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Increasing reports of invasive Streptococcus pyogenes infections mandate surveillance for toxigenic lineage M1UK. An allele-specific PCR was developed to distinguish M1UK from other emm1 strains. The M1UK lineage represented 91% of invasive emm1 isolates in England in 2020. Allele-specific PCR will permit surveillance for M1UK without need for genome sequencing.

Objectives Several articles have provided conflicting results regarding the role of single nucleotide polymorphisms (SNPs) in the promoter region of the TNF gene in susceptibility to sepsis. Former articles have been based on previous definitions of sepsis. This study investigated the influence of TNF haplotypes on the development of sepsis using the new Sepsis-3 definitions. Methods DNA was isolated from patients suffering from infection and systemic inflammatory response syndrome. Haplotyping was performed for six SNPs of TNF. The serum levels of tumour necrosis factor alpha (TNF-α) of these patients were measured using an enzyme immunosorbent assay. Patients were classified into infection and sepsis categories using the Sepsis-3 definitions. Associations between the TNF haplotypes and the clinical characteristics and serum TNF-α levels of the patients were examined. Results The most common TNF haplotype h1 was composed of major alleles of the studied SNPs. Carriage of haplotypes composed of minor frequency alleles was associated with a lower risk of developing sepsis (odds ratio 0.41, 95% confidence interval 0.19–0.88, p = 0.022), but this did not affect the 28-day outcome. Serum TNF-α levels were significantly higher among patients homozygous for h1 haplotypes who developed sepsis compared to infection (p = 0.032); a similar result was not observed for patients carrying other haplotypes. Conclusions Haplotypes containing minor frequency SNP alleles of TNF protect against the development of sepsis without affecting the outcome. © 2017 The Author(s)

Background/Aims: Prostate cancer represents the cancer with the highest worldwide prevalence in men. Chromosome 8p23 has shown suggestive genetic linkage to early-onset familial prostate cancer and is frequently deleted in cancer cells of the urogenital tract. Within this locus some β-defensin genes (among them DEFB4, DEFB103, DEFB104) are localized, which are arranged in a gene cluster shown to exhibit an extensive copy number variation in the population. This structural variation considerably hampers genetic studies. In a new approach considering both sequence as well as copy number variations we aimed to compare the defensin locus at 8p23 in prostate cancer patients and controls. Methods: We apply PCR/cloning-based haplotyping and high-throughput copy number determination methods which allow assessment of both individual haplotypes and gene copy numbers not accessible to conventional SNP-based genotyping. Results: We demonstrate association of four common DEFB104 haplotypes with the risk of prostate cancer in two independent patient cohorts. Moreover, we show that high copy numbers (>9) of the defensin gene cluster are significantly underrepresented in both patient samples. Conclusions: Our findings imply a role of the antibacterial defensins in prostate cancerogenesis qualifying distinct gene variants and copy numbers as potential tumor markers.

Sepsis is a life-threatening organ dysfunction caused by dysregulated host response to infection. For its clinical course, host genetic factors are important and rare genomic variants are suspected to contribute. We sequenced the exomes of 59 Greek and 15 German patients with bacterial sepsis divided into two groups with extremely different disease courses. Variant analysis was focusing on rare deleterious single nucleotide variants (SNVs). We identified significant differences in the number of rare deleterious SNVs per patient between the ethnic groups. Classification experiments based on the data of the Greek patients allowed discrimination between the disease courses with estimated sensitivity and specificity > 75%. By application of the trained model to the German patients we observed comparable discriminatory properties despite lower population-specific rare SNV load. Furthermore, rare SNVs in genes of cell signaling and innate immunity related pathways were identified as classifiers discriminating between the sepsis courses. Sepsis patients with favorable disease course after sepsis, even in the case of unfavorable preconditions, seem to be affected more often by rare deleterious SNVs in cell signaling and innate immunity related pathways, suggesting a protective role of impairments in these processes against a poor disease course. © 2016 The Authors

Sepsis is the systemic inflammatory host response to infection. Cystathionine beta-synthase (CBS)-dependent homocysteine (Hcy) pathway was demonstrated to affect disease severity and mortality in patients with severe sepsis/septic shock. Independent studies identified a single-nucleotide polymorphism (SNP, rs6586282, hg19 chr21:g.44478497C4T) in intron 14 of the CBScoding gene (CBS) associated with Hcy plasma levels. We aimed to describe the association of this SNP and variants of a splice donor-affecting variable-number tandem repeat (VNTR, NG-008938.1:g.22763-22793[16-22]) 243 bp downstream of rs6586282 with severe human sepsis. We analyzed the VNTR structure and genotyped variants of rs6586282 and a neighboring SNP (rs34758144, hg19 chr21:g.44478582G4A) in two case-control studies including patients with severe sepsis/septic shock from Germany (n=168) and Greece (n=237). In both studies, we consistently observed an association of CBS VNTR alleles with sepsis susceptibility. Risk linearly increased with number of tandem repeats (per allele odds ratio in the adjusted analysis 1.34; 95% confidence interval (CI)=1.17-1.55; Po0.001). Association had also been shown for rs34758144 whose risk allele is in linkage disequilibrium with one long VNTR allele (19 repeat). In contrast, we observed no evidence for an effect on 28-day survival in patients with severe sepsis/septic shock (per allele hazard ratio in the adjusted analysis for VNTR 1.10; 95% CI=0.95-1.28; P=0.20). In a minigene approach, we demonstrated alternative splicing in distinct VNTR alleles, which, however, was independent of the number of tandem units. In conclusion, there is no ordinary conjunction between human CBS and severe sepsis/septic shock, but CBS genotypes are involved in disease susceptibility. © 2016 Macmillan Publishers Limited. All rights reserved.

