sequenced, and shown to be expressed in cartilage, ligament, and placenta. DSPG3 was mapped to human chromosome 12q21, and the genomic structure was identified. 1.6 kb of the promoter region has been sequenced, and several putative SOX9 sites were identified as well as 3 TATA sites. Furthermore, an evolutionary tree of the SLRP gene family, which includes DSPG3, is presented.^ The promoter region of COMP was cloned and sequenced. Several putative transcription factor binding sites were identified including multiple AP2 and SP1 sites. Three transcription start sites were found to be located directly downstream of one of the SP1 sites. In addition, the expression of COMP was demonstrated to be higher in tendon than in cartilage and ligament by both Northern and Western blot analysis, and several regions of the COMP promoter were shown to contain cell-specific regulatory elements. Analysis of the proximal 370bp region of the COMP promoter has also identified distinct patterns of nuclear protein binding for the three tissues, and two SP1 sites may play a role in the tissue-specific expression of COMP. ^

The Swiss Neonatal Quality Cycle, a monitor for clinical performance and tool for quality improvement

BACKGROUND We describe the setup of a neonatal quality improvement tool and list which peer-reviewed requirements it fulfils and which it does not. We report on the so-far observed effects, how the units can identify quality improvement potential, and how they can measure the effect of changes made to improve quality. METHODS Application of a prospective longitudinal national cohort data collection that uses algorithms to ensure high data quality (i.e. checks for completeness, plausibility and reliability), and to perform data imaging (Plsek's p-charts and standardized mortality or morbidity ratio SMR charts). The collected data allows monitoring a study collective of very low birth-weight infants born from 2009 to 2011 by applying a quality cycle following the steps 'guideline - perform - falsify - reform'. RESULTS 2025 VLBW live-births from 2009 to 2011 representing 96.1% of all VLBW live-births in Switzerland display a similar mortality rate but better morbidity rates when compared to other networks. Data quality in general is high but subject to improvement in some units. Seven measurements display quality improvement potential in individual units. The methods used fulfil several international recommendations. CONCLUSIONS The Quality Cycle of the Swiss Neonatal Network is a helpful instrument to monitor and gradually help improve the quality of care in a region with high quality standards and low statistical discrimination capacity.

A Conceptual Model to Combine Creativity Techniques with Fuzzy Cognitive Maps for Enhanced Knowledge Management

This chapter introduces a conceptual model to combine creativity techniques with fuzzy cognitive maps (FCMs) and aims to support knowledge management methods by improving expert knowledge acquisition and aggregation. The aim of the conceptual model is to represent acquired knowledge in a manner that is as computer-understandable as possible with the intention of developing automated reasoning in the future as part of intelligent information systems. The formal represented knowledge thus may provide businesses with intelligent information integration. To this end, we introduce and evaluate various creativity techniques with a list of attributes to define the most suitable to combine with FCMs. This proposed combination enables enhanced knowledge management through the acquisition and representation of expert knowledge with FCMs. Our evaluation indicates that the creativity technique known as mind mapping is the most suitable technique in our set. Finally, a scenario from stakeholder management demonstrates the combination of mind mapping with FCMs as an integrated system.

Microstructural and mechanical characterization of contemporary lingual orthodontic brackets.

OBJECTIVES To investigate the composition and the microstructural and mechanical characterization of three different types of lingual brackets. MATERIALS AND METHODS Incognito™ (3M Unitek), In-Ovation L (DENTSPLY GAC) and STb™ (Light Lingual System, ORMCO) lingual brackets were studied under the scanning electron microscope employing backscattered electron imaging and their elemental composition was analysed by energy-dispersive X-ray microanalysis. Additionally, Vickers hardness was assessed using a universal hardness-testing machine, and the indentation modulus was measured according to instrumented indentation test. Two-way analysis of variance was conducted employing bracket type and location (base and wing) as discriminating variable. Significant differences among groups were allocated by post hoc Student-Newman-Keuls multiple comparison analysis at 95% level of significance. RESULTS Three different phases were identified for Incognito and In-Ovation L bracket based on mean atomic number contrast. On the contrary, STb did not show mean atomic contrast areas and thus it is recognized as a single phase. Incognito is a one-piece bracket with the same structure in wing and base regions. Incognito consists mainly of noble metals while In-Ovation L and STb show similar formulations of ferrous alloys in wing and base regions. No significant differences were found between ferrous brackets in hardness and modulus values, but there were significant differences between wing and base regions. Incognito illustrated intermediate values with significant differences from base and wing values of ferrous brackets. CONCLUSIONS/IMPLICATIONS Significant differences exist in microstructure, elemental composition, and mechanical properties among the brackets tested; these might have a series of clinical implications during mechanotherapy.

