Cross-Protection by Inactivated H5 Prepandemic Vaccine Seed Strains against Diverse Goose/Guangdong Lineage H5N1 Highly Pathogenic Avian Influenza Viruses.

The highly pathogenic avian influenza virus (HPAIV) H5N1 A/goose/Guangdong/1996 lineage (Gs/GD) is endemic in poultry across several countries in the world and has caused sporadic lethal infections in humans. Vaccines are important in HPAIV control both for poultry and in prepandemic preparedness for humans. This study assessed inactivated prepandemic vaccine strains in a One Health framework across human and agricultural and wildlife animal health, focusing on the genetic and antigenic diversity of field H5N1 Gs/GD viruses from the agricultural sector and assessing cross-protection in a chicken challenge model. Nearly half (47.92%) of the 48 combinations of vaccine and challenge viruses examined had bird protection of 80% or above. Most vaccinated groups had prolonged mean death times (MDT), and the virus-shedding titers were significantly lower than those of the sham-vaccinated group (P ≤ 0.05). The antibody titers in the prechallenge sera were not predictive of protection. Although vaccinated birds had higher titers of hemagglutination-inhibiting (HI) antibodies against the homologous vaccine antigen, most of them also had lower or no antibody titer against the challenge antigen. The comparison of all parameters and homologous or closely related vaccine and challenge viruses gave the best prediction of protection. Through additional analysis, we identified a pattern of epitope substitutions in the hemagglutinin (HA) of each challenge virus that impacted protection, regardless of the vaccine used. These changes were situated in the antigenic sites and/or reported epitopes associated with virus escape from antibody neutralization. As a result, this study highlights virus diversity, immune response complexity, and the importance of strain selection for vaccine development to control H5N1 HPAIV in the agricultural sector and for human prepandemic preparedness. We suggest that the engineering of specific antigenic sites can improve the immunogenicity of H5 vaccines.IMPORTANCE The sustained circulation of highly pathogenic avian influenza virus (HPAIV) H5N1 A/goose/Guangdong/1996 (Gs/GD) lineage in the agricultural sector and some wild birds has led to the evolution and selection of distinct viral lineages involved in escape from vaccine protection. Our results using inactivated vaccine candidates from the human pandemic preparedness program in a chicken challenge model identified critical antigenic conformational epitopes on H5 hemagglutinin (HA) from different clades that were associated with antibody recognition and escape. Even though other investigators have reported epitope mapping in the H5 HA, much of this information pertains to epitopes reactive to mouse antibodies. Our findings validate changes in antigenic epitopes of HA associated with virus escape from antibody neutralization in chickens, which has direct relevance to field protection and virus evolution. Therefore, knowledge of these immunodominant regions is essential to proactively develop diagnostic tests, improve surveillance platforms to monitor AIV outbreaks, and design more efficient and broad-spectrum agricultural and human prepandemic vaccines.

Consensus on improving the comprehensive care of patients with acute heart failure. / Consenso para la mejora de la atención integral de los pacientes con insuficiencia cardíaca aguda.

The latest acute heart failure consensus document from the Spanish Society of Cardiology, Spanish Society of Internal Medicine, and Spanish Society of Emergency Medicine was published in 2015, which made an update covering the main novelties regarding acute heart failure from the last few years necessary. These include publication of updated European guidelines on heart failure in 2016, new studies on the pharmacological treatment of patients during hospitalization, and other recent developments regarding acute heart failure such as early treatment, intermittent treatment, advanced heart failure, and refractory congestion. This consensus document was drafted with the aim of updating all aspects related to acute heart failure and to create a document that comprehensively describes the diagnosis, treatment, and management of this disease.

Plasmodium berghei EXP-1 interacts with host Apolipoprotein H during Plasmodium liver-stage development.

