Species-specific responses during Seoul orthohantavirus infection in human and rat lung microvascular endothelial cells

Seoul orthohantavirus (SEOV) is a rat-borne zoonotic virus that is transmitted via inhalation of aerosolized infectious excreta, and can cause hemorrhagic fever with renal syndrome (HFRS) in humans worldwide. In rats, SEOV predominantly exists as a persistent infection in the absence of overt clinical signs. Lack of disease in rats is attributed to downregulation of pro-inflammatory and upregulation of regulatory host responses. As lung microvascular endothelial cells (LMECs) represent a primary target of infection in both human and rats, infections in these cells provide a unique opportunity to study the central role of LMECs in the dichotomy between pathogenicity in both species. In this study, host responses to SEOV infection in primary human and rat LMECs were directly compared on a transcriptional level. As infection of rat LMECs was more efficient than human LMECs, the majority of anti-viral defense responses were observed earlier in rat LMECs. Most prominently, SEOV-induced processes in both species included responses to cytokine stimulus, negative regulation of innate immune responses, responses to type I and II interferons, regulation of pattern recognition receptor signaling and MHC-I signaling. However, over time, in the rat LMECs, responses shifted from an anti-viral state towards a more immunotolerant state displayed by a PD-L1, B2M-, JAK2-focused interaction network aiding in negative regulation of cytotoxic CD8-positive T cell activation. This suggests a novel mechanism by which species-specific orthohantavirus-induced endothelium and T cell crosstalk may play a crucial role in the development of acute disease in humans and persistence in rodents.</p

Species-specific responses during Seoul orthohantavirus infection in human and rat lung microvascular endothelial cells

Seoul orthohantavirus (SEOV) is a rat-borne zoonotic virus that is transmitted via inhalation of aerosolized infectious excreta, and can cause hemorrhagic fever with renal syndrome (HFRS) in humans worldwide. In rats, SEOV predominantly exists as a persistent infection in the absence of overt clinical signs. Lack of disease in rats is attributed to downregulation of pro-inflammatory and upregulation of regulatory host responses. As lung microvascular endothelial cells (LMECs) represent a primary target of infection in both human and rats, infections in these cells provide a unique opportunity to study the central role of LMECs in the dichotomy between pathogenicity in both species. In this study, host responses to SEOV infection in primary human and rat LMECs were directly compared on a transcriptional level. As infection of rat LMECs was more efficient than human LMECs, the majority of anti-viral defense responses were observed earlier in rat LMECs. Most prominently, SEOV-induced processes in both species included responses to cytokine stimulus, negative regulation of innate immune responses, responses to type I and II interferons, regulation of pattern recognition receptor signaling and MHC-I signaling. However, over time, in the rat LMECs, responses shifted from an anti-viral state towards a more immunotolerant state displayed by a PD-L1, B2M-, JAK2-focused interaction network aiding in negative regulation of cytotoxic CD8-positive T cell activation. This suggests a novel mechanism by which species-specific orthohantavirus-induced endothelium and T cell crosstalk may play a crucial role in the development of acute disease in humans and persistence in rodents.</p

Psychometric assessment of the short-form Child Perceptions Questionnaire: an international collaborative study.

OBJECTIVE: To examine the factor structure and other psychometric characteristics of the most commonly used child oral-health-related quality-of-life (OHRQoL) measure (the 16-item short-form CPQ11-14 ) in a large number of children (N = 5804) from different settings and who had a range of caries experience and associated impacts. METHODS: Secondary data analyses used subnational epidemiological samples of 11- to 14-year-olds in Australia (N = 372), New Zealand (three samples: 352, 202, 429), Brunei (423), Cambodia (244), Hong Kong (542), Malaysia (439), Thailand (220, 325), England (88, 374), Germany (1055), Mexico (335) and Brazil (404). Confirmatory factor analysis (CFA) was used to examine the factor structure of the CPQ11-14 across the combined sample and within four regions (Australia/NZ, Asia, UK/Europe and Latin America). Item impact and internal reliability analysis were also conducted. RESULTS: Caries experience varied, with mean DMFT scores ranging from 0.5 in the Malaysian sample to 3.4 in one New Zealand sample. Even more variation was noted in the proportion reporting only fair or poor oral health; this was highest in the Cambodian and Mexican samples and lowest in the German sample and one New Zealand sample. One in 10 reported that their oral health had a marked impact on their life overall. The CFA across all samples revealed two factors with eigenvalues greater than 1. The first involved all items in the oral symptoms and functional limitations subscales; the second involved all emotional well-being and social well-being items. The first was designated the 'symptoms/function' subscale, and the second was designated the 'well-being' subscale. Cronbach's alpha scores were 0.72 and 0.84, respectively. The symptoms/function subscale contained more of the items with greater impact, with the item 'Food stuck in between your teeth' having greatest impact; in the well-being subscale, the 'Felt shy or embarrassed' item had the greatest impact. Repeating the analyses by world region gave similar findings. CONCLUSION: The CPQ11-14 performed well cross-sectionally in the largest analysis of the scale in the literature to date, with robust and mostly consistent psychometric characteristics, albeit with two underlying factors (rather than the originally hypothesized four-factor structure). It appears to be a sound, robust measure which should be useful for research, practice and policy

