Schmallenberg virus pathogenesis, tropism and interaction with the innate immune system of the host

Schmallenberg virus (SBV) is an emerging orthobunyavirus of ruminants associated with outbreaks of congenital malformations in aborted and stillborn animals. Since its discovery in November 2011, SBV has spread very rapidly to many European countries. Here, we developed molecular and serological tools, and an experimental in vivo model as a platform to study SBV pathogenesis, tropism and virus-host cell interactions. Using a synthetic biology approach, we developed a reverse genetics system for the rapid rescue and genetic manipulation of SBV. We showed that SBV has a wide tropism in cell culture and “synthetic” SBV replicates in vitro as efficiently as wild type virus. We developed an experimental mouse model to study SBV infection and showed that this virus replicates abundantly in neurons where it causes cerebral malacia and vacuolation of the cerebral cortex. These virus-induced acute lesions are useful in understanding the progression from vacuolation to porencephaly and extensive tissue destruction, often observed in aborted lambs and calves in naturally occurring Schmallenberg cases. Indeed, we detected high levels of SBV antigens in the neurons of the gray matter of brain and spinal cord of naturally affected lambs and calves, suggesting that muscular hypoplasia observed in SBV-infected lambs is mostly secondary to central nervous system damage. Finally, we investigated the molecular determinants of SBV virulence. Interestingly, we found a biological SBV clone that after passage in cell culture displays increased virulence in mice. We also found that a SBV deletion mutant of the non-structural NSs protein (SBVΔNSs) is less virulent in mice than wild type SBV. Attenuation of SBV virulence depends on the inability of SBVΔNSs to block IFN synthesis in virus infected cells. In conclusion, this work provides a useful experimental framework to study the biology and pathogenesis of SBV

Nitrogen transfer from forage legumes to nine neighbouring plants in a multi-species grassland

Legumes play a crucial role in nitrogen supply to grass-legume mixtures for ruminant fodder. To quantify N transfer from legumes to neighbouring plants in multi-species grasslands we established a grass-legume-herb mixture on a loamy-sandy site in Denmark. White clover (Trifolium repens L.), red clover (Trifolium pratense L.) and lucerne (Medicago sativa L.) were leaf-labelled with 15N enriched urea during one growing season. N transfer to grasses (Lolium perenne L. and xfestulolium), white clover, red clover, lucerne, birdsfoot trefoil (Lotus corniculatus L.), chicory (Cichorium intybus L.), plantain (Plantago lanceolata L.), salad burnet (Sanguisorba minor L.)and caraway (Carum carvi L.) was assessed. Neighbouring plants contained greater amounts of N derived from white clover (4.8 gm-2) compared with red clover (2.2 gm-2) and lucerne (1.1 gm-2). Grasses having fibrous roots received greater amounts of N from legumes than dicotyledonous plants which generally have taproots. Slurry application mainly increased N transfer from legumes to grasses. During the growing season the three legumes transferred approximately 40 kg N ha-1 to neighbouring plants. Below-ground N transfer from legumes to neighbouring plants differed among nitrogen donors and nitrogen receivers and may depend on root characteristics and regrowth strategies of plant species in the multi-species grassland

Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms

Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide. Although 58 genomic regions have been associated with CAD thus far, most of the heritability is unexplained, indicating that additional susceptibility loci await identification. An efficient discovery strategy may be larger-scale evaluation of promising associations suggested by genome-wide association studies (GWAS). Hence, we genotyped 56,309 participants using a targeted gene array derived from earlier GWAS results and performed meta-analysis of results with 194,427 participants previously genotyped, totaling 88,192 CAD cases and 162,544 controls. We identified 25 new SNP-CAD associations (P < 5 × 10(-8), in fixed-effects meta-analysis) from 15 genomic regions, including SNPs in or near genes involved in cellular adhesion, leukocyte migration and atherosclerosis (PECAM1, rs1867624), coagulation and inflammation (PROCR, rs867186 (p.Ser219Gly)) and vascular smooth muscle cell differentiation (LMOD1, rs2820315). Correlation of these regions with cell-type-specific gene expression and plasma protein levels sheds light on potential disease mechanisms

