Pesticide use and risk of systemic autoimmune diseases in the Agricultural Health Study.

BACKGROUND: Systemic lupus erythematosus (SLE) risk has been associated with pesticide use, but evidence on specific pesticides or other agricultural exposures is lacking. We investigated history of pesticide use and risk of SLE and a related disease, Sjögren's syndrome (SS), in the Agricultural Health Study. METHODS: The study sample (N = 54,419, 52% male, enrolled in 1993-1997) included licensed pesticide applicators from North Carolina and Iowa and spouses who completed any of the follow-up questionnaires (1999-2003, 2005-2010, 2013-2015). Self-reported cases were confirmed by medical records or medication use (total: 107 incident SLE or SS, 79% female). We examined ever use of 31 pesticides and farm tasks and exposures reported at enrollment in association with SLE/SS, using Cox regression to estimate hazard ratios (HR) and 95% confidence intervals (CI), with age as the timescale and adjusting for gender, state, and correlated pesticides. RESULTS: In older participants (>62 years), SLE/SS was associated with ever use of the herbicide metribuzin (HR 5.33; 95%CI 2.19, 12.96) and applying pesticides 20+ days per year (2.97; 1.20, 7.33). Inverse associations were seen for petroleum oil/distillates (0.39; 0.18, 0.87) and the insecticide carbaryl (0.56; 0.36, 0.87). SLE/SS was inversely associated with having a childhood farm residence (0.59; 0.39, 0.91), but was not associated with other farm tasks/exposures (except welding, HR 2.65; 95%CI 0.96, 7.35). CONCLUSIONS: These findings suggest that some agricultural pesticides may be associated with higher or lower risk of SLE/SS. However, the overall risk associated with farming appears complex, involving other factors and childhood exposures.

Identification of carbohydrate anomers using ion mobility-mass spectrometry.

Carbohydrates are ubiquitous biological polymers that are important in a broad range of biological processes. However, owing to their branched structures and the presence of stereogenic centres at each glycosidic linkage between monomers, carbohydrates are harder to characterize than are peptides and oligonucleotides. Methods such as nuclear magnetic resonance spectroscopy can be used to characterize glycosidic linkages, but this technique requires milligram amounts of material and cannot detect small amounts of coexisting isomers. Mass spectrometry, on the other hand, can provide information on carbohydrate composition and connectivity for even small amounts of sample, but it cannot be used to distinguish between stereoisomers. Here, we demonstrate that ion mobility-mass spectrometry--a method that separates molecules according to their mass, charge, size, and shape--can unambiguously identify carbohydrate linkage-isomers and stereoisomers. We analysed six synthetic carbohydrate isomers that differ in composition, connectivity, or configuration. Our data show that coexisting carbohydrate isomers can be identified, and relative concentrations of the minor isomer as low as 0.1 per cent can be detected. In addition, the analysis is rapid, and requires no derivatization and only small amounts of sample. These results indicate that ion mobility-mass spectrometry is an effective tool for the analysis of complex carbohydrates. This method could have an impact on the field of carbohydrate synthesis similar to that of the advent of high-performance liquid chromatography on the field of peptide assembly in the late 1970s.

Computed tomography textural analysis for the differentiation of chronic lymphocytic leukemia and diffuse large B cell lymphoma of Richter syndrome.

OBJECTIVE: To test the hypothesis that both indolent and aggressive chronic lymphocytic leukemia (CLL) can be differentiated from diffuse large B cell lymphoma (DLBCL) of Richter syndrome (RS) by CT texture analysis (CTTA) of involved lymph nodes. MATERIAL AND METHODS: We retrospectively included 52 patients with indolent CLL (26/52), aggressive CLL (8/52), and DLBCL of RS (18/52), who underwent standardized contrast-enhanced CT. In main lymphoma tissue, VOIs were generated from which CTTA features including first-, second-, and higher-order textural features were extracted. CTTA features were compared between the entire CLL group, the indolent CLL subtype, the aggressive CLL subtype, and DLBCL using a Kruskal-Wallis test. All p values were adjusted after the Bonferroni correction. ROC analyses for significant CTTA features were performed to determine cut-off values for differentiation between the groups. RESULTS: Compared with DLBCL of RS, CTTA of the entire CLL group showed significant differences of entropy heterogeneity (p < 0.001), mean intensity (p < 0.001), mean average (p = 0.02), and number non-uniformity gray-level dependence matrix (NGLDM) (p = 0.03). Indolent CLL significantly differed for entropy (p < 0.001), uniformity of heterogeneity (p = 0.02), mean intensity (p < 0.001), and mean average (p = 0.01). Aggressive CLL showed significant differences in mean intensity (p = 0.04). For differentiation between CLL and DLBCL of RS, cut-off values for mean intensity and entropy of heterogeneity were defined (e.g., 6.63 for entropy heterogeneity [aggressive CLL vs. DLBCL]; sensitivity 0.78; specificity 0.63). CONCLUSIONS: CTTA features of ultrastructure and vascularization significantly differ in CLL compared with that in DLBCL of Richter syndrome, allowing complementary to visual features for noninvasive differentiation by contrast-enhanced CT. KEY POINTS: • Richter transformation of CLL into DLBCL results in structural changes in lymph node architecture and vascularization that can be detected by CTTA. • First-order CT textural features including intensity and heterogeneity significantly differ between both indolent CLL and aggressive CLL and DLBCL of Richter syndrome. • CT texture analysis allows for noninvasive detection of Richter syndrome which is of prognostic value.