The first, obligatory replication phase of malaria parasite infections is characterized by rapid expansion and differentiation of single parasites in liver cells, resulting in the formation and release of thousands of invasive merozoites into the bloodstream. Hepatic Plasmodium development occurs inside a specialized membranous compartment termed the parasitophorous vacuole (PV). Here, we show that, during the parasite's hepatic replication, the C-terminal region of the parasitic PV membrane protein exported protein 1 (EXP-1) binds to host Apolipoprotein H (ApoH) and that this molecular interaction plays a pivotal role for successful Plasmodium liver-stage development. Expression of a truncated EXP-1 protein, missing the specific ApoH interaction site, or down-regulation of ApoH expression in either hepatic cells or mouse livers by RNA interference resulted in impaired intrahepatic development. Furthermore, infection of mice with sporozoites expressing a truncated version of EXP-1 resulted in both a significant reduction of liver burden and delayed blood-stage patency, leading to a disease outcome different from that generally induced by infection with wild-type parasites. This study identifies a host-parasite protein interaction during the hepatic stage of infection by Plasmodium parasites. The identification of such vital interactions may hold potential toward the development of novel malaria prevention strategies.

Partial replacement of soybean meal with different protein sources in piglet feed during the nursery phase.

OBJECTIVE: Evaluate the partial replacement of soybean meal with different protein sources in piglet feed during the nursery phase in terms of digestibility of feed, nitrogen balance, growth performance and blood parameters. METHODS: Experiment I involved 24 crossbred entire male pigs with an initial body weight of 18.28 ± 0.7 kg, and used a randomized complete block design consisting of three treatments (Fish Meal - FM, Soybean Protein Concentrate - SPC, and Soybean Meal - SM) and eight replicates, with one pig per experimental unit. Experiment II involved 1843 crossbred male and female pigs with an initial body weight of 6.79 ± 0.90 kg, and was based on a completely randomized design with a 2 × 3 factorial arrangement (two sexes and three protein sources) and 13 replicates. RESULTS: The results of Experiment I indicate a significant effect (p <0.05) of the treatment on digestible protein (FM: 17.84%; SPC: 16.72% and SM: 18.13%) and on total nitrogen excretion (TNE, g/kg BW0.75/day) in which pigs fed with SM-based feed had TNE values that were 5.36% and 3.72% higher than SPC and FM, respectively. In the Experiment II, there was difference (p <0.01) between sexes in the starter phase and total period in daily feed intake (DFI) values, which were higher in females, and between the protein sources in DFI, final weight and daily weight gain, which were higher in piglets fed with SPC. For urea in both phases and glucose in the pre-starter II phase, there was a difference (p <0.05) between protein sources and between sexes, in starter phase in urea levels (females: 57.11 mg/dL and males: 50.60 mg/dL). CONCLUSION: The use of feed only at basis of SM influences larger TNE (g/kg BW0.75/day), promotes a reduction in the growth performance of piglets and increases plasma urea levels in pre-starter II.

Reactivity of Metal Carbenes with Olefins: Theoretical Insights on the Carbene Electronic Structure and Cyclopropanation Reaction Mechanism.

Present work addresses the reactivity of several phenyl-substituted metal-carbene complexes with 4-methylstyrene by means of density functional theory OPBE simulations. Different paths that lead to cyclopropanation were explored and compared to the olefin metathesis mechanism. For this purpose, we chose four different catalysts: (i) the Grubbs second-generation olefin metathesis catalyst, (ii) a Grubs second-generation-like complex, in which ruthenium is replaced by iron, and (iii) two iron carbene complexes (a piano stool and a porphyrin iron carbene) that experimentally catalyze alkene cyclopropanation. Results suggest that the nature of the applying mechanism is very sensitive to the coordination around the metal center and the spin state of the metal-carbene complex. Cyclopropanation by open-shell metal-carbene complexes seems to preferentially proceed through a two-step radical mechanism, in which the two C-C bonds are sequentially formed (path C). Singlet-state carbenes proceed either through a direct attack of the olefin to the carbene (path D) when the formation of the metallacycle is not feasible or through a reductive elimination from the metallacyclobutane when this intermediate is accessible both kinetically and thermodynamically (path B).

Exercise-related severe cardiac events.