Plant-symbiotic fungi as chemical engineers: multi-genome analysis of the Clavicipitaceae reveals dynamics of alkaloid Loci

The fungal family Clavicipitaceae includes plant symbionts and parasites that produce several psychoactive and bioprotective alkaloids. The family includes grass symbionts in the epichloae clade (Epichloë and Neotyphodium species), which are extraordinarily diverse both in their host interactions and in their alkaloid profiles. Epichloae produce alkaloids of four distinct classes, all of which deter insects, and some—including the infamous ergot alkaloids—have potent effects on mammals. The exceptional chemotypic diversity of the epichloae may relate to their broad range of host interactions, whereby some are pathogenic and contagious, others are mutualistic and vertically transmitted (seed-borne), and still others vary in pathogenic or mutualistic behavior. We profiled the alkaloids and sequenced the genomes of 10 epichloae, three ergot fungi (Claviceps species), a morning-glory symbiont (Periglandula ipomoeae), and a bamboo pathogen (Aciculosporium take), and compared the gene clusters for four classes of alkaloids. Results indicated a strong tendency for alkaloid loci to have conserved cores that specify the skeleton structures and peripheral genes that determine chemical variations that are known to affect their pharmacological specificities. Generally, gene locations in cluster peripheries positioned them near to transposon-derived, AT-rich repeat blocks, which were probably involved in gene losses, duplications, and neofunctionalizations. The alkaloid loci in the epichloae had unusual structures riddled with large, complex, and dynamic repeat blocks. This feature was not reflective of overall differences in repeat contents in the genomes, nor was it characteristic of most other specialized metabolism loci. The organization and dynamics of alkaloid loci and abundant repeat blocks in the epichloae suggested that these fungi are under selection for alkaloid diversification. We suggest that such selection is related to the variable life histories of the epichloae, their protective roles as symbionts, and their associations with the highly speciose and ecologically diverse cool-season grasses

Medical treatment of prolactinomas.

Prolactinomas, the most prevalent type of neuroendocrine disease, account for approximately 40% of all pituitary adenomas. The most important clinical problems associated with prolactinomas are hypogonadism, infertility and hyposexuality. In patients with macroprolactinomas, mass effects, including visual field defects, headaches and neurological disturbances, can also occur. The objectives of therapy are normalization of prolactin levels, to restore eugonadism, and reduction of tumor mass, both of which can be achieved in the majority of patients by treatment with dopamine agonists. Given their association with minimal morbidity, these drugs currently represent the mainstay of treatment for prolactinomas. Novel data indicate that these agents can be successfully withdrawn in a subset of patients after normalization of prolactin levels and tumor disappearance, which suggests the possibility that medical therapy may not be required throughout life. Nevertheless, multimodal therapy that involves surgery, radiotherapy or both may be necessary in some cases, such as patients who are resistant to the effects of dopamine agonists or for those with atypical prolactinomas. This Review reports on efficacy and safety of pharmacotherapy in patients with prolactinomas

Cerebrospinal fluid leakage after radioisotope cisternography is not influenced by needle size at lumbar puncture in patients with intracranial hypotension

<p>Abstract</p> <p>Background</p> <p>Radioisotope (RI) cisternography is considered to be the most important examination for the final diagnosis of intracranial hypotension, typically indicating cerebrospinal fluid (CSF) leakage as RI parathecal activity. Early bladder filling (EBF) of RI is another important finding. However, whether EBF without parathecal activity represents real CSF leakage due to intracranial hypotension or only an epiphenomenon of lumbar puncture causing CSF leak through a needle hole has been questioned.</p> <p>Methods</p> <p>To address this issue, we performed quantitative analysis of RI cisternography on 171 patients with suspected intracranial hypotension using different needle sizes (22 G, 23 G and 25 G) and compared RI residual activity in the CSF at different time points after injection. We also analyzed occurrence of early bladder filling and post-lumbar puncture headache.</p> <p>Results</p> <p>No significant difference in RI residual activity was identified between the 22 G, 23 G and 25 G groups. The incidence of parathecal activity and early bladder filling was not significantly different between groups. The 22 G and 23 G groups had a higher but non-significant incidence of post lumbar headache.</p> <p>Conclusion</p> <p>The results suggest that needle size, at least for 22–25 G, does not affect the results of RI cisternographic diagnostic tests for CSF leakage and bladder filling in intracranial hypotension.</p