Effects of Enhanced Flexibility and Pore Size Distribution on Adsorption-Induced Deformation of Mesoporous Materials.

Here, we present a new model of adsorption-induced deformation of mesoporous solids. The model is based on a simplified version of local density functional theory in the framework of solvation free energy. Instead of density, which is treated as constant here, we used film thickness and pore radius as order parameters. This allows us to obtain a self-consistent system of equations describing simultaneously the processes of gas adsorption and adsorbent deformation, as well as conditions for capillary condensation and evaporation. In the limit of infinitely rigid pore walls, when the film becomes several monolayers thick, the model reduces to the well-known Derjaguin-Broekhoff-de Boer theory for pores with cylindrical geometry. We have investigated the effects of enhanced flexibility of the solid as well as the influence of pore size distribution on the adsorption/deformation process. The formulation of the theory allows to determine the average pore size and its width from the desorption branch of the strain isotherm only. The model reproduces the nonmonotonic behavior of the strain isotherm at low relative pressure. Furthermore, we discuss the effect of rigidity of the adsorbent on the pore size distribution, showing qualitatively different results of the adsorption isotherms for rigid and highly flexible materials, in particular, the shift of evaporation pressure to lower values and the absence of a limiting value of the loading at high relative pressure. We also discuss the results of the theory with respect to experimental data obtained from the literature.

Steep rise in norovirus cases and emergence of a new recombinant strain GII.P16-GII.2, Germany, 2016.

Since early November 2016, the number of laboratory-confirmed norovirus infections reported in Germany has been increasing steeply. Here, we report the detection and genetic characterisation of an emerging norovirus recombinant, GII.P16-GII.2. This strain was frequently identified as the cause of sporadic cases as well as outbreaks in nine federal states of Germany. Our findings suggest that the emergence of GII.P16-GII.2 contributed to rising case numbers of norovirus gastroenteritis in Germany.

International cancer seminars: a focus on kidney cancer.

Recent years have seen important advances in our understanding of the etiology, biology and genetics of kidney cancer. To summarize important achievements and identify prominent research questions that remain, a workshop was organized by IARC and the US NCI. A series of 'difficult questions' were formulated, which should be given future priority in the areas of population, genomic and clinical research.

The role of oral hygiene in head and neck cancer: results from International Head and Neck Cancer Epidemiology (INHANCE) consortium.

BACKGROUND: Poor oral hygiene has been proposed to contribute to head and neck cancer (HNC) risk, although causality and independency of some indicators are uncertain. This study investigates the relationship of five oral hygiene indicators with incident HNCs. METHODS: In a pooled analysis of 8925 HNC cases and 12 527 controls from 13 studies participating in the International Head and Neck Cancer Epidemiology Consortium, comparable data on good oral hygiene indicators were harmonized. These included: no denture wear, no gum disease (or bleeding), <5 missing teeth, tooth brushing at least daily, and visiting a dentist ≥once a year. Logistic regression was used to estimate the effects of each oral hygiene indicator and cumulative score on HNC risk, adjusting for tobacco smoking and alcohol consumption. RESULTS: Inverse associations with any HNC, in the hypothesized direction, were observed for <5 missing teeth [odds ratio (OR) = 0.78; 95% confidence interval (CI) 0.74, 0.82], annual dentist visit (OR = 0.82; 95% CI 0.78, 0.87), daily tooth brushing (OR = 0.83, 95% CI 0.79, 0.88), and no gum disease (OR = 0.94; 95% CI 0.89, 0.99), and no association was observed for wearing dentures. These associations were relatively consistent across specific cancer sites, especially for tooth brushing and dentist visits. The population attributable fraction for ≤ 2 out of 5 good oral hygiene indicators was 8.9% (95% CI 3.3%, 14%) for oral cavity cancer. CONCLUSION: Good oral hygiene, as characterized by few missing teeth, annual dentist visits, and daily tooth brushing, may modestly reduce the risk of HNC.