Physical activity has benefits on health. However, there is a small risk of effort-related adverse events. The aim of this study is to describe exercise-related severe cardiovascular events and to relate them with the type of sport performed. We performed a ten-year retrospective study in eight Spanish cardiac intensive care units. Adverse cardiac events were defined as acute myocardial infarction, cardiac arrest or syncope related to physical activity. From 117 patients included, 109 were male (93.2%), and mean age was 51.6 ± 12.3 years; 56 presented acute myocardial infarction without cardiac arrest (47.9%), 55 sudden cardiac death (47.0%) and six syncope (5.1%). The sports with higher number of events were cycling (33%-28.2%), marathon or similar running competitions (19%-16.2%), gymnastics (18%-15.3%) and soccer (17%-14.5%). Myocardial infarction was observed more frequently in cyclists compared to other sports (69.7% vs 39.3%, P = .001). The most common cause of sudden cardiac death was myocardial infarction in those >35 years (23%-63.9%) and idiopathic ventricular fibrillation in younger patients (5%-62.5%). Significant coronary artery disease was present in 85 (79.4%). Only one patient with cardiac arrest presented with a non-shockable rhythm (asystole). Eleven patients (9.4%) died during hospitalization; in all cases, they had presented cardiac arrest. All discharged patients were alive at the end of follow-up. Exercise-related severe cardiac events are mainly seen in men. Coronary heart disease is very frequent; about half present acute myocardial infarction and the other half cardiac arrest. In our cohort, prognosis was good in patients without cardiac arrest.

Effects of backpack load and positioning on nonlinear gait features in young adults.

Overloaded backpacks can cause changes in posture and gait dynamic balance. Therefore, the aim of this study was to assess gait regularity and local dynamic stability in young adults as they carried a backpack in different positions, and with different loads. Twenty-one healthy young adults participated in the study, carrying a backpack that was loaded with 10 and 20% of their body weight (BW). The participants walked on a level treadmill at their preferred walking speeds for 4 min under different conditions of backpack load and position (i.e. with backpack positioned back bilaterally, back unilaterally, frontally or without a backpack). Results indicate that backpack load and positioning significantly influence gait stability and regularity, with the exception of the 10% BW bilateral back position. Therefore, the recommended safe load for school-age children and adolescents (10% of BW) should also be considered for young adults. Practitioner summary: Increase in load results in changes in posture, muscle activity and gait parameters, so we investigated the gait adaptations related to regularity and stability. Conditions with high backpack loads significantly influenced gait stability and regularity in a position-dependent manner, except for 10% body weight bilateral back position.

Chemical attenuation of Plasmodium in the liver modulates severe malaria disease progression.

Cerebral malaria is one of the most severe complications of malaria disease, attributed to a complicated series of immune reactions in the host. The syndrome is marked by inflammatory immune responses, margination of leukocytes, and parasitized erythrocytes in cerebral vessels leading to breakdown of the blood-brain barrier. We show that chemical attenuation of the parasite at the very early, clinically silent liver stage suppresses parasite development, delays the time until parasites establish blood-stage infection, and provokes an altered host immune response, modifying immunopathogenesis and protecting from cerebral disease. The early response is proinflammatory and cell mediated, with increased T cell activation in the liver and spleen, and greater numbers of effector T cells, cytokine-secreting T cells, and proliferating, proinflammatory cytokine-producing T cells. Dendritic cell numbers, T cell activation, and infiltration of CD8(+) T cells to the brain are decreased later in infection, possibly mediated by the anti-inflammatory cytokine IL-10. Strikingly, protection can be transferred to naive animals by adoptive transfer of lymphocytes from the spleen at very early times of infection. Our data suggest that a subpopulation belonging to CD8(+) T cells as early as day 2 postinfection is responsible for protection. These data indicate that liver stage-directed early immune responses can moderate the overall downstream host immune response and modulate severe malaria outcome.

Quantification and mapping of urban fluxes under climate change: Application of WRF-SUEWS model to Greater Porto area (Portugal).

Climate change and the growth of urban populations are two of the main challenges facing Europe today. These issues are linked as climate change results in serious challenges for cities. Recent attention has focused on how urban surface-atmosphere exchanges of heat and water will be affected by climate change and the implications for urban planning and sustainability. In this study energy fluxes for Greater Porto area, Portugal, were estimated and the influence of the projected climate change evaluated. To accomplish this, the Weather Research and Forecasting Model (WRF) and the Surface Urban Energy and Water Balance Scheme (SUEWS) were applied for two climatological scenarios: a present (or reference, 1986-2005) scenario and a future scenario (2046-2065), in this case the Representative Concentration Pathway RCP8.5, which reflects the worst set of expectations (with the most onerous impacts). The results show that for the future climate conditions, the incoming shortwave radiation will increase by around 10%, the sensible heat flux around 40% and the net storage heat flux around 35%. In contrast, the latent heat flux will decrease about 20%. The changes in the magnitude of the different fluxes result in an increase of the net all-wave radiation by 15%. The implications of the changes of the energy balance on the meteorological variables are discussed, particularly in terms of temperature and precipitation.