Prevalence and Outcomes for Heavily Treatment-Experienced (HTE) Individuals Living with Human Immunodeficiency Virus in a European Cohort

BACKGROUND: Although antiretroviral treatments have improved survival of persons living with HIV, their long-term use may limit available drug options. We estimated the prevalence of heavily treatment-experienced (HTE) status and the potential clinical consequences of becoming HTE. SETTING: EuroSIDA, a European multicentre prospective cohort study. METHODS: A composite definition for HTE was developed, based on estimates of antiretroviral resistance and prior exposure to specific antiretroviral regimens. Risks of progressing to clinical outcomes were assessed by Poisson regression, comparing every HTE individual with three randomly-selected controls who never became HTE. RESULTS: Of 15,570 individuals under follow-up in 2010-2016, 1617 (10.4%, 95% CI 9.9-10.9%) were classified as HTE. 1093 individuals became HTE during prospective follow-up (HTE incidence rate 1.76, CI 1.66-1.87 per 100 person-years of follow-up). The number of HTE individuals was highest in West/Central Europe (636/4019 persons, 15.7%) and lowest in East Europe (26/2279 persons, 1.1%). Although most HTE individuals maintained controlled viral loads (<400 copies/ml), many had low CD4 counts (≤350 cells/µl). After controlling for age, immunological parameters and pre-existing comorbidities, HTE status was not associated with the risk of new AIDS (adjusted incidence rate ratio, aIRR 1.44, CI 0.86-2.40, p = 0.16) or non-AIDS clinical events (aIRR 0.96, CI 0.74-1.25, p = 0.77). CONCLUSIONS: HTE prevalence increased with time. After adjusting for key confounding factors, there was no evidence for an increased risk of new AIDS or non-AIDS clinical events in HTE. Additional therapeutic options and effective management of comorbidities remain important to reduce clinical complications in HTE individuals

Clinical Outcomes in Persons Coinfected With Human Immunodeficiency Virus and Hepatitis C Virus: Impact of Hepatitis C Virus Treatment

Background: A hepatitis C (HCV) cure is associated with changes in lipids and inflammatory biomarkers, but its impact on clinical endpoints among treated human immunodeficiency virus (HIV)/HCV coinfected persons is unclear. / Methods: People living with HIV from EuroSIDA with a known HCV status after January 2001 were classified into strata based on time-updated HCV RNA measurements and HCV treatment, as either HCV antibody–negative; spontaneously resolved HCV; chronic, untreated HCV; cured HCV (HCV RNA–negative); or HCV treatment failures (HCV RNA–positive). Poisson regression was used to compare incidence rates between HCV groups for end-stage liver disease (ESLD; including hepatocellular carcinoma [HCC]), non–acquired immunodeficiency virus defining malignancy (NADM; excluding HCC), and cardiovascular disease (CVD). / Results: There were 16 618 persons included (median follow-up 8.3 years, interquartile range 3.1–13.7). There were 887 CVD, 902 NADM, and 436 ESLD events; crude incidence rates/1000 person-years follow-up were 6.4 (95% confidence interval [CI] 6.0–6.9) for CVD, 6.5 (95% CI 6.1–6.9) for NADM, and 3.1 (95% CI 2.8–3.4) for ESLD. After adjustment, there were no differences in incidence rates of NADM or CVD across the 5 groups. HCV-negative individuals (adjusted incidence rate ratio [aIRR] 0.22, 95% CI 0.14–0.34) and those with spontaneous clearance (aIRR 0.61, 95% CI 0.36–1.02) had reduced rates of ESLD compared to cured individuals. Persons with chronic, untreated HCV infections (aIRR 1.47, 95% CI 1.02–2.13) or treatment failure (aIRR 1.80, 95% CI 1.22–2.66) had significantly raised rates of ESLD, compared to those who were cured. / Conclusions: Incidences of NADM or CVD were independent of HCV group, whereas those cured had substantially lower incidences of ESLD, underlining the importance of successful HCV treatment for reducing ESLD