Watt-level second-harmonic generation at 589 nm with a PPMgO:LN ridge waveguide crystal pumped by a DBR tapered diode laser.

A DBR tapered diode laser in continuous wave operation was used to generate second-harmonic radiation at 589 nm in a PPMgO:LN ridge waveguide crystal. An optical output power of 0.86 W at an optical-to-optical and an electrical-to-optical efficiency of 42% and 11%, respectively, was achieved. The visible radiation was characterized by a spectral bandwidth ΔνFWHM of 230 MHz and a beam propagation parameter M1/e22 better than 1.1. The integration of such a system into a housing of a small footprint will enable a portable and highly efficient module featuring a visible output power in the watt-level range.

Brincidofovir clearance of acyclovir-resistant herpes simplex virus-1 and adenovirus infection after stem cell transplantation.

Infections with adenovirus (AdV) and herpesviruses can result in considerable morbidity and mortality in pediatric hematopoietic stem cell transplant (SCT) recipients. Herpes simplex virus (HSV) reactivations are usually prevented by acyclovir (ACV) prophylaxis, whereas cidofovir (CDV) has been used off indication to manage AdV infections. We report a child with myelodysplastic syndrome undergoing multiple SCT, who experienced HSV-1 disease including severe mucositis and herpetic whitlow, as well as high viral load AdV DNAemia. Both ACV and CDV were ineffective; however, viral loads were decreased with brincidofovir, resulting in viral clearance. A subsequent Epstein-Barr virus disease with relevant meningoencephalitis responded to rituximab.

Factors that influence the suitability of human organ-cultured corneas.

PURPOSE: The purpose was to assess the influence of donor and storage factors on the suitability of organ-cultured corneas for transplantation. METHODS: Data from 1340 donor corneas stored between 2009 and 2015 were analyzed retrospectively. Logistic regression analysis was used to assess the influence of different factors on the suitability of grafts for transplantation. RESULTS: Forty-one percent (553/1340) of corneas were discarded. The leading causes were medical contraindication (20.2 %) and poor endothelial quality (19.3 %). Donor age influenced suitability for transplantation significantly. Corneas from donors aged 80 years and older were more likely to be discarded because of endothelial insufficiency (P < 0.0001). The cause of donor death including infection and multiple organ dsyfunction syndrom (MODS) increased the risk of bacterial or fungal contamination during organ culture (P = 0.007 and P = 0.014, respectively). Prolonged time between death and enucleation was associated with an increased risk of unsuitability for transplantation (P < 0.0001). The amount of time between death and corneoscleral disc excision and duration of storage influenced the suitability for transplantation (P = 0.0007 and P < 0.0001, respectively). CONCLUSION: Donor age, cause of death, storage time, death to enucleation and death to disc excision times influenced transplantation suitability. The percentage of discarded corneas may be reduced by shortening storage time, death to enucleation, and death to corneoscleral disc excision times. Setting a maximum donor age could reduce the percentage of discarded corneas. However, as long as there is a lack of donor corneas, we do not recommend any donor age limit.

An ORF1-rearranged hepatitis E virus derived from a chronically infected patient efficiently replicates in cell culture.

Hepatitis E is an increasingly reported disease in industrialized countries. Studies on the replication cycle of hepatitis E virus (HEV) are hampered due to the lack of efficient and robust cell culture systems for this virus. We describe the successful isolation of HEV derived from a chronically infected kidney transplant patient held under immunosuppressive therapy. Inoculation of serum sample 47832 onto the human lung carcinoma cell line A549 resulted in the replication of the virus as shown by RT-qPCR. This novel human-derived HEV strain is closely related to a wild boar-derived genotype 3 strain, which did not replicate in A549 cells. It carries a 186 nucleotide insertion in the hypervariable ORF1-region, derived from two parts of its ORF1. By passaging of the infected cells, a cell line continuously producing HEV particles was generated as demonstrated by RT-qPCR, immuno-electron microscopy, density gradient centrifugation and immunohistochemistry. Replication of the produced virus was demonstrated after its inoculation onto fresh A549 cells and two consecutive passages, whereas heating at 65 °C for 2 min abolished its infectivity. Several point mutations scattered along the whole genome were present in the HEV strain from the second passage; however, the ORF1 insertion was still present. Previously, cell culture isolation of two other HEV strains carrying insertions in their hypervariable regions, but originating from human ribosomal protein genes, has been described. The findings may indicate that cell culture adaptation of is mostly dependent on the length and position of the insertion, rather than from the sequence itself.