Vaccination of chickens decreased Newcastle disease virus contamination in eggs.

Newcastle disease is an important health issue of poultry causing major economic losses and inhibits trade worldwide. Vaccination is used as a control measure, but it is unknown whether vaccination will prevent virus contamination of eggs. In this study, hens were sham-vaccinated or received one or two doses of inactivated LaSota vaccine, followed three weeks later by virulent Newcastle disease virus (NDV) challenge. Eggs were collected daily and shell, albumen and yolk were subjected to virus isolation, as were oral and cloacal swabs at 2 and 4 days post-challenge (dpc). A second experiment evaluated the distribution of the virus in the reproductive tract of non-vaccinates. All vaccinated chickens survived challenge, and the levels of virus shed from cloacal swabs were decreased significantly when compared to shams. In non-vaccinated hens, virus was detected in the ovary and all segments of the oviduct. Yolk, albumen and eggshell surface from eggs laid at day 4 and 5 post-infection by sham-vaccinated hens were positive for NDV, but eggs from LaSota vaccinated hens lacked virus in internal egg components (i.e. yolk and albumen) and had reduction in the number of positive eggshell surfaces. These results indicate virulent NDV can replicate in the reproductive tract of hens and contaminate internal components of eggs and eggshell surface, but vaccination was able to prevent internal egg contamination, reducing eggshell surface contamination, and reducing shedding from digestive and respiratory tracts in virulent NDV challenged hens.

P2X7-induced zeiosis promotes osteogenic differentiation and mineralization of postmenopausal bone marrow-derived mesenchymal stem cells.

Polymorphisms of the P2X7 receptor have been associated with increased risk of fractures in postmenopausal women. Although both osteoblasts and osteoclasts express P2X7 receptors, their function in osteogenesis remains controversial. Here, we investigated the role of the P2X7 receptor on osteogenic differentiation and mineralization of bone marrow mesenchymal stem cell (BMSC) cultures from postmenopausal women (age 71±3 yr, n=18). We focused on the mechanisms related to intracellular [Ca(2+)]i oscillations and plasma membrane-dynamics. ATP, and the P2X7 agonist BzATP (100 µM), increased [Ca(2+)]i in parallel to the formation of membrane pores permeable to TO-PRO-3 dye uptake. ATP and BzATP elicited reversible membrane blebs (zeiosis) in 38 ± 1 and 70 ± 1% of the cells, respectively. P2X7-induced zeiosis was Ca(2+) independent, but involved phospholipase C, protein kinase C, and Rho-kinase activation. BzATP (100 µM) progressively increased the expression of Runx-2 and Osterix transcription factors by 452 and 226% (at d 21), respectively, alkaline phosphatase activity by 88% (at d 28), and mineralization by 329% (at d 43) of BMSC cultures in a Rho-kinase-dependent manner. In summary, reversible plasma membrane zeiosis involving cytoskeleton rearrangements due to activation of the P2X7-Rho-kinase axis promotes osteogenic differentiation and mineralization of BMSCs, thus providing new therapeutic targets for postmenopausal bone loss.

Genetic diversity of 3' region of glycoprotein D gene of bovine herpesvirus 1 and 5.