The Western Denmark Myocardial Perfusion Imaging Registry: A Review and Validation Study

Jacob Hartmann Søby,1 Morten Schmidt,1,2 Louise Nissen,1 June Anita Ejlersen,3 Lars Christian Gormsen,4,5 Kasper Tholstrup Pedersen,6 Paw Christian Holdgaard,7 Jesper Mortensen,8 Laust Dupont Rasmussen,1,9 Søren Ravn,10 Rika Horvat,11 Simon Winther,1,2 Morten Böttcher1,2 1University Clinic for Cardiovascular Research, Department of Cardiology, Gødstrup Hospital, Herning, Denmark; 2Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus N, Denmark; 3Department of Clinical Physiology, Viborg Regional Hospital, Viborg, Denmark; 4Department of Nuclear Medicine & PET Centre, Aarhus University Hospital, Aarhus N, Denmark; 5Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; 6Department of Nuclear Medicine, Odense University Hospital, Odense, Denmark; 7Department of Nuclear Medicine, Lillebaelt Hospital, Vejle, Denmark; 8Department of Nuclear Medicine, Gødstrup Hospital, Herning, Denmark; 9Department of Cardiology, Aalborg University Hospital, Aalborg, Denmark; 10Department of Nuclear Medicine, Aalborg University Hospital, Aalborg, Denmark; 11Department of Radiology and Nuclear Medicine, Hospital of South West Jutland, Esbjerg, DenmarkCorrespondence: Jacob Hartmann Søby, Department of Cardiology, University Clinic for Cardiovascular Research, Hospitalsparken 15, Herning, DK-7400, Denmark, Tel +45 61 65 91 31, Email [email protected]: Myocardial perfusion imaging (MPI) procedures from single photon emission computed tomography and positron emission tomography imaging have been registered in the Western Denmark Heart Registry (WDHR) since 2017 as a sub-registry (WDHR-MPI). The aim was to review the content, quality, and research potential of the WDHR-MPI and assess the completeness and validity of its key variables.Patients and Methods: Using the Danish National Patient Registry (DNPR) as a reference, we calculated the completeness of procedure registration as the proportion of procedures registered in the WDHR-MPI from 2017 to 2021. We defined completeness of variable registration as the proportion of non-missing values for a given variable and examined it for 38 key variables. We assessed validity by estimating the positive predictive values (PPV) and negative predictive values (NPV) with 95% confidence intervals (CI) for 26 selected key variables using corresponding extracted information from 300 randomly selected patient records.Results: We identified 19,084 procedures in 17,871 patients from all seven cardiac centers performing nuclear cardiology procedures in the WDHR uptake area. The registry accumulated 4000– 6000 procedures each year from 2019 to 2021. The overall completeness of procedure registration was 72% (95% CI 72– 73), increasing from 14% (95% CI 13– 15) in 2017 to 98% (95% CI 98– 98) in 2021. The mean completeness of variable registration was 89%. The validity of entered data was high, with an overall PPV for the selected key variables of 95% (95% CI 94– 95) and NPV of 94% (95% CI 93– 96).Conclusion: The WDHR-MPI is one of the largest systematic MPI cohorts. The overall high completeness and validity of the data support its potential for cardio-epidemiological research.Plain language summary: If you have ischemic heart disease, you may experience symptoms such as chest tightness and shortness of breath due to decreased blood supply to the heart muscle. To help identify decreased blood supply to the heart muscle, doctors can use a specialized scan which involves the injection of low doses of radioactive tracers into the bloodstream. Since 2017, doctors in Denmark have been recording these scans in the Western Denmark Myocardial Perfusion Imaging Registry (WDHR-MPI). This study found a high completeness and validity of the registry. With 19,084 scans recorded from 2017 to 2021, this registry provides a high-quality resource that could improve diagnosis and treatment for people with heart disease.Keywords: ischemic heart disease, chronic coronary syndromes, cardiac imaging, database, registries, validatio