Combination of immunoglobulins and natural killer cells in the context of CMV and EBV infection.

Cytomegalovirus (CMV)-specific hyperimmunoglobulin (CMV-HIG) is used to treat and prevent CMV infection in immunocompromised patients, and anti-CD20 monoclonal antibody is successfully used in the treatment for post-transplant lymphoproliferative disease caused by Epstein-Barr virus (EBV). Two immunological approaches have been suggested to further improve the control of viral reproduction in patients with active disease: first, the use of monoclonal antibodies with specificity against viral epitopes and second, coadministration of cells with the capacity to promote antibody-dependent cell-mediated cytotoxicity. Here, we have evaluated the effectiveness of these strategies in vitro (alone and in combination) with neutralization and cytotoxicity assays. Our results indicate that monoclonal antibodies (in particular SM5-1) can be as effective as CMV-HIG in neutralizing-cell-free CMV. Moreover, our data indicate that antibody-mediated elimination (either by moAb or by HIG) of EBV-infected cells can be significantly enhanced by NK cells. Using human NK cells that have been purified, cultured and expanded under GMP conditions, we were able to demonstrate that the combination of NK cells and antibodies could represent a feasible and highly effective clinical approach to achieve control of EBV infections. Especially in leukopenic patients with low numbers of ADCC-promoting cells, the combination of adoptively transferred NK cells and antiviral antibodies offers a promising strategy that should be tested in clinical trials.

Performance of the MagNA Pure 96 system for cytomegalovirus nucleic acid amplification testing in clinical samples.

This report shows the performance of MagNA Pure 96 automated nucleic acid extraction for the quantitative detection of cytomegalovirus DNA in clinical samples by real-time PCR. The obtained results demonstrate that this workflow is characterized by high sensitivity and linearity and ensures reliable, reproducible clinical diagnostics.

Piriformospora indica antagonizes cyst nematode infection and development in Arabidopsis roots.

The beneficial endophytic fungus Piriformospora indica colonizes the roots of many plant species, including the model plant Arabidopsis thaliana. Its colonization promotes plant growth, development, and seed production as well as resistance to various biotic and abiotic stresses. In the present work, P. indica was tested as potential antagonist of the sedentary plant-parasitic nematode Heterodera schachtii. This biotrophic cyst-forming nematode induces severe host plant damage by changing the morphogenesis and physiology of infected roots. Here it is shown that P. indica colonization, as well as the application of fungal exudates and cell-wall extracts, significantly affects the vitality, infectivity, development, and reproduction of H. schachtii.

16(th) IHIW: global analysis of registry HLA haplotypes from 20 million individuals: report from the IHIW Registry Diversity Group.

This project has the goal to validate bioinformatics methods and tools for HLA haplotype frequency analysis specifically addressing unique issues of haematopoietic stem cell registry data sets. In addition to generating new methods and tools for the analysis of registry data sets, the intent is to produce a comprehensive analysis of HLA data from 20 million donors from the Bone Marrow Donors Worldwide (BMDW) database. This report summarizes the activity on this project as of the 16IHIW meeting in Liverpool.

Immune cell dynamics deconvoluted by single-cell RNA sequencing in normothermic machine perfusion of the liver.

Normothermic machine perfusion (NMP) has emerged as an innovative organ preservation technique. Developing an understanding for the donor organ immune cell composition and its dynamic changes during NMP is essential. We aimed for a comprehensive characterization of immune cell (sub)populations, cell trafficking and cytokine release during liver NMP. Single-cell transcriptome profiling of human donor livers prior to, during NMP and after transplantation shows an abundance of CXC chemokine receptor 1+/2+ (CXCR1+/CXCR2+) neutrophils, which significantly decreased during NMP. This is paralleled by a large efflux of passenger leukocytes with neutrophil predominance in the perfusate. During NMP, neutrophils shift from a pro-inflammatory state towards an aged/chronically activated/exhausted phenotype, while anti-inflammatory/tolerogenic monocytes/macrophages are increased. We herein describe the dynamics of the immune cell repertoire, phenotypic immune cell shifts and a dominance of neutrophils during liver NMP, which potentially contribute to the inflammatory response. Our findings may serve as resource to initiate future immune-interventional studies.