Bovine herpesviruses 1 (BoHV-1) and 5 (BoHV-5) are closely related alphaherpesviruses of cattle. While BoHV-1 is mainly associated with respiratory/genital disease and rarely associated with neurological disease, BoHV-5 is the primary agent of meningoencephalitis in cattle. The envelope glycoprotein D of alphaherpesviruses (BoHV-1/gD1 and BoHV-5/gD5) is involved in the early steps of virus infection and may influence virus tropism and neuropathogenesis. This study performed a sequence analysis of the 3' region of gD gene (gD3') of BoHV-1 isolates recovered from respiratory/genital disease (n = 6 and reference strain Cooper) or from neurological disease (n = 7); and from seven typical neurological BoHV-5 isolates. After PCR amplification, nucleotide (nt) sequencing, and aminoacid (aa) sequence prediction; gD3' sequences were compared, identity levels were calculated, and selective pressure was analyzed. The phylogenetic reconstruction based on nt and aa sequences allowed for a clear differentiation of BoHV-1 (n = 14) and BoHV-5 (n = 7) clusters. The seven BoHV-1 isolates from neurological disease are grouped within the BoHV-1 branch. A consistent alignment of 346 nt revealed a high similarity within each viral species (gD1 = 98.3 % nt and aa; gD5 = 97.8 % nt and 85.8 % aa) and an expected lower similarity between gD1 and gD5 (73.7 and 64.1 %, nt and aa, respectively). The analysis of molecular evolution revealed an average negative selection at gD3'. Thus, the phylogeny and similarity levels allowed for differentiation of BoHV-1 and BoHV-5 species, but not further division in subspecies. Sequence analysis did not allow for the identification of genetic differences in gD3' potentially associated with the respective clinical/pathological phenotypes, yet revealed a lower level of gD3' conservation than previously reported.

Epidemiological profile of individuals with American cutaneous leishmaniasis in Jequitinhonha Valley, Brazil.

This study aimed to characterize the epidemiological profile of patients with American cutaneous leishmaniasis (ACL) in 34 municipalities in Jequitinhonha Valley, Minas Gerais, Brazil, registered from 2005 to 2010 with the Regional Health Superintendence, using data from the Brazilian Disease Notification Information System. Among 281 cases, 156 (55.5%) were included in the study. A statistically significant difference was found in ACL among men between 21 and 60 years of age (P = 0.034) in relation to women and other age groups. Analysing the male sample, a significant association was found between ACL and occupation (P = 0.04). The cutaneous form occurred in 87.3% of cases. The medication most often employed was pentavalent antimony (87.3%), with cure achieved in 91.1% of cases. The epidemiological profile of ACL in the Jequitinhonha Valley is similar to that reported for other regions of Brazil, exhibiting a rural occupational nature and affecting men with low levels of schooling within the productive age.

Anticancer steroids: linking natural and semi-synthetic compounds.

Steroids, a widespread class of natural organic compounds occurring in animals, plants and fungi, have shown great therapeutic value for a broad array of pathologies. The present overview is focused on the anticancer activity of steroids, which is very representative of a rich structural molecular diversity and ability to interact with various biological targets and pathways. This review encompasses the most relevant discoveries on steroid anticancer drugs and leads through the last decade and comprises 668 references.

High-pathogenicity avian influenza virus in the reproductive tract of chickens.

Infection with high-pathogenicity avian influenza virus (HPAIV) has been associated with a wide range of clinical manifestations in poultry, including severe depression in egg production and isolation of HPAIV from eggs laid by infected hens. To evaluate the pathobiology in the reproductive tract of chickens, adult hens were inoculated intranasally with 3 HPAIV strains. All 3 strains induced lesions in the reproductive tract 36 to 72 hours after inoculation. Positive immunostaining was observed in all segments of the reproductive tract, occurring predominantly in stromal cells and superficial germinal epithelium of the ovary, in mucosal epithelial cells and less often glandular epithelium throughout the oviduct, and in vascular endothelium. This study generates important data and explains previously reported virus isolation from yolk, due to ovarian virus replication, and virus recovery from albumin, due to virus replication in epithelial cells in several segments of the oviduct.

"Social malaise... demonic agitation:" anarchism according to the criminology of the French physician Alexandre Lacassagne. / "Mal-estar social... uma agitação demoníaca": o anarquismo segundo a criminologia do médico francês Alexandre Lacassagne.

This article analyzes the way anarchism and its followers were understood in L'assassinat du président Carnot, by the French physician Alexandre Lacassagne. A few months before the book was published, in June 1894, the president of France, Sadi Carnot, had been killed by the Italian anarchist Sante Geronimo Caserio. Lacassagne was called upon to perform the autopsy of Carnot's body and a psychiatric examination of Caserio. The results of these two analyses were published in the aforementioned book. He made his observations on the anarchist in the broader context of criminological debates pursued in the late nineteenth century, which were not restricted solely to the authors of Italian criminology.