Numisheet 2016: the 10th International Conference and Workshop on Numerical Simulation of 3D Sheet Metal Forming Processes : part A - benchmark problems and results : part B - general papers : Bristol, United Kingdom, 4-9 September 2016 / editors: part A: Rui P.R. Cardoso, Jeong Whan Yoon and Robert E. Dick ; part B: Rui P.R. Cardoso, Eduardo Souza Neto, J.M.A Cesar de Sa and O.B. Adetoro 10th International Conference and Workshop on Numerical Simulation of 3D Sheet Metal Forming Forming Processes, Numisheet 2016, Bristol, UK, 4 Sep 2016 - 9 Sep 2016; Bristol : IOP Publ., Journal of physics / Conference Series 734, 032011, 4 Seiten (2016). doi:10.1088/1742-6596/734/3/032011, Published by IOP Publ., Bristol

Hidradenitis suppurativa/acne inversa (HS) has a multifactorial pathogenesis, with many patients reporting positive family history. Nine β-defensin genes (among them DEFB4 and DEFB103, encoding for proinflammatory mediators human β-defensin–2 and human β-defensin–3, respectively) exist as a cluster (DEFB) affected by copy number (CN). We hypothesized that CNs are greater in patients with HS and that they are linked to genetic susceptibility. CNs of DEFB were studied in two independent patient cohorts: 163 patients from Greece and 98 from Germany. CNs were greater in patients than control subjects in both studied cohorts. Carriage of more than six CNs was associated with a 7.53 odds ratio for HS in the Greek cohort and a 5.76 odds ratio for HS in the German cohort. The common odds ratio after meta-analysis was 6.72 (P < 0.0001). However, presence of fewer than six copies was linked with disease onset at an earlier age (P = 0.048), less frequent presentation of permanent purulence of the affected skin lesions (P = 0.036), and fewer skin localizations (P = 0.042). A robust genetic trait for susceptibility to HS is provided, and this is confirmed in two independent cohorts. Susceptibility arises from carriage of more than six DEFB copies, which interferes directly with the HS phenotype. © 2016 The Authors

Antigen presentation in chronic skin disorders is mediated through the interleukin (IL)-12/IL-23 pathway and, hence, through the IL-12 receptor. Recent evidence suggesting dysregulated antigen presentation in skin lesions of hidradenitis suppurativa (HS) led to investigate the role of single nucleotide polymorphisms (SNPs) of the gene IL-12RB1 coding for the IL12-Rβ1 receptor subunit. Genomic DNA was isolated from 139 patients and 113 healthy controls; nine SNPs in the transcribed region of IL12RB1 were genotyped. No significant differences of genotype and allele frequencies were found between the two groups. Two common haplotypes were recognized, namely h1 and h2. Carriage of h2 related with minor frequency alleles was associated with a greater risk for the acquisition of Hurley III disease stage and with the involvement of a greater number of skin areas. Patients with the h1 haplotype presented disease at an older age. This is the genetic study enrolling the largest number of patients with HS to date. Although SNPs of IL12RB1 do not seem to convey genetic predisposition, they are associated directly with the phenotype of the disease. © 2013 Elsevier Ltd.

Heme and its breakdown products CO, Fe2+, and bilirubin are being recognized as signaling molecules or even therapeutic agents, but also exert adverse effects when released at high concentrations. Manipulating the pathway confers protection in rodent sepsis models via both control of free heme and formation of its first and higher-order products. Thus, regulatory elements present in human heme oxygenase 1 (HMOX1) and biliverdin reductases (BLVRA/B) genes might impact outcome. We tested whether a highly polymorphic (GT) n microsatellite and single-nucleotide polymorphisms in HMOX1 and BLVRA/B genes are associated with outcome of sepsis. Two cohorts (n = 430 and 398 patients) with severe sepsis were screened for single-nucleotide polymorphisms and/or the microsatellite by fragment length analysis and genotyping techniques. Heme oxygenase 1 plasma levels were determined in additional patients with severe sepsis (n = 92) by enzyme-linked immunosorbent assay. Based on mean Sepsis-related Organ Failure Assessment scores, patients homozygous for rs2071746 A allele or medium length (GT)n microsatellites of HMOX1 showed higher 28-day mortality (P = 0.047 and P = 0.033) in one cohort compared with other genotypes, whereas 90-day mortality rates showed no association. The T allele was less frequently observed in both cohorts than would be expected according to Hardy-Weinberg equilibrium. Heme oxygenase 1 plasma levels were elevated in septic patients, independent of the genotype. Single-nucleotide polymorphisms within BLVRA/B showed no association with outcome. Short (GT)n repeats that are in linkage disequilibrium with the T allele of rs2071746 in HMOX1 are associated with favorable outcome, whereas no association with gene variants of BLVRA/B, involved in the generation of higher-order metabolites, was noticed. © 2012 by the Shock Society.

Targets that could improve the treatment of brain tumors remain important to define. This study of a transformation-associated isoform of alpha 2-macroglobulin (A2M*) and its interaction with the low-density lipoprotein receptor-related protein-1 (LRP1) suggests a new mechanism for abrogating the malignant potential of astrocytoma cells. LRP1 bound A2M* found to be associated with an inhibition of tumor cell proliferation, migration, invasion, spheroid formation, and anchorage-independent growth. Transcriptional studies implicated effects on the Wnt/beta-catenin signaling pathway. Notably, LRP1 antibodies could phenocopy the effects of A2M*. Our findings suggest a pathway of tumor suppression in astrocytoma that might be tractable to therapeutic exploitation.