Structure, Function, and Immunogenic Applications of AB\u3csub\u3e5\u3c/sub\u3e-type ADP-Ribosylating Bacterial Toxins

Bacterial mono-ADP-ribosyltransferases (ARTs) catalyze the singular transfer of an ADP-ribose moiety from an NAD+ molecule onto a target molecule. ARTs contain an ancient and highly conserved tertiary structure and have a wide variety of intracellular targets and effects. Some, but not all, bacterial ARTs have an AB5-type multimeric structure consisting of an enzymatically active subunit non-covalently situated atop of a non-toxic pentamer. The active, or A, subunit of AB5-type toxins has a catalytic action that contributes to bacterial pathogenicity, and it is sometimes, but not always, an ART. ArtAB is an ART with AB5-type structure from the virulent and highly antibiotic resistant Salmonella Typhimurium DT104. In the studies described here, we tested the hypothesis that the active subunit of ArtAB is structurally and enzymatically homologous to that of the well-characterized AB5-type ART pertussis toxin. ArtAB was purified from E. coli and was used to characterize ArtAB’s cellular effects, predicted structure, and biophysical properties. In addition, a set of single-residue mutants was constructed and purified to probe ArtAB’s active site. AB5-type toxins have long been studied for their immunogenic properties, and some of these bacterial munitions have been harnessed and repurposed as vaccines or vaccine adjuvants to prevent infectious disease. Their receptor-binding pentamer, abbreviated as B5, binds to, and facilitates entry into, host cells. In additional work presented here, we tested the hypothesis that the B5 subunit of cholera toxin (CTB) from Vibrio cholerae could be used to construct a safe and effective mucosal vaccine against Staphylococcus aureus-caused mastitis. We constructed a bovine vaccine by conjugating Staphylococcus aureus antigens to the CTB-based adjuvant platform, and the immunogenicity of the vaccine was characterized in a bovine clinical trial. Finally, clinical isolates of caprine S. aureus were screened for the presence of surface antigens that could be use in a caprine version of the vaccine against mastitis. The work on bacterial AB5-type ARTs presented here contributes to a growing global understanding of the bacterial ART family, lays a foundation for the potential incorporation of ArtAB in a vaccine against Salmonella, and advances the development of bovine and caprine vaccines against S. aureus-caused mastitis

Herregårdenes avlsbygninger: En kulturarv?

MAA Sonja Marie Overgaard behandler i denne artikel herregårdens avlsbygninger med fokus på både bevaring og udvikling af kulturarven

The risk of preterm birth in combinations of socioeconomic position and mental health conditions in different age groups:A Danish nationwide register-based cohort study

Abstract Background Inequality in preterm birth is a world-wide challenge that has proved difficult for maternity care services to meet. Reducing the inequality requires identification of pregnant women at particularly high risk of preterm birth in order to target interventions. Therefore, the aim was to estimate the risk of preterm birth in women with different combinations of socioeconomic position, mental health conditions, and age. Methods In this nationwide register-based cohort study, we included all first-time mothers that gave birth to a singleton liveborn infant in Denmark between 2000 and 2016. The absolute and relative risk of preterm birth (< 37 weeks of gestation) was examined in different combinations of educational level (high, intermediate, and low) and mental health conditions (no, minor, and moderate/severe) in three age strata (≤23, 24–30, and ≥ 31 years). We estimated the relative risk using Poisson regression with a robust error variance. As additive interaction can help identify subgroups where limited resources can be of best use, we measured the attributable proportion to assess the risk that is due to interaction of the different exposures. Results Of the 415,523 included first-time mothers, 6.3% gave birth prematurely. The risk of preterm birth increased with decreasing educational level and increasing severity of mental health conditions in all age strata, but most in women aged ≥31 years. The highest absolute risk was 12.9% [95% CI: 11.2;14.8%] in women aged ≥31 years with low education and moderate/severe mental health conditions resulting in a relative risk of 2.23 [95% CI: 1.93–2.58] compared to the unexposed reference group in that age strata. We found positive additive interaction between low education and mental health conditions in women aged 24–30 and ≥ 31 years and between age ≥ 31 years and combinations of mental health conditions and educational levels. Conclusion The inequality in preterm birth increased with increasing age. To reduce inequality in preterm birth focused attention on women with higher age further combined with lower educational levels and mental health conditions is essential