Study of failures in a rabbit line selected for growth rate

[EN] Selection for growth rate is negatively related with reproductive fitness. The aim of this work was to analyse the causes of fertility failure in rabbit does selected for growth rate and characterised for reproductive deficiencies (line R). In the experiment, 82 does were divided into 2 groups: naturally mated (NM) and artificially inseminated (AI), to relate luteinizing hormone (LH) concentration with ovulation induction and pregnancy rate by laparoscopic determination. Additionally, in 38 of these females ovulation rate and metabolites determination (leptin, NEFA, BOHB and glucose) were analysed and perirenal fat thickness measurement and live body weight (LBW) determined. The results showed that all ovulated does (both NM and AI) presented higher concentrations of LH than non-ovulated females. In addition, non-ovulated females showed high levels of leptin and BOHB, as well as LBW. Females from line R have an inherit reduced fertility due to ovulation failure as a consequence of a reduction in LH release, which could be explained by a heavier body weight and higher leptin concentrations.This work was supported by the Spanish Research Project AGL2011-30170-C02-01 (CICYT). Carmen Naturil-Alfonso was supported by a research grant from the Education Ministry of the Valencian Regional Government (programme VALi+d. ACIF/2013/296). English text version was revised by N. Macowan English Language Service.Naturil Alfonso, C.; Lavara García, R.; Millán, P.; Rebollar, P.; Vicente Antón, JS.; Marco Jiménez, F. (2016). Study of failures in a rabbit line selected for growth rate. World Rabbit Science. 24(1):47-53. https://doi.org/10.4995/wrs.2016.4016SWORD475324

Immunomodulation in Heart Failure with Preserved Ejection Fraction: Current State and Future Perspectives

The heart failure (HF) epidemic is growing and approximately half of the HF patients have heart failure with preserved ejection fraction (HFpEF). HFpEF is a heterogeneous syndrome, characterized by a preserved left ventricular ejection fraction (LVEF ≥ 50%) with diastolic dysfunction, and is associated with high morbidity and mortality. Underlying comorbidities of HFpEF, i.e., hypertension, type 2 diabetes mellitus, obesity, and renal failure, lead to a systemic pro-inflammatory state, thereby affecting normal cardiac function. Increased inflammatory biomarkers predict incident HFpEF and are higher in patients with HFpEF as compared with heart failure with reduced ejection fraction (HFrEF). Randomized trials in HFpEF patients using traditional HF medication failed to demonstrate a clear benefit on hard endpoints (mortality and/or HF hospitalization). Therefore, therapies targeting underlying comorbidities and systemic inflammation in early HFpEF may provide better opportunities. Here, we provide an overview of the current state and future perspectives of immunomodulatory therapies for HFpEF

Rabies Virus Populations in Humans and Mice Show Minor Inter-Host Variability within Various Central Nervous System Regions and Peripheral Tissues

Rabies virus (RABV) has a broad host range and infects multiple cell types throughout the infection cycle. Next-generation sequencing (NGS) and minor variant analysis are powerful tools for studying virus populations within specific hosts and tissues, leading to novel insights into the mechanisms of host-switching and key factors for infecting specific cell types. In this study we investigated RABV populations and minor variants in both original (non-passaged) samples and in vitro-passaged isolates of various CNS regions (hippocampus, medulla oblongata and spinal cord) of a fatal human rabies case, and of multiple CNS and non-CNS tissues of experimentally infected mice. No differences in virus populations were detected between the human CNS regions, and only one non-synonymous single nucleotide polymorphism (SNP) was detected in the fifth in vitro passage of virus isolated from the spinal cord. However, the appearance of this SNP shows the importance of sequencing newly passaged virus stocks before further use. Similarly, we did not detect apparent differences in virus populations isolated from different CNS and non-CNS tissues of experimentally infected mice. Sequencing of viruses obtained from pharyngeal swab and salivary gland proved difficult, and we propose methods for improving sampling

7th Drug hypersensitivity meeting: part two

No abstract availabl

Flow cytometric immunobead assay for fast and easy detection of PML-RARA fusion proteins for the diagnosis of acute promyelocytic leukemia

The PML-RARA fusion protein is found in approximately 97% of patients with acute promyelocytic leukemia (APL). APL can be associated with life-threatening bleeding complications when undiagnosed and not treated expeditiously. The PML-RARA fusion protein arrests maturation of myeloid cells at the promyelocytic stage, leading to the accumulation of neoplastic promyelocytes. Complete remission can be obtained by treatment with all-trans-retinoic acid (ATRA) in combination with chemotherapy. Diagnosis of APL is based on the detection of t(15;17) by karyotyping, fluorescence in situ hybridization or PCR. These techniques are laborious and demand specialized laboratories. We developed a fast (performed within 4-5 h) and sensitive (detection of at least 10% malignant cells in normal background) flow cytometric immunobead assay for the detection of PML-RARA fusion proteins in cell lysates using a bead-bound anti-RARA capture antibody and a phycoerythrin-conjugated anti-PML detection antibody. Testing of 163 newly diagnosed patients (including 46 APL cases) with the PML-RARA immunobead assay showed full concordance with the PML-RARA PCR results. As the applied antibodies recognize outer domains of the fusion protein, the assay appeared to work independently of the PML gene break point region. Importantly, the assay can be used in parallel with routine immunophenotyping for fast and easy diagnosis of APL