Characteristics and comprehensiveness of adult HIV care and treatment programmes in Asia-Pacific, sub-Saharan Africa and the Americas: results of a site assessment conducted by the International epidemiologic Databases to Evaluate AIDS (IeDEA) Collaboration

INTRODUCTION HIV care and treatment programmes worldwide are transforming as they push to deliver universal access to essential prevention, care and treatment services to persons living with HIV and their communities. The characteristics and capacity of these HIV programmes affect patient outcomes and quality of care. Despite the importance of ensuring optimal outcomes, few studies have addressed the capacity of HIV programmes to deliver comprehensive care. We sought to describe such capacity in HIV programmes in seven regions worldwide. METHODS Staff from 128 sites in 41 countries participating in the International epidemiologic Databases to Evaluate AIDS completed a site survey from 2009 to 2010, including sites in the Asia-Pacific region (n=20), Latin America and the Caribbean (n=7), North America (n=7), Central Africa (n=12), East Africa (n=51), Southern Africa (n=16) and West Africa (n=15). We computed a measure of the comprehensiveness of care based on seven World Health Organization-recommended essential HIV services. RESULTS Most sites reported serving urban (61%; region range (rr): 33-100%) and both adult and paediatric populations (77%; rr: 29-96%). Only 45% of HIV clinics that reported treating children had paediatricians on staff. As for the seven essential services, survey respondents reported that CD4+ cell count testing was available to all but one site, while tuberculosis (TB) screening and community outreach services were available in 80 and 72%, respectively. The remaining four essential services - nutritional support (82%), combination antiretroviral therapy adherence support (88%), prevention of mother-to-child transmission (PMTCT) (94%) and other prevention and clinical management services (97%) - were uniformly available. Approximately half (46%) of sites reported offering all seven services. Newer sites and sites in settings with low rankings on the UN Human Development Index (HDI), especially those in the President's Emergency Plan for AIDS Relief focus countries, tended to offer a more comprehensive array of essential services. HIV care programme characteristics and comprehensiveness varied according to the number of years the site had been in operation and the HDI of the site setting, with more recently established clinics in low-HDI settings reporting a more comprehensive array of available services. Survey respondents frequently identified contact tracing of patients, patient outreach, nutritional counselling, onsite viral load testing, universal TB screening and the provision of isoniazid preventive therapy as unavailable services. CONCLUSIONS This study serves as a baseline for on-going monitoring of the evolution of care delivery over time and lays the groundwork for evaluating HIV treatment outcomes in relation to site capacity for comprehensive care.

Regional differences of physical activity and sedentary behaviour in Swiss children are not explained by socio-demographics or the built environment

Objective We evaluated whether regional differences in physical activity (PA) and sedentary behaviour (SB) existed along language boundaries within Switzerland and whether potential differences would be explained by socio-demographics or environmental characteristics. Methods We combined data of 611 children aged 4 to 7 years from four regional studies. PA and SB were assessed by accelerometers. Information about the socio-demographic background was obtained by questionnaires. Objective neighbourhood attributes could be linked to home addresses. Multivariate regression models were used to test associations between PA and SB and socio-demographic characteristics and neighbourhood attributes. Results Children from the German compared to the French-speaking region were more physically active and less sedentary (by 10–15 %, p < 0.01). Although German-speaking children lived in a more favourable environment and a higher socioeconomic neighbourhood (differences p < 0.001), these characteristics did not explain the differences in PA behaviour between French and German speaking. Conclusions Factors related to the language region, which might be culturally rooted were among the strongest correlates of PA and SB among Swiss children, independent of individual, social and environmental factors.