Liver transplant from a donor with occult HEV infection induced chronic hepatitis and cirrhosis in the recipient.

Acute hepatitis E virus (HEV) infection is a self-limiting symptomatic or asymptomatic disease. However, as recently observed, it can manifest itself as chronic hepatitis in patients receiving solid organ transplants as well as in patients with HIV infection or severe hematologic disorders. Here, we describe the clinical course of a 73-year-old male patient in whom HEV transmission occurred after receiving a HEV-infected liver from a donor with occult HEV infection, whereby the patient had tested negative for HEV RNA and anti-HEV antibodies shortly before explantation. Anti-HEV IgG, IgM, and HEV RNA were detected in the first tested serum sample of the liver recipient obtained 150 days after liver transplantation and remained positive (earlier samples after OLT were not available). Liver cirrhosis developed within 15 months and the patient died of septic shock. Based on phylogenetic analyses of the donor and recipient's HEV strains, we were able to prove that the occult HEV infection was transmitted via the graft.

Antiviral function and efficacy of polyvalent immunoglobulin products against CMV isolates in different human cell lines.

Primary infection and reactivation of human cytomegalovirus (CMV) remain a major problem in immunocompromised patients, frequently resulting in a life threatening CMV disease. Intravenous polyvalent (hyper)-immunoglobulins (IVIG) can be administered for therapy and prophylaxis of CMV infections. However, only limited data about the efficacy and mechanism of action of IVIG products against viral infections in vitro are available so far. In this study, the effect of IVIG on CMV infection in vitro was investigated using isolates from CMV-infected patients as well as the laboratory strains AD169 and TB40. A qualitative and quantitative comparison of five different commercially available IVIG products in different human cell lines was performed concerning their ability (1) to neutralize cell-free virus, (2) to inhibit cell-to-cell spread and cell-associated transmission and (3) to influence CMV mRNA levels. All IVIG tested exhibited a high neutralization activity in epithelial and endothelial cell cultures (50% inhibition dose <0.1 mg/ml). However, qualitative differences between the products could be demonstrated in neutralization tests using human embryonal lung fibroblasts (HELF). The IVIG products also significantly differed in their ability to inhibit cell-to-cell spread within an CMV-infected HELF monolayer displaying inhibition rates that varied between 61 and 100%. No correlation between the ability to neutralize cell-free virus and to inhibit cell-to-cell spread could be observed. The incubation with IVIG influenced the amount of CMV immediate early and late mRNA, as indicated by a significant reduction in CMV mRNA in infected epithelial cells after incubation with IVIG in a dose-dependent manner. This study suggests different antiviral functions of polyvalent IVIG and confirms their potential to inhibit a CMV infection in vitro, with profound differences between the hereby used IVIG products.

[Behaviour-orientated exercise therapy--initiating and maintaining a physically active lifestyle]. / Verhaltensbezogene Bewegungstherapie--Bindung an einen körperlich aktiven Lebensstil.

BACKGROUND: The promotion of a physically active lifestyle has become an important issue in exercise therapy. Exercise-only interventions are frequently used for the rehabilitation of individuals with chronic diseases. These do indeed improve functional and physical performance, but they are not alone sufficient to initiate long lasting changes in physical-activity behaviour. Behaviour-related aspects are rarely integrated into exercise-therapy interventions. OBJECTIVE: Based on theories of health behaviour change, effective techniques for changing physical-activity behaviour in the context of exercise therapy will be identified. METHODOLOGY: The starting point is a theory-driven definition of individual behavioural determinants of physical activity and the identification of techniques for influencing the determinants. Subsequently, the potential of the techniques for enhancing physical activity is evaluated. The available evidence was reviewed on the basis of international reviews and control-group studies from the German rehabilitation setting. Finally, recommendations are offered for designing exercise-based interventions to promote participation in and adherence to physical activity. RESULTS: A total of 28 techniques for the promotion of physical activity behaviour were identified. An approach that proved particularly effective was self-monitoring of physical activity behaviour in a variety of combinations with other techniques, such as contracting, feedback, rewards, generating one's own varied exercise experience, action planning and barrier management. DISCUSSION: The integration of behaviour-related techniques in the context of exercise therapy interventions shows great promise as a means of initiating and promoting a physically active lifestyle.