O artigo analisa a maneira como o anarquismo e os seus adeptos foram compreendidos na obra do médico Alexandre Lacassagne L'assassinat du président Carnot (1894). Poucos meses antes da circulação do livro, em junho, o presidente da França, Sadi Carnot, foi morto pelo anarquista italiano Sante Geronimo Caserio. Em razão desse atentado, Lacassagne foi convocado para realizar a autópsia do corpo de Carnot e um exame psiquiátrico de Caserio. Os resultados dessas duas análises foram publicados na referida obra. As suas observações sobre o ácrata estavam inseridas nos debates criminológicos promovidos no final do século XIX, os quais não se restringiram unicamente aos autores da criminologia italiana.

Would surgical Apgar score be useful to predict postoperative complications after proximal femoral fracture surgery? - A retrospective cohort study.

BACKGROUND: The surgical Apgar score (SAS) is a perioperative risk evaluation score, which considers intraoperative minimum heart rate, minimum mean arterial pressure and estimated blood loss. Although validated in multiple surgical fields, SAS remains quite controversial in the orthopedic one. The main purpose of this study was to investigate if SAS relates with the occurrence of complications during the first 30-days after proximal femoral fracture surgery. METHODS: Retrospective study including all consecutive patients submitted to proximal femoral fracture surgery between January and July 2019. Patients with no information about SAS were excluded. Patients were divided in two groups, based on the occurrence of complications during the first 30 post-operative days and their SAS calculated. Receiver operating characteristic (ROC) curves were used to assess SAS power as a predictive model of complications. RESULTS: Forty-two percent (n = 76) of the 181 patients included in the study developed complications during the first 30 postoperative days. Eight patients (4,4%) died during that period. The patient's mean age was 79 years and 30,9% (n = 56) were men. Heart failure, pacemaker use, chronic kidney disease, chronic obstructive pulmonary disease and dementia were significantly associated with post-operative morbidity. There was no significant correlation between SAS and the occurrence of complications during the first 30 postoperative days. The AUC of SAS as a predictive model for postoperative complications after proximal femoral fracture surgery was 0,522, being insufficient to be considered an accepted model of prediction. CONCLUSION: Based on this study, we conclude that SAS is not predictive of the development of complications in the first 30 post-operative days in patients submitted to proximal femoral fracture surgery. However, other clinical factors have been identified as associated with postoperative morbidity. In the future, prospective-based studies with higher samples may better clarify the role of SAS in this context.

Volumetric Absorptive Microsampling in the Analysis of Endogenous Metabolites.

Volumetric absorptive microsampling (VAMS) has arisen as a relevant tool in biological analysis, offering simplified sampling procedures and enhanced stability. Most of the attention VAMS has received in the past decade has been from pharmaceutical research, with most of the published work employing VAMS targeting drugs or other exogenous compounds, such as toxins and pollutants. However, biomarker analysis by employing blood microsampling has high promise. Herein, a comprehensive review on the applicability of VAMS devices for the analysis of endogenous metabolites/biomarkers was performed. The study presents a full overview of the analysis process, incorporating all the steps in sample treatment and validation parameters. Overall, VAMS devices have proven to be reliable tools for the analysis of endogenous analytes with biological importance, often offering improved analyte stability in comparison with blood under ambient conditions as well as a convenient and straightforward sample acquisition model.

Mental health throughout the medical career: A comparison of depression, anxiety, and stress levels among medical students, residents, and physicians.

BACKGROUND: Different stages of a physician's career may be associated with different types of mental health impairment. AIMS: This study aimed to compare symptoms of anxiety, depression, and stress and their associated factors among medical students, medical residents, and physicians. METHODS: A cross-sectional study was conducted. Data collection included sociodemographic data, religiosity (Duke University Religion Index), and mental health (21-item Depression, Anxiety and Stress Scale - DASS-21) data. The comparison between the groups was performed using ANOVA, and the associated factors were evaluated via linear regression models. RESULTS: The sample consisted of 1,417 participants: 778 medical students, 190 medical residents, and 468 established physicians. Medical students had significantly higher depression, anxiety, and stress scores as compared to medical residents and established physicians. However, regarding DASS 21 scores, no significant differences were found between established physicians and medical residents. The factors associated with mental health in the different groups showed that being married and male were associated with better mental health among physicians and medical residents, while the factors of male gender, being in later years of the course, and lower religious attendance were associated with better mental health in students. CONCLUSION: Medical students had worse mental health outcomes when compared to residents and established physicians. Interventions are needed to minimize suffering during medical education and career.