Bicyclo[3.2.1]amide-DNA: a chiral, non-chiroselective base-pairing system

The design, synthesis and base-pairing properties of bicyclo[3.2.1]amide-(bca)DNA, a novel phosphodiester based DNA analogue, is reported. This analogue consists of a conformationally constrained backbone entity which emulates a B-DNA geometry, to which the nucleobases were attached via an extended, acyclic amide linker. Homobasic adenine-containing bca-decamers form duplexes with complementary oligonucleotides containing the bca-, the DNA the RNA and, surprisingly, also the L-RNA backbone. UV- and CD-spectroscopic investigations revealed the duplexes with D- or L-complement to be of similar stability and enantiomorphic in structure. Bca-oligonucleotides containing all four bases form strictly antiparallel, left-handed complementary duplexes with itself and complementary DNA but not with RNA. Base-mismatch discrimination is comparable to that of DNA while the overall thermal stabilities of bca-oligonucleotide duplexes are inferior relative to that of DNA or RNA. A detailed molecular modeling study of left- and right-handed bca-DNA containing duplexes showed only minor changes in the backbone structure and revealed a structural switch around the base-linker unit to be responsible for the generation of enantiomorphic duplex structures. The obtained data are discussed with respect to the structural and energetic role of the ribofuranose entities in DNA and RNA association

Inhibition of HIV-1 multiplication by antisense U7 snRNAs and siRNAs targeting cyclophilin A.

Human immunodeficiency virus 1 (HIV-1) multiplication depends on a cellular protein, cyclophilin A (CyPA), that gets integrated into viral particles. Because CyPA is not required for cell viability, we attempted to block its synthesis in order to inhibit HIV-1 replication. For this purpose, we used antisense U7 small nuclear RNAs (snRNAs) that disturb CyPA pre-mRNA splicing and short interfering RNAs (siRNAs) that target CyPA mRNA for degradation. With dual-specificity U7 snRNAs targeting the 3' and 5' splice sites of CyPA exons 3 or 4, we obtained an efficient skipping of these exons and a strong reduction of CyPA protein. Furthermore, short interfering RNAs targeting two segments of the CyPA coding region strongly reduced CyPA mRNA and protein levels. Upon lentiviral vector-mediated transduction, prolonged antisense effects were obtained for both types of antisense RNAs in the human T-cell line CEM-SS. These transduced CEM-SS cells showed a delayed, and for the siRNAs also reduced, HIV-1 multiplication. Since the two types of antisense RNAs function by different mechanisms, combining the two approaches may result in a synergistic effect.

Trends in incidence of oesophageal and gastric cancer according to morphology and anatomical location, in Switzerland 1982-2011.

QUESTION UNDER STUDY/PRINCIPLES This study aimed to evaluate trends in the incidence of oesophageal and gastric cancer by anatomical location and histology using nationally representative Swiss data. METHODS We included all oesophageal and gastric cancers recorded in 10 Swiss population-based cancer registries 1982-2011. We calculated age-standardised incidence rates (ASIRs) per 100 000 person-years (PY) (European standard) for both cancer sites stratified by sex, language region (German, French-Italian), morphology and anatomical location. To assess time trends, we estimated annual percentage changes (APCs) with 95% confidence intervals (95% CIs). RESULTS ASIR of oesophageal adenocarcinoma increased in both sexes and language regions (p <0.001). The steepest increase occurred in males of the German-speaking region (APC 6.8%, 95% CI 5.8-7.8) with ASIRs of 0.8 per 100,000 PY in 1982-1987 and 3.9 per 100.000 PY in 2007-2011. Incidence of oesophageal squamous cell carcinoma decreased significantly in males of both language regions by around -1.5% per year. In contrast, a slight but significant increase (APC 1.4%, 95% CI 0.3-2.4]) of oesophageal squamous cell carcinoma was observed in females of the German-speaking region. We observed stable rates for cancer of the gastric cardia. The incidence of noncardia gastric cancer decreased substantially in both sexes and language regions (p <0.001). CONCLUSION In Switzerland, the incidence of oesophageal adenocarcinoma has risen whereas incidence of noncardia gastric cancer has decreased substantially as observed in other developed countries.