Water channels in the brain and spinal cord—overview of the role of aquaporins in traumatic brain injury and traumatic spinal cord injury

Knowledge about the mechanisms underlying the fluid flow in the brain and spinal cord is essential for discovering the mechanisms implicated in the pathophysiology of central nervous system diseases. During recent years, research has highlighted the complexity of the fluid flow movement in the brain through a glymphatic system and a lymphatic network. Less is known about these pathways in the spinal cord. An important aspect of fluid flow movement through the glymphatic pathway is the role of water channels, especially aquaporin 1 and 4. This review provides an overview of the role of these aquaporins in brain and spinal cord, and give a short introduction to the fluid flow in brain and spinal cord during in the healthy brain and spinal cord as well as during traumatic brain and spinal cord injury. Finally, this review gives an overview of the current knowledge about the role of aquaporins in traumatic brain and spinal cord injury, highlighting some of the complexities and knowledge gaps in the field

Outcome in design-specific comparisons between highly crosslinked and conventional polyethylene in total hip arthroplasty

<p>Background and purpose — Most registry studies regarding highly crosslinked polyethylene (XLPE) have focused on the overall revision risk. We compared the risk of cup and/or liner revision for specific cup and liner designs made of either XLPE or conventional polyethylene (CPE), regarding revision for any reason and revision due to aseptic loosening and/or osteolysis.</p> <p>Patients and methods — Using the Nordic Arthroplasty Register Association (NARA) database, we identified cup and liner designs where either XLPE or CPE had been used in more than 500 THAs performed for primary hip osteoarthritis. We assessed risk of revision for any reason and for aseptic loosening using Cox regression adjusted for age, sex, femoral head material and size, surgical approach, stem fixation, and presence of hydroxyapatite coating (uncemented cups).</p> <p>Results — The CPE version of the ZCA cup had a risk of revision for any reason similar to that of the XLPE version (p = 0.09), but showed a 6-fold higher risk of revision for aseptic loosening (p < 0.001). The CPE version of the Reflection All Poly cup had an 8-fold elevated risk of revision for any reason (p < 0.001) and a 5-fold increased risk of revision for aseptic loosening (p < 0.001). The Charnley Elite Ogee/Marathon cup and the Trilogy cup did not show such differences.</p> <p>Interpretation — Whether XLPE has any advantage over CPE regarding revision risk may depend on the properties of the polyethylene materials being compared, as well as the respective cup designs, fixation type, and follow-up times. Further research is needed to elucidate how cup design factors interact with polyethylene type to affect the risk of revision.</p

Absence of <i>Pneumocystis jirovecii</i> colonization in human immunodeficiency virus-infected individuals with and without airway obstruction and with undetectable viral load

Pneumocystis jirovecii colonization has been associated with non-acquired immune deficiency syndrome (AIDS) pulmonary comorbidity. We used spirometry to measure pulmonary function and analyzed oral wash specimens by quantitative polymerase chain reaction (PCR), targeting the large mitochondrial ribosomal subunit. For sensitivity control, a blinded subsample was subjected to touch-down PCRs, targeting both large and small ribosomal subunits and the major surface glycoprotein. Pneumocystis jirovecii deoxyribonucleic acid (DNA) was detected in 1 of 156 (95% confidence interval, .1%–3.5%) virologically suppressed human immunodeficiency virus (HIV)-infected individuals confirmed by all PCR methods. Thus, prevalence of P jirovecii colonization was low and unlikely to be a major cause of pulmonary comorbidity in this group of well treated HIV-infected individuals

Association of perioperative thromboprophylaxis on revision rate due to infection and aseptic loosening in primary total hip arthroplasty - new evidence from the Nordic Arthroplasty Registry Association (NARA)

Background and purpose: Results regarding the impact of anticoagulants on revision rate are conflicting. We examined the association between the use of low molecular weight heparin (LMWH) or non-vitamin K oral anticoagulants (NOACs) as thromboprophylaxis after primary total hip arthroplasty (THA) and the revision rate due to infection, aseptic loosening, and all causes. Patients and methods: We conducted a cohort study (n = 53,605) based on prospectively collected data from the national hip arthroplasty registries from Denmark and Norway. The outcome was time to revision due to infection, aseptic loosening, and all causes, studied separately. Kaplan–Meier (KM) survival analysis and a Cox proportional hazard model was used to estimate implant survival and cause-specific hazard ratios (HRs) with 95% confidence intervals (CI) adjusting for age, sex, Charlson Comorbidity Index, fixation type, start, and duration of thromboprophylaxis, and preoperative use of Vitamin K antagonists, NOAC, aspirin, and platelet inhibitors as confounders. Results: We included 40,451 patients in the LMWH group and 13,154 patients in the NOAC group. Regarding revision due to infection, the 1-year and 5-year KM survival was 99% in both the LMWH group and in the NOAC group. During the entire follow-up period, the adjusted HR for revision due to infection was 0.9 (CI 0.7–1.1), 1.6 (CI 1.3–2.1) for aseptic loosening, and 1.2 (CI 1.1–1.4) for all-cause revision for the NOAC compared with the LMWH group. The absolute differences in revision rates between the groups varied from 0.2% to 1%. Interpretation: Compared with LMWH, NOACs were associated with a slightly lower revision rate due to infection, but higher revisions rates due to aseptic loosening and all-cause revision. The absolute differences between groups are small and most likely not clinically relevant. In addition, the observed associations might partly be explained by selection bias and unmeasured confounding, and should be a topic for further research.publishedVersio

Worksite interventions for preventing physical deterioration among employees in job-groups with high physical work demands: Background, design and conceptual model of FINALE

<p>Abstract</p> <p>Background</p> <p>A mismatch between individual physical capacities and physical work demands enhance the risk for musculoskeletal disorders, poor work ability and sickness absence, termed physical deterioration. However, effective intervention strategies for preventing physical deterioration in job groups with high physical demands remains to be established. This paper describes the background, design and conceptual model of the FINALE programme, a framework for health promoting interventions at 4 Danish job groups (i.e. cleaners, health-care workers, construction workers and industrial workers) characterized by high physical work demands, musculoskeletal disorders, poor work ability and sickness absence.</p> <p>Methods/Design</p> <p>A novel approach of the FINALE programme is that the interventions, i.e. 3 randomized controlled trials (RCT) and 1 exploratory case-control study are tailored to the physical work demands, physical capacities and health profile of workers in each job-group. The RCT among cleaners, characterized by repetitive work tasks and musculoskeletal disorders, aims at making the cleaners less susceptible to musculoskeletal disorders by physical coordination training or cognitive behavioral theory based training (CBTr). Because health-care workers are reported to have high prevalence of overweight and heavy lifts, the aim of the RCT is long-term weight-loss by combined physical exercise training, CBTr and diet. Construction work, characterized by heavy lifting, pushing and pulling, the RCT aims at improving physical capacity and promoting musculoskeletal and cardiovascular health. At the industrial work-place characterized by repetitive work tasks, the intervention aims at reducing physical exertion and musculoskeletal disorders by combined physical exercise training, CBTr and participatory ergonomics. The overall aim of the FINALE programme is to improve the safety margin between individual resources (i.e. physical capacities, and cognitive and behavioral skills) and physical work demands, and thereby reduce the physical deterioration in a long term perspective by interventions tailored for each respective job-group.</p> <p>Discussion</p> <p>The FINALE programme has the potential to provide evidence-based knowledge of significant importance for public health policy and health promotion strategies for employees at high risk for physical deterioration.</p> <p>Trial registrations</p> <p>ISRCTN96241850, NCT01015716 and NCT